This document discusses the history and mechanisms of immunosuppressant drugs. It begins by outlining the early development of corticosteroids and other drugs in the 1940s-1970s to prevent organ transplant rejection. It then details several classes of immunosuppressants based on their molecular targets and cellular effects, including monoclonal antibodies, T cell-directed agents like calcineurin inhibitors, B cell-directed agents like Rituximab, agents targeting cytokines and chemokines, and non-specific pan-lymphocyte depleting agents. For each drug class and example drug, it describes the relevant immune cells and pathways that are modulated to achieve immunosuppression.
This document provides an overview of IgG4-Related disease including its epidemiology, pathogenesis, clinical presentation, diagnostic criteria, and organ involvement. Some key points include:
- It predominantly affects men aged 50-70 years.
- Pathogenesis involves IgG4-positive plasma cells and T-helper type 2 immune responses leading to fibrosis and organ swelling.
- Diagnosis requires specific histological findings and elevated serum IgG4 levels.
- It can affect many organs including lacrimal glands, salivary glands, lungs, pancreas, kidney, and lymph nodes, causing swelling.
The document discusses and compares traditional and advanced techniques for detecting autoantibodies in autoimmune diseases. It describes several methods including indirect immunofluorescence (IIF), ELISA, line blot, and multiplex bead-based immunoassays. IIF using HEp-2 cells is considered the reference standard for initial ANA screening due to its ability to detect over 100 targets, but it has limitations like subjectivity. ELISA and line blots are useful for confirming specific autoantibodies. Newer multiplex bead-based assays allow simultaneous detection of multiple autoantibodies and have advantages like automation, but may miss some targets. The optimal testing approach depends on the clinical scenario and usually involves initial screening by IIF followed
This document discusses antiplatelet drug resistance in Asian populations. It covers several topics:
- Aspirin and clopidogrel resistance, their types and mechanisms. Genetic polymorphisms can impact drug metabolism and effectiveness.
- Laboratory tests to identify resistance, including platelet function tests and genetic testing to identify variants affecting drug metabolism.
- Factors that can influence drug resistance, such as medication compliance, drug interactions, and genetic factors affecting metabolic pathways.
- Management strategies depending on the resistance type, such as increasing drug doses or trying alternative medications.
Adalimumab is a human monoclonal antibody used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease by blocking tumor necrosis factor-alpha (TNF-α). It was discovered in 1993 and approved by the FDA in 2008. Adalimumab works by binding to TNF-α molecules in the blood and tissues to block their interaction with cell surface receptors and lyse TNF-expressing cells, reducing inflammation. Clinical trials demonstrated its efficacy in treating psoriasis and other conditions. While common side effects include pain, nausea and fatigue, it poses risks like severe infections and cancer with long term use.
New guidelines for Tuberculosis treatment (NTEP)SHOEBULHAQUE
This document provides guidelines for the treatment of tuberculosis, including:
- Recommendations for a shorter 9-11 month oral regimen for MDR-TB including bedaquiline.
- Guidance on using longer oral regimens for MDR/XDR-TB lasting 18-20 months including bedaquiline, linezolid, and clofazimine.
- Considerations for managing MDR-TB patients during pregnancy, noting certain drugs should be avoided during certain stages of pregnancy.
- Algorithms for diagnosing and treating rifampin-resistant and isoniazid mono/poly drug-resistant TB.
Hypereosinophilic Syndrome (HES) is a rare condition characterized by elevated levels of eosinophils in the blood (eosinophilia) and tissue damage caused by eosinophils. The document discusses the historical background, definition, pathogenesis, epidemiology, classification, and clinical manifestations of HES. It defines HES based on eosinophilia greater than 1500 cells/microliter for more than 6 months with evidence of organ damage after ruling out other causes. HES can be classified into myeloproliferative and lymphocytic forms based on the underlying pathogenesis. The myeloproliferative form involves mutations in hematopoietic cells that drive eosinophil production while the lymphocy
IgG4-Related Disease is a fibroinflammatory condition characterized by elevated serum IgG4 levels that can affect nearly any organ. It was first described in the early 20th century but is now recognized more frequently. The pathogenesis involves IgG4 antibody production triggered by innate immune signals, leading to a TH2/Treg cytokine response and tissue fibrosis. It occurs worldwide with variable incidence rates reported in different regions. Affected individuals can experience swelling of involved organs and elevated serum IgG4 levels. Treatment involves glucocorticoids which can improve organ function, though relapses are common upon tapering of medication.
This document provides an overview of IgG4-Related disease including its epidemiology, pathogenesis, clinical presentation, diagnostic criteria, and organ involvement. Some key points include:
- It predominantly affects men aged 50-70 years.
- Pathogenesis involves IgG4-positive plasma cells and T-helper type 2 immune responses leading to fibrosis and organ swelling.
- Diagnosis requires specific histological findings and elevated serum IgG4 levels.
- It can affect many organs including lacrimal glands, salivary glands, lungs, pancreas, kidney, and lymph nodes, causing swelling.
The document discusses and compares traditional and advanced techniques for detecting autoantibodies in autoimmune diseases. It describes several methods including indirect immunofluorescence (IIF), ELISA, line blot, and multiplex bead-based immunoassays. IIF using HEp-2 cells is considered the reference standard for initial ANA screening due to its ability to detect over 100 targets, but it has limitations like subjectivity. ELISA and line blots are useful for confirming specific autoantibodies. Newer multiplex bead-based assays allow simultaneous detection of multiple autoantibodies and have advantages like automation, but may miss some targets. The optimal testing approach depends on the clinical scenario and usually involves initial screening by IIF followed
This document discusses antiplatelet drug resistance in Asian populations. It covers several topics:
- Aspirin and clopidogrel resistance, their types and mechanisms. Genetic polymorphisms can impact drug metabolism and effectiveness.
- Laboratory tests to identify resistance, including platelet function tests and genetic testing to identify variants affecting drug metabolism.
- Factors that can influence drug resistance, such as medication compliance, drug interactions, and genetic factors affecting metabolic pathways.
- Management strategies depending on the resistance type, such as increasing drug doses or trying alternative medications.
Adalimumab is a human monoclonal antibody used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease by blocking tumor necrosis factor-alpha (TNF-α). It was discovered in 1993 and approved by the FDA in 2008. Adalimumab works by binding to TNF-α molecules in the blood and tissues to block their interaction with cell surface receptors and lyse TNF-expressing cells, reducing inflammation. Clinical trials demonstrated its efficacy in treating psoriasis and other conditions. While common side effects include pain, nausea and fatigue, it poses risks like severe infections and cancer with long term use.
New guidelines for Tuberculosis treatment (NTEP)SHOEBULHAQUE
This document provides guidelines for the treatment of tuberculosis, including:
- Recommendations for a shorter 9-11 month oral regimen for MDR-TB including bedaquiline.
- Guidance on using longer oral regimens for MDR/XDR-TB lasting 18-20 months including bedaquiline, linezolid, and clofazimine.
- Considerations for managing MDR-TB patients during pregnancy, noting certain drugs should be avoided during certain stages of pregnancy.
- Algorithms for diagnosing and treating rifampin-resistant and isoniazid mono/poly drug-resistant TB.
Hypereosinophilic Syndrome (HES) is a rare condition characterized by elevated levels of eosinophils in the blood (eosinophilia) and tissue damage caused by eosinophils. The document discusses the historical background, definition, pathogenesis, epidemiology, classification, and clinical manifestations of HES. It defines HES based on eosinophilia greater than 1500 cells/microliter for more than 6 months with evidence of organ damage after ruling out other causes. HES can be classified into myeloproliferative and lymphocytic forms based on the underlying pathogenesis. The myeloproliferative form involves mutations in hematopoietic cells that drive eosinophil production while the lymphocy
IgG4-Related Disease is a fibroinflammatory condition characterized by elevated serum IgG4 levels that can affect nearly any organ. It was first described in the early 20th century but is now recognized more frequently. The pathogenesis involves IgG4 antibody production triggered by innate immune signals, leading to a TH2/Treg cytokine response and tissue fibrosis. It occurs worldwide with variable incidence rates reported in different regions. Affected individuals can experience swelling of involved organs and elevated serum IgG4 levels. Treatment involves glucocorticoids which can improve organ function, though relapses are common upon tapering of medication.
Humira is a monoclonal antibody produced through recombinant DNA technology in mammalian cells. It consists of 1330 amino acids and has a molecular weight of around 148 kilodaltons. Humira works by binding to tumor necrosis factor-alpha (TNFα), which normally triggers inflammation. By blocking the interaction of TNFα with its receptors, Humira reduces the inflammatory response associated with autoimmune diseases like rheumatoid arthritis. AbbVie, which markets Humira, has secured over 100 patents over its lifetime to prevent copying of the biologic and maintain its multi-billion dollar annual sales.
This document provides an overview of immunosuppressive drugs. It begins with an introduction to immunosuppression and the roles of immunosuppressive drugs in treating autoimmune diseases and preventing organ transplant rejection. The document then classifies immunosuppressive drugs and discusses several classes in more detail, including glucocorticoids, calcineurin inhibitors like cyclosporine and tacrolimus, sirolimus, cytostatics like cyclophosphamide, and mycophenolate mofetil. For each drug, the document provides information on mechanisms of action, indications, dosages, and side effects. The document aims to provide clinicians an overview of commonly used immunosuppressive drugs.
This document discusses immunotherapeutics and immunity. It defines immunity as the body's ability to protect itself from infectious disease. There are two main types of immunity: innate and adaptive. Immunotherapy involves stimulating, enhancing, suppressing, or desensitizing the immune system to treat or prevent disease like cancer or autoimmune disorders. The document outlines various immunotherapeutic approaches including immunostimulants, monoclonal antibodies, antibody-directed enzyme prodrug therapy, immunotoxins, and immunomodulators like adaptive cell therapy and cancer vaccines.
The document discusses drug promotion, including the sources and types of promotional materials used by pharmaceutical companies. It notes that drug promotion is a major activity for pharmaceutical companies and involves direct engagement with physicians through materials, gifts, and sponsored education events. The document outlines regulatory guidelines for ethical drug promotion from WHO, IFPMA, and OPPI, including providing accurate information about active ingredients, approved uses, safety, and references. It also discusses evaluating promotional literature for adherence to these guidelines.
1. Acute myelogenous leukemia (AML) is a clonal, malignant disease characterized by accumulation of abnormal blast cells in the bone marrow and impaired production of normal blood cells.
2. AML results from a series of somatic mutations in a primitive hematopoietic progenitor cell. Additional mutations are required for progression to AML.
3. Standard induction treatment involves "7+3" chemotherapy with cytarabine and an anthracycline, achieving remission in 55-90% of patients. Post-remission therapy aims to prolong remission.
The document discusses properties, modes of action, indications, and administration of intravenous immunoglobulin (IVIg). It provides details on the plasma fractionation process used to produce IVIg and notes that IVIg contains 98% IgG and traces of other immunoglobulins. The document also examines IVIg's mechanisms of action, FDA-approved uses, evidence for off-label uses, and potential adverse effects.
This document discusses autoantibodies known as antinuclear antibodies (ANA) that are directed against nuclear antigens. It covers the prevalence of ANA, various nuclear antigens they may be directed against like DNA and histones, mechanisms of autoimmunity and autoantibody production, roles of B cells and T cells, and methods of detecting ANAs. It also describes different patterns of ANA fluorescence and their associations with various autoimmune diseases.
Humanisation of antibodies & immunotherapeutics in clinical practice Aaqib Naseer
This document discusses humanization of monoclonal antibodies and immunotherapeutics used in clinical practice. It describes the techniques used to humanize antibodies, including CDR grafting, phage display, and transgenic animals. It then discusses various immunotherapeutics used clinically such as monoclonal antibodies, cytokines, cancer vaccines, and cell-based therapies. Monoclonal antibodies target specific antigens on cancer cells and can be naked or conjugated. Checkpoint inhibitors like anti-CTLA-4 and anti-PD-1 antibodies work by releasing brakes on the immune system. Cytokines such as interferons and interleukins modulate immune responses. Cancer vaccines aim to stimulate immunity against tumor antigens.
Approach to a patient with positive ana levels (2)Mohit Aggarwal
This document discusses the approach to evaluating a patient with a positive ANA test result. It provides background on ANA testing and discusses the significance of various ANA patterns and titers. The document emphasizes that a positive ANA alone does not indicate a specific disease and must be interpreted based on the clinical context. It then reviews how to approach and evaluate common conditions associated with ANA positivity like SLE, Scleroderma, RA, and Sjogren's Syndrome.
This document provides an overview of hemophagocytic lymphohistiocytosis (HLH). It begins by introducing HLH and describing its characteristics such as fever, hepatosplenomegaly, and cytopenias. It then discusses the classification of primary and secondary HLH, epidemiology, genetic causes, clinical features, diagnostic guidelines, treatment protocols, and long-term follow up recommendations. For the patient presented, the document recommends following the HLH-2004 treatment protocol initially and considering continuation therapy or stem cell transplant depending on the disease response and severity.
Immunosuppressive drugs used to treat transplant rejection include calcineurin inhibitors like cyclosporine and tacrolimus, mTOR inhibitors like sirolimus and everolimus, anti-proliferatives like azathioprine and mycophenolic acid, corticosteroids like prednisolone and hydrocortisone, and antibodies like the monoclonal anti-IL-2Rα receptor antibodies basiliximab and daclizumab or polyclonal anti-T-cell antibodies like anti-thymocyte globulin. The IL-2 receptor antagonist daclizumab is approved for use in renal, cardiac transplant, and multiple sclerosis.
Lab diagnosis of ctd By Dr Arif Iqbal MD Dermatology UCMS & GTBH7867878678
This document discusses laboratory diagnosis of connective tissue diseases through detection of antinuclear antibodies. It provides details on the sensitivity and specificity of various antinuclear antibody tests for different diseases. Indirect immunofluorescence is the standard technique for antinuclear antibody detection while ELISA is also commonly used. The document outlines the clinical significance and interpretation of several specific antinuclear antibodies including anti-DNA, anti-histone, anti-RNP, anti-Ro, and anti-La antibodies.
TNF antagonists such as infliximab, adalimumab, and certolizumab are monoclonal antibodies used to treat inflammatory bowel disease by binding to TNF and preventing its interaction with receptors. They are effective for moderate to severe Crohn's disease and ulcerative colitis. While helpful for many patients, they can cause serious infections by suppressing the immune response. Careful screening and monitoring is required when using these powerful anti-inflammatory drugs.
1) Antiphospholipid syndrome (APS) is associated with arterial and venous thromboses and obstetric complications, and is diagnosed based on clinical criteria and positive laboratory tests for antiphospholipid antibodies.
2) Patients with APS have an increased risk of thrombosis even when receiving anticoagulation, so long-term anticoagulation is typically recommended over short-term treatment.
3) Treatment depends on the patient's history and risk factors, but options include warfarin, low molecular weight heparin, and direct oral anticoagulants, sometimes in combination with low-dose
Macrophage activation syndrome (MAS) is a life-threatening condition that can occur in patients with rheumatological disorders. It is characterized by proliferation and activation of macrophages that leads to cytokine overproduction and hemophagocytosis. The document discusses the pathogenesis, triggers, clinical features, diagnostic guidelines, management, and prognosis of MAS. Treatment involves high-dose corticosteroids as initial therapy, with cyclosporine A and other immunosuppressants used for severe or steroid-resistant cases. Early diagnosis and treatment have improved outcomes for MAS patients.
Thalidomide was developed in the 1950s as a sedative but caused birth defects in thousands of babies. It was banned in 1961 but has since been revived for conditions like leprosy, cancer, and graft-versus-host disease due to its anti-inflammatory and immunomodulatory effects. New derivatives like lenalidomide and pomalidomide were approved for multiple myeloma in 2005 and 2013. Thalidomide remains an important treatment option today for several cancers and inflammatory diseases due to its unique pharmacology modulating cytokines like TNFα and ILs.
This document provides an overview of immunomodulators. It begins with definitions of immunity and antigens. It describes the types of immunity and components of the immune system. It then discusses mechanisms of immunomodulation and how drugs can suppress or stimulate the immune response. The document focuses on clinically used immunomodulators, dividing them into immunosuppressants and immunostimulants. Several commonly used immunosuppressants are described in detail, including their mechanisms of action, uses, and toxicities.
This document provides a nomenclature system for monoclonal antibodies (mAbs) based on suffixes added to the root "mab". The suffixes indicate the type and application of the mAb, such as "-mo-mab" denoting a mouse mAb, "-zu-mab" a humanized mAb that is 95% human, and suffixes like "-tu-xx-mab" indicating a tumor-directed mAb. The nomenclature system aims to concisely convey whether mAbs are mouse, chimeric, humanized, or human as well as their intended therapeutic area.
An approach to a patient with Thrombocytopeniaaminanurnova
This document discusses thrombocytopenia (low platelet count) and its causes and evaluation. It describes the normal physiology of platelets and hemostasis. Common causes of thrombocytopenia include decreased platelet production (bone marrow problems), increased platelet destruction (immune mechanisms like ITP), and increased consumption (DIC). Evaluation involves history, exam, blood smear review, and identifying potential causes like drugs, infections, malignancies or autoimmune disorders. Specific conditions discussed in detail include ITP, HIT, DIC, and thrombocytopenia in cardiac patients.
This document provides an overview of immunohistochemistry techniques. It defines key terms like antigen, antibody, epitope and discusses different antibody classifications. It also describes different antibody production methods like polyclonal antisera and monoclonal antibodies. Finally, it discusses immunofluorescence and enzyme-based immunohistochemistry techniques for visualizing antibody-antigen reactions, including common enzymes and chromogens used.
The document discusses the immunology of tuberculosis. It covers the stages of pathogenesis of M. tuberculosis infection, the host immune response including innate and acquired immunity, and the pro-inflammatory and anti-inflammatory mediators involved in tuberculosis. The key points are:
1) M. tuberculosis is an intracellular pathogen that infects the lungs and can spread to other organs. The host immune response involves phagocytosis by alveolar macrophages and recruitment of other immune cells.
2) Both the innate and acquired immune responses are involved in the host defense against M. tuberculosis. Important components include neutrophils, NK cells, TLR signaling, and the cell-mediated immune response involving CD4 and CD8 T cells.
Humira is a monoclonal antibody produced through recombinant DNA technology in mammalian cells. It consists of 1330 amino acids and has a molecular weight of around 148 kilodaltons. Humira works by binding to tumor necrosis factor-alpha (TNFα), which normally triggers inflammation. By blocking the interaction of TNFα with its receptors, Humira reduces the inflammatory response associated with autoimmune diseases like rheumatoid arthritis. AbbVie, which markets Humira, has secured over 100 patents over its lifetime to prevent copying of the biologic and maintain its multi-billion dollar annual sales.
This document provides an overview of immunosuppressive drugs. It begins with an introduction to immunosuppression and the roles of immunosuppressive drugs in treating autoimmune diseases and preventing organ transplant rejection. The document then classifies immunosuppressive drugs and discusses several classes in more detail, including glucocorticoids, calcineurin inhibitors like cyclosporine and tacrolimus, sirolimus, cytostatics like cyclophosphamide, and mycophenolate mofetil. For each drug, the document provides information on mechanisms of action, indications, dosages, and side effects. The document aims to provide clinicians an overview of commonly used immunosuppressive drugs.
This document discusses immunotherapeutics and immunity. It defines immunity as the body's ability to protect itself from infectious disease. There are two main types of immunity: innate and adaptive. Immunotherapy involves stimulating, enhancing, suppressing, or desensitizing the immune system to treat or prevent disease like cancer or autoimmune disorders. The document outlines various immunotherapeutic approaches including immunostimulants, monoclonal antibodies, antibody-directed enzyme prodrug therapy, immunotoxins, and immunomodulators like adaptive cell therapy and cancer vaccines.
The document discusses drug promotion, including the sources and types of promotional materials used by pharmaceutical companies. It notes that drug promotion is a major activity for pharmaceutical companies and involves direct engagement with physicians through materials, gifts, and sponsored education events. The document outlines regulatory guidelines for ethical drug promotion from WHO, IFPMA, and OPPI, including providing accurate information about active ingredients, approved uses, safety, and references. It also discusses evaluating promotional literature for adherence to these guidelines.
1. Acute myelogenous leukemia (AML) is a clonal, malignant disease characterized by accumulation of abnormal blast cells in the bone marrow and impaired production of normal blood cells.
2. AML results from a series of somatic mutations in a primitive hematopoietic progenitor cell. Additional mutations are required for progression to AML.
3. Standard induction treatment involves "7+3" chemotherapy with cytarabine and an anthracycline, achieving remission in 55-90% of patients. Post-remission therapy aims to prolong remission.
The document discusses properties, modes of action, indications, and administration of intravenous immunoglobulin (IVIg). It provides details on the plasma fractionation process used to produce IVIg and notes that IVIg contains 98% IgG and traces of other immunoglobulins. The document also examines IVIg's mechanisms of action, FDA-approved uses, evidence for off-label uses, and potential adverse effects.
This document discusses autoantibodies known as antinuclear antibodies (ANA) that are directed against nuclear antigens. It covers the prevalence of ANA, various nuclear antigens they may be directed against like DNA and histones, mechanisms of autoimmunity and autoantibody production, roles of B cells and T cells, and methods of detecting ANAs. It also describes different patterns of ANA fluorescence and their associations with various autoimmune diseases.
Humanisation of antibodies & immunotherapeutics in clinical practice Aaqib Naseer
This document discusses humanization of monoclonal antibodies and immunotherapeutics used in clinical practice. It describes the techniques used to humanize antibodies, including CDR grafting, phage display, and transgenic animals. It then discusses various immunotherapeutics used clinically such as monoclonal antibodies, cytokines, cancer vaccines, and cell-based therapies. Monoclonal antibodies target specific antigens on cancer cells and can be naked or conjugated. Checkpoint inhibitors like anti-CTLA-4 and anti-PD-1 antibodies work by releasing brakes on the immune system. Cytokines such as interferons and interleukins modulate immune responses. Cancer vaccines aim to stimulate immunity against tumor antigens.
Approach to a patient with positive ana levels (2)Mohit Aggarwal
This document discusses the approach to evaluating a patient with a positive ANA test result. It provides background on ANA testing and discusses the significance of various ANA patterns and titers. The document emphasizes that a positive ANA alone does not indicate a specific disease and must be interpreted based on the clinical context. It then reviews how to approach and evaluate common conditions associated with ANA positivity like SLE, Scleroderma, RA, and Sjogren's Syndrome.
This document provides an overview of hemophagocytic lymphohistiocytosis (HLH). It begins by introducing HLH and describing its characteristics such as fever, hepatosplenomegaly, and cytopenias. It then discusses the classification of primary and secondary HLH, epidemiology, genetic causes, clinical features, diagnostic guidelines, treatment protocols, and long-term follow up recommendations. For the patient presented, the document recommends following the HLH-2004 treatment protocol initially and considering continuation therapy or stem cell transplant depending on the disease response and severity.
Immunosuppressive drugs used to treat transplant rejection include calcineurin inhibitors like cyclosporine and tacrolimus, mTOR inhibitors like sirolimus and everolimus, anti-proliferatives like azathioprine and mycophenolic acid, corticosteroids like prednisolone and hydrocortisone, and antibodies like the monoclonal anti-IL-2Rα receptor antibodies basiliximab and daclizumab or polyclonal anti-T-cell antibodies like anti-thymocyte globulin. The IL-2 receptor antagonist daclizumab is approved for use in renal, cardiac transplant, and multiple sclerosis.
Lab diagnosis of ctd By Dr Arif Iqbal MD Dermatology UCMS & GTBH7867878678
This document discusses laboratory diagnosis of connective tissue diseases through detection of antinuclear antibodies. It provides details on the sensitivity and specificity of various antinuclear antibody tests for different diseases. Indirect immunofluorescence is the standard technique for antinuclear antibody detection while ELISA is also commonly used. The document outlines the clinical significance and interpretation of several specific antinuclear antibodies including anti-DNA, anti-histone, anti-RNP, anti-Ro, and anti-La antibodies.
TNF antagonists such as infliximab, adalimumab, and certolizumab are monoclonal antibodies used to treat inflammatory bowel disease by binding to TNF and preventing its interaction with receptors. They are effective for moderate to severe Crohn's disease and ulcerative colitis. While helpful for many patients, they can cause serious infections by suppressing the immune response. Careful screening and monitoring is required when using these powerful anti-inflammatory drugs.
1) Antiphospholipid syndrome (APS) is associated with arterial and venous thromboses and obstetric complications, and is diagnosed based on clinical criteria and positive laboratory tests for antiphospholipid antibodies.
2) Patients with APS have an increased risk of thrombosis even when receiving anticoagulation, so long-term anticoagulation is typically recommended over short-term treatment.
3) Treatment depends on the patient's history and risk factors, but options include warfarin, low molecular weight heparin, and direct oral anticoagulants, sometimes in combination with low-dose
Macrophage activation syndrome (MAS) is a life-threatening condition that can occur in patients with rheumatological disorders. It is characterized by proliferation and activation of macrophages that leads to cytokine overproduction and hemophagocytosis. The document discusses the pathogenesis, triggers, clinical features, diagnostic guidelines, management, and prognosis of MAS. Treatment involves high-dose corticosteroids as initial therapy, with cyclosporine A and other immunosuppressants used for severe or steroid-resistant cases. Early diagnosis and treatment have improved outcomes for MAS patients.
Thalidomide was developed in the 1950s as a sedative but caused birth defects in thousands of babies. It was banned in 1961 but has since been revived for conditions like leprosy, cancer, and graft-versus-host disease due to its anti-inflammatory and immunomodulatory effects. New derivatives like lenalidomide and pomalidomide were approved for multiple myeloma in 2005 and 2013. Thalidomide remains an important treatment option today for several cancers and inflammatory diseases due to its unique pharmacology modulating cytokines like TNFα and ILs.
This document provides an overview of immunomodulators. It begins with definitions of immunity and antigens. It describes the types of immunity and components of the immune system. It then discusses mechanisms of immunomodulation and how drugs can suppress or stimulate the immune response. The document focuses on clinically used immunomodulators, dividing them into immunosuppressants and immunostimulants. Several commonly used immunosuppressants are described in detail, including their mechanisms of action, uses, and toxicities.
This document provides a nomenclature system for monoclonal antibodies (mAbs) based on suffixes added to the root "mab". The suffixes indicate the type and application of the mAb, such as "-mo-mab" denoting a mouse mAb, "-zu-mab" a humanized mAb that is 95% human, and suffixes like "-tu-xx-mab" indicating a tumor-directed mAb. The nomenclature system aims to concisely convey whether mAbs are mouse, chimeric, humanized, or human as well as their intended therapeutic area.
An approach to a patient with Thrombocytopeniaaminanurnova
This document discusses thrombocytopenia (low platelet count) and its causes and evaluation. It describes the normal physiology of platelets and hemostasis. Common causes of thrombocytopenia include decreased platelet production (bone marrow problems), increased platelet destruction (immune mechanisms like ITP), and increased consumption (DIC). Evaluation involves history, exam, blood smear review, and identifying potential causes like drugs, infections, malignancies or autoimmune disorders. Specific conditions discussed in detail include ITP, HIT, DIC, and thrombocytopenia in cardiac patients.
This document provides an overview of immunohistochemistry techniques. It defines key terms like antigen, antibody, epitope and discusses different antibody classifications. It also describes different antibody production methods like polyclonal antisera and monoclonal antibodies. Finally, it discusses immunofluorescence and enzyme-based immunohistochemistry techniques for visualizing antibody-antigen reactions, including common enzymes and chromogens used.
The document discusses the immunology of tuberculosis. It covers the stages of pathogenesis of M. tuberculosis infection, the host immune response including innate and acquired immunity, and the pro-inflammatory and anti-inflammatory mediators involved in tuberculosis. The key points are:
1) M. tuberculosis is an intracellular pathogen that infects the lungs and can spread to other organs. The host immune response involves phagocytosis by alveolar macrophages and recruitment of other immune cells.
2) Both the innate and acquired immune responses are involved in the host defense against M. tuberculosis. Important components include neutrophils, NK cells, TLR signaling, and the cell-mediated immune response involving CD4 and CD8 T cells.
HIV primarily infects CD4+ T-cells, establishing chronic immune activation that allows the virus to thrive. During infection, HIV uses error-prone reverse transcription to establish latent reservoirs within the host. This makes eradication of the virus difficult as it develops escape mutants to evade both humoral immunity through antibody neutralization and cellular immunity from CD8+ T cells. While monocytes, macrophages, dendritic cells and natural killer cells are less affected numerically, they show functional deficiencies that allow persistence and spread of the infection throughout the immune system.
This document summarizes information about HIV/AIDS. It begins by noting that the first reported HIV case was in 1981 and the virus was isolated in 1983. There are two types of HIV - HIV-1 and HIV-2. HIV is believed to have originated from closely related viruses found in non-human primates. The virus is transmitted primarily through unprotected sexual intercourse and contaminated blood/needles. While antiretroviral therapy has slowed the pandemic, there is still no cure for HIV/AIDS. The document outlines the pathogenesis, clinical stages, diagnosis, and transmission routes of HIV in further detail over multiple pages.
1. Innate immunity provides the first line of defense against pathogens and includes anatomical barriers, inflammation, phagocytosis, and antimicrobial proteins/peptides.
2. Adaptive immunity develops over time upon exposure to specific pathogens and provides enhanced protection through antibody production and immunological memory.
3. The major categories of innate immunity defenses are anatomical barriers, inflammation, phagocytosis, microbial antagonism by normal flora, and antimicrobial substances in tissues. Adaptive immunity involves B cells, T cells, and production of antibodies.
The document summarizes antigen processing and presentation by cells. It describes how T lymphocytes recognize short peptide antigens displayed by MHC molecules on antigen-presenting cells. Dendritic cells are specialized to capture antigens through receptors and transport them to lymph nodes for presentation to T cells. Proteins are broken down by proteasomes and cathepsins into peptides that bind MHC class I and class II, respectively, for recognition by CD8+ and CD4+ T cells.
This document contains an outline of lecture topics covering virology, medical microbiology, environmental microbiology, and industrial microbiology. The virology section includes figures and tables on virus isolation. The medical microbiology section covers pathogenicity, diseases, and microbial relationships. Environmental microbiology discusses water and food microbiology. Industrial microbiology focuses on microbes relevant to food production and other industries.
This document provides an overview of immunoglobulin gene families and antibody diversity. It discusses the organization and expression of light chain and heavy chain gene families, including multiple V and C region genes separated by introns on different chromosomes. During B cell development, DNA rearrangements bring a V gene next to a J region (and D region for heavy chains), which allows transcription and expression of a single antibody gene from the multiple gene segments. This genetic rearrangement and alternative splicing mechanisms contribute greatly to antibody diversity.
Specific antibody deficiency is characterized by a failure to respond to polysaccharide antigens, leading to recurrent sinopulmonary infections, despite normal immunoglobulin levels and response to protein antigens. It has a variety of clinical and immunological phenotypes that can be transient or permanent. Diagnosis involves evaluating the pattern of infections and measuring pneumococcal antibody levels before and after vaccination. Management includes immunizations, antibiotic prophylaxis and treatment, and potentially immunoglobulin replacement therapy to prevent organ damage from infections. With proper treatment, the prognosis is generally good, but permanent sequelae can occur if left undiagnosed or untreated.
This document provides an overview of basic concepts in health planning. It discusses that health planning is a process that culminates in decisions around future health facilities and services to meet community needs. There are different types of planning based on time frame (short, medium, long term) and hierarchy of goals (health policy, program, operational). Effective health planning is multidisciplinary, takes a multisectoral approach, and involves teamwork. The key steps in health planning include situation analysis, problem identification and prioritization, setting goals and targets, determining and analyzing strategies, identifying major activities, developing a budget, and establishing monitoring and evaluation.
Advanced Immunology: Antigen Processing and PresentationHercolanium GDeath
1. Antigens are internalized by antigen presenting cells through endocytosis and degraded within lysosomes into peptide fragments.
2. Peptide fragments from extracellular antigens bind to MHC class II molecules within antigen processing vesicles. The vesicles containing MHC class II-peptide complexes fuse with the cell membrane and present the complexes to CD4+ T cells.
3. Peptide fragments from intracellular antigens are degraded by the proteasome and transported into the endoplasmic reticulum by TAP proteins. The peptides bind to MHC class I molecules and the complexes are presented on the cell surface to CD8+ T cells.
The document summarizes a biology lecture on hypersensitivities and immunity to infectious diseases. It discusses the four types of hypersensitivities - type I or immediate hypersensitivity, type II or cytotoxic hypersensitivity, type III or immune complex-mediated hypersensitivity, and type IV or delayed hypersensitivity. It also covers immunity against various infectious agents such as viruses, bacteria, fungi, parasites and emerging/re-emerging infections. The lecture focuses on innate and adaptive immune responses mounted by the host against infectious diseases.
Cell-mediated immunity involves T lymphocytes that combat intracellular microbes. There are two phases: activation of naive T cells by antigen-presenting cells in lymphoid tissues, followed by migration of effector T cells to sites of infection. Effector T cells differentiate into subsets like TH1 and TH2 cells that secrete cytokines activating other immune cells. CD8+ T cells become cytotoxic T lymphocytes that directly kill infected cells. Memory T cells remain after infection clearance to provide rapid protection upon reexposure.
Immunological Disorders can be classified into 3 distinct categories.They are Hypersensitivity, Autoimmunity and Immunodeficiency.Here in this presentation we talk about Immunodeficiency disorders.Get more on our blog : http://dentistryandmedicine.blogspot.com/
This document summarizes several viral infections including measles, mumps, poliovirus, viral hemorrhagic fevers, herpes viruses, cytomegalovirus, varicella-zoster virus, hepatitis B virus, Epstein-Barr virus, and human papillomaviruses. It describes the viruses that cause each infection, how they are transmitted, the path they take in the body, clinical manifestations, morphologic findings, and potential complications. Chronic infections like herpes viruses and hepatitis B are able to evade the immune system and cause long-term infections while others like measles and mumps typically cause acute, transient infections.
This document discusses immunity to various infectious diseases. It covers innate and adaptive immunity, immunity to viruses, bacteria, fungi, protozoa and helminths. For bacteria, both extracellular and intracellular types are discussed. The roles of antibodies and cell-mediated responses are described for different pathogens depending on where they reside in the host. Mechanisms by which pathogens evade immunity are also summarized.
This document summarizes cell-mediated effector response biology. It discusses how cell-mediated immunity detects and eliminates intracellular pathogens and tumor cells through cells like CD8+ cytotoxic T lymphocytes and cytokine-secreting CD4+ T cells. It describes the mechanisms by which cytotoxic T cells and natural killer cells kill infected or abnormal cells through directed release of cytotoxic proteins or interaction of membrane-bound ligands and receptors on target cells.
This document provides an overview of biodiversity in the Philippines. It begins by defining key terms like endemism. It then discusses the high plant diversity in the Philippines, noting there are an estimated 12,000 plant species, with many ferns, orchids, and mosses being endemic. The document highlights some examples of endemic species within these groups. It also addresses the country's status as one of 17 megadiverse countries and notes the large numbers of endemic animal species like birds, mammals, and reptiles found in the Philippines. Threats to the country's biodiversity like habitat loss are also examined.
This document discusses antigens and antibodies. It defines antigens as any molecule that can bind specifically to an antibody. Antigens include sugars, lipids, proteins and more. They can be found on microbes or in the environment. The document discusses the properties of antigens including their ability to induce immune responses or tolerance. It also discusses immunogens versus haptens. Factors that influence antigen immunogenicity are also covered such as molecular size, composition, and an antigen's susceptibility to processing and presentation. The role of adjuvants in enhancing immune responses is also summarized.
This document discusses immunological tolerance and regulatory T cells. It defines tolerance as unresponsiveness to antigen induced by previous exposure. Central tolerance occurs in the thymus through deletion of self-reactive T cells. Peripheral tolerance occurs through several mechanisms in tissues, including regulatory T cells that suppress immune responses. The key transcription factor controlling regulatory T cells is FOXP3. Mutations in FOXP3 can lead to immune dysregulation diseases like IPEX syndrome.
Monoclonal antibodies (mAbs) are identical antibodies produced by a single clone of B cells or hybridoma cell line. Paul Ehrlich first described antibodies as "magic bullets" in search of toxins. Key developments included methods to isolate hybrid cell lines producing mAbs. mAbs can be murine, chimeric, humanized, or human. They have diagnostic applications like pregnancy tests and therapeutic uses like treating cancer, transplants, and autoimmune disorders. Common side effects include allergic reactions and infusion reactions. mAbs have revolutionized biotechnology and improved human health.
Kidney transplantation is the most effective therapy for end-stage renal disease. It involves transplanting a kidney from a living or deceased donor. Immunosuppressive medications are used to prevent rejection and include corticosteroids, calcineurin inhibitors like cyclosporine and tacrolimus, mTOR inhibitors like sirolimus, and antimetabolites. Common post-transplant complications include infection from viruses like CMV and BK virus, acute rejection, chronic allograft dysfunction, and malignancy. Long-term management requires monitoring for these complications and adjusting immunosuppression.
Immunosuppressant are drugs or medicines that lower the body's ability to reject a transplanted organ. Another term for these drugs is anti-rejection drugs. There are 2 types of immunosuppressants: Induction drugs: Powerful antirejection medicine used at the time of transplant.
This document discusses various biologic therapies used to treat kidney diseases. It defines biologics as substances derived from biological sources using biotechnology. Biologics are classified into categories including hormones, growth factors, cytokines, vaccines, enzymes and antibodies. Specific biologics discussed that target the immune system include monoclonal antibodies against TNFα, IL-2, IL-6, CD20, C5, VEGF, and TWEAK. Conditions where biologics may be used include glomerular diseases, transplantation, lupus nephritis, ANCA-associated vasculitis, and hepatitis C infection. Potential benefits and risks of different biologics are presented.
Systematic screening of generic drugs for progressive multiple sclerosis iden...Jalormi Parekh
This document describes experiments investigating the effects of clomipramine in models of multiple sclerosis. Clomipramine showed neuroprotective effects against iron-mediated toxicity in neurons in culture. It also demonstrated antioxidant properties and reduced T-lymphocyte and B-lymphocyte proliferation. In mouse models of EAE, clomipramine decreased disease burden and inflammation when administered from disease onset. Further experiments explored the effects of clomipramine in various EAE models induced with different antigens. Overall, the results suggest clomipramine has therapeutic potential for reducing inflammation and neurodegeneration in multiple sclerosis.
1. Transplant immunology involves replacing nonfunctioning organs or tissues with healthy donor grafts. Major barriers include innate immune responses like complement activation and adaptive responses like allograft rejection mediated by T cells recognizing donor HLA antigens.
2. Acute rejection occurs within days/weeks and includes cellular rejection from CTL killing and antibody-mediated rejection from donor HLA antibodies. Chronic rejection develops over months/years and is characterized by vascular occlusion.
3. Immunosuppression minimizes immunogenicity differences and uses drugs like cyclosporine, tacrolimus and mycophenolate to inhibit T cell responses or antibody production against donor antigens.
Literature Review on Development of Monoclonal Antibodies and Hybridoma Techn...Tuhin Samanta
Antibodies or immunoglobulin's are protein particles delivered by a specific gathering of cells called B-lymphocytes in creatures. These are a piece of the guard framework to ensure the body against the attacking outside substances to be specific antigens.
Monoclonal immunizer (Mab) is a solitary sort of neutralizer that is coordinated against a particular antigenic determinant (epitope). Eternal monoclonal counter acting agent are found in patients experiencing an infection called different myeloma. In 1975 George Kohler and Cesar Milstein were effectively hybridize counter acting agent delivering B-lymphocytes with myeloma cells in vitro and make a hybridoma. The creation of monoclonal immune response by half and half cells is alluded to as hybridoma innovation.
Monoclonal antibodies are identical antibodies produced from a single clone that target specific antigens. They are used widely in targeted cancer therapies. The document discusses the various methods used to produce monoclonal antibodies including hybridoma technology, phage display, and transgenic mice. It also covers the structure and functions of antibodies as well as the pharmacokinetics and mechanisms of several monoclonal antibodies used to treat various cancers and other diseases by targeting cell surface receptors like CD20, HER2, EGFR, VEGF.
This document provides an overview of immunomodulators, which are drugs that modulate the immune system by either suppressing or stimulating it. It discusses the components of the immune system and classifies immunomodulators into immunosuppressants and immunostimulants. Examples of immunosuppressants discussed include corticosteroids like prednisolone, antimetabolites like methotrexate, antibiotics like cyclosporine. Their mechanisms of action and uses for suppressing the immune system, such as for organ transplants, are described. Immunostimulants are also briefly introduced as substances that can activate or increase immune system activity.
Monoclonal antibodies (mAbs) are identical antibodies produced by a single clone of immune cells that are all clones of the same parent cell. mAbs can be produced against almost any substance and are important tools in biochemistry and medicine. They are produced through the fusion of antibody-producing cells with myeloma cells to form hybridomas that produce identical antibodies. mAbs have applications in research, diagnostics, and therapy due to their specificity and ability to detect or purify target substances.
An antibody is a protein produced by the immune system to identify and neutralize foreign objects like bacteria and viruses. Antibodies recognize specific antigens unique to their target. Biological therapies for treating diseases employ substances like monoclonal antibodies, interferons, and interleukins. Monoclonal antibodies in particular are increasingly prominent in medicine. They are named using a standardized nomenclature indicating the target, source species, and whether it is a monoclonal, chimeric, or humanized antibody. Common examples of monoclonal antibodies used for treatment include rituximab, infliximab, and adalimumab.
1) The document discusses various in vitro and in vivo models used to study immunomodulatory activity, including inhibition of histamine release from mast cells, lymphocyte proliferation assays, and animal models of autoimmune diseases and hypersensitivity reactions.
2) Test protocols are provided for studying immunomodulation using assays such as mixed lymphocyte reactions, lymphocyte stimulation and cytokine production.
3) Animal models described include adjuvant-induced arthritis in rats and various spontaneous autoimmune disease models in mice and other species. Standard protocols are given for evaluating compounds in these disease models.
1) The document discusses various in vitro and in vivo models used to study immunomodulatory activity, including inhibition of histamine release from mast cells, lymphocyte proliferation assays, and animal models of autoimmune diseases and hypersensitivity reactions.
2) Specific protocols are provided for studying inhibition of T cell proliferation using mixed lymphocyte reactions and lymphokine production.
3) Methods for evaluating potential immunomodulatory compounds in animal models of adjuvant-induced arthritis and delayed type hypersensitivity reactions are also summarized.
This document provides an overview of monoclonal antibodies and gene therapy. It discusses the discovery of monoclonal antibodies by Kohler and Milstein in 1975. It also describes the multi-step process of producing monoclonal antibodies through cell fusion and hybridoma technology. Several types of monoclonal antibodies are outlined, along with their purification techniques and therapeutic applications in cancer treatment and other diseases. Gene therapy approaches including ex vivo and in vivo methods are briefly introduced.
This document discusses the history and key concepts of immunology. It describes some of the earliest observations of immunity in the 4th century BC by Thucydides. It then outlines major developments in vaccination by Jenner in 1790 and the later proposals of the germ theory of disease by Pasteur and the concept of acquired cellular immunity by Metchnikoff and Ehrlich in the late 19th century. The document also summarizes the three lines of defense in the immune system (non-specific, specific, and adaptive immunity), the roles of antibodies, B cells and T cells, and the processes of humoral and cell-mediated immunity.
This document discusses monoclonal antibodies, including their history, production via hybridoma technology, types, applications, and FDA-approved examples. It describes how monoclonal antibodies are produced by fusing B cells from immunized mice with myeloma cells to create hybridomas that produce identical antibodies targeting a specific antigen. This technology was developed in 1975 by Kohler and Milstein, earning them a Nobel Prize. Monoclonal antibodies have various diagnostic and therapeutic uses due to their specificity and homogeneity.
The document discusses transplantation and the immune response. It begins by defining transplantation as moving cells, tissues, or organs from one site to another, either within an individual or between donors and recipients. There are several types of transplantation - autografts within an individual, isografts between identical twins, allografts between non-identical individuals of the same species, and xenografts between different species. Rejection can be acute, occurring within 6 months, or chronic with repeated acute episodes ultimately causing transplant failure. Immunosuppressive drugs are used to reduce rejection by dampening the immune response.
This document provides an overview of monoclonal antibodies including their history, development, preparation, and applications. It discusses how monoclonal antibodies are produced through the fusion of B cells and myeloma cells to form hybridomas. The document outlines the key applications of monoclonal antibodies in diagnosis (e.g. biochemical analysis, imaging), therapy (e.g. cancer, transplantation), and protein purification. It also provides examples of commercially available monoclonal antibodies for various diseases and conditions.
- Cat and dog allergens such as Fel d 1 and Can f 1 are major allergens found in fur, dander, and saliva that can become airborne and cause sensitization in a large percentage of allergic individuals.
- Lipocalins make up many mammalian allergens and show cross-reactivity between species due to structural similarities, explaining co-sensitizations between cats, dogs, horses, and other animals.
- Higher levels of IgE antibodies to specific dog lipocalins are associated with more severe asthma in children with dog allergy.
1) DRESS syndrome is a severe cutaneous drug reaction characterized by fever, lymphadenopathy, hematologic abnormalities, multisystem involvement, and viral reactivation. It has a delayed onset of 2-3 weeks after starting the culprit drug.
2) The skin manifestations are typically a polymorphous maculopapular eruption and facial edema. Systemic involvement can include the liver, kidneys, lungs and other organs.
3) Diagnosis is based on clinical criteria including the RegiSCAR scoring system which evaluates morphology, timing of onset, organ involvement, hematologic abnormalities and viral reactivation.
Wheat is one of the most important global food sources and wheat allergy prevalence varies from 0.4-4% depending on age and region. Several wheat proteins have been identified as major allergens, including omega-5-gliadin, alpha-amylase inhibitors, and glutenins. Studies have found that serum testing for IgE antibodies to specific wheat allergens, such as omega-5-gliadin, glutenins, and alpha-amylase inhibitors, can help diagnose wheat allergy and distinguish between mild and severe cases. Sensitization to different wheat allergens is associated with wheat-dependent exercise-induced anaphylaxis versus occupational baker's asthma. Proper diagnosis and
Major indoor allergens include dust mites, domestic animals like cats and dogs, insects like cockroaches, mice, and fungi. Dust mites thrive in warm, humid environments like mattresses, bedding, and upholstered furniture, where they feed on human skin scales and excrete allergenic fecal particles. Cat allergens like Fel d 1 accumulate in fur and can become airborne, causing worse asthma outcomes in sensitized individuals. Minimizing exposure involves removing carpets, frequent washing of bedding, humidity control, HEPA filtration and ventilation.
This document provides information on Hymenoptera, focusing on the families Apidae and Vespidae. It discusses the epidemiology and prevalence of insect venom allergy. It also covers the taxonomy, venom composition, and clinical manifestations of common stinging insects like honeybees, hornets, wasps and yellow jackets. Key allergens are identified for different species.
- NSAIDs hypersensitivity can present with distinct clinical phenotypes based on organ system involvement and timing of symptoms. It is estimated that less than 20% of reported adverse reactions to NSAIDs are true hypersensitivities.
- AERD/NERD involves eosinophilic rhinosinusitis, asthma, and nasal polyps. Exposure to aspirin or other NSAIDs exacerbates bronchospasms and rhinitis. Management involves lifelong avoidance of culprit and cross-reacting NSAIDs.
- Various phenotypes are described beyond the EAACI classification, including blended reactions involving multiple organs, food-dependent NSAID-induced anaphylaxis, and NSAID-selective immediate reactions. Proper diagnosis relies
The document discusses food immunotherapy for treating food allergies. It provides definitions and outlines immune mechanisms and efficacy evidence from studies on peanut, cow's milk, egg, and wheat oral immunotherapy (OIT). Peanut OIT studies showed 67-78% of children achieved desensitization and 21-46% achieved sustained unresponsiveness. Cow's milk and egg OIT also demonstrated desensitization in 50-75% of children. Wheat OIT studies found 52-69% achieved desensitization. OIT was effective at increasing tolerance but also increased rates of adverse events during treatment.
This document summarizes X-linked agammaglobulinemia (XLA), an inherited primary immunodeficiency caused by mutations in the Bruton's tyrosine kinase (Btk) gene. XLA is characterized by absent B cells and low immunoglobulin levels, leading to recurrent bacterial infections starting in infancy. Management involves immunoglobulin replacement and antibiotic therapy. With treatment, life expectancy has improved dramatically though complications can include lung disease. The document also briefly discusses other forms of agammaglobulinemia caused by defects in genes important for early B cell development.
This document discusses histamine and anti-histamines. It provides information on:
1. The structure and function of histamine and its receptors in immune response regulation. Histamine plays a role in processes like antigen presentation and influencing T and B cell responses.
2. The classification and structures of different types of anti-histamines, including first and second generation anti-histamines from different chemical classes.
3. Some anti-histamines have the potential to cause hypersensitivity in rare cases, even those from different chemical classes with no structural similarity.
The document discusses beta-lactam allergy, including penicillin and cephalosporin allergies. It covers the epidemiology, classifications, structures, mechanisms, and investigations of beta-lactam allergies. Specifically, it notes that penicillin is the most commonly reported antibiotic allergy. It describes the hapten concept of small molecules like beta-lactams binding covalently to proteins to form antigen complexes. Skin testing and in vitro tests are used to investigate immediate IgE-mediated allergies, while patch testing is used for delayed reactions.
This document provides an overview of intravenous immunoglobulin (IVIG) therapy. It discusses the structure and classes of immunoglobulins, mechanisms of action including neutralization, opsonization, and modulation of immune cells. It also covers the manufacturing process, pharmacokinetics, indications for use in primary immunodeficiencies and autoimmune diseases, dosing, administration, and adverse effects. The differences between IVIG products are also reviewed.
More from Chulalongkorn Allergy and Clinical Immunology Research Group (20)
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
TEST BANK For Community Health Nursing A Canadian Perspective, 5th Edition by...Donc Test
TEST BANK For Community Health Nursing A Canadian Perspective, 5th Edition by Stamler, Verified Chapters 1 - 33, Complete Newest Version Community Health Nursing A Canadian Perspective, 5th Edition by Stamler, Verified Chapters 1 - 33, Complete Newest Version Community Health Nursing A Canadian Perspective, 5th Edition by Stamler Community Health Nursing A Canadian Perspective, 5th Edition TEST BANK by Stamler Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Pdf Chapters Download Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Pdf Download Stuvia Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Study Guide Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Ebook Download Stuvia Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Questions and Answers Quizlet Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Studocu Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Quizlet Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Stuvia Community Health Nursing A Canadian Perspective, 5th Edition Pdf Chapters Download Community Health Nursing A Canadian Perspective, 5th Edition Pdf Download Course Hero Community Health Nursing A Canadian Perspective, 5th Edition Answers Quizlet Community Health Nursing A Canadian Perspective, 5th Edition Ebook Download Course hero Community Health Nursing A Canadian Perspective, 5th Edition Questions and Answers Community Health Nursing A Canadian Perspective, 5th Edition Studocu Community Health Nursing A Canadian Perspective, 5th Edition Quizlet Community Health Nursing A Canadian Perspective, 5th Edition Stuvia Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Pdf Chapters Download Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Pdf Download Stuvia Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Study Guide Questions and Answers Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Ebook Download Stuvia Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Questions Quizlet Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Studocu Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Quizlet Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Stuvia
Adhd Medication Shortage Uk - trinexpharmacy.comreignlana06
The UK is currently facing a Adhd Medication Shortage Uk, which has left many patients and their families grappling with uncertainty and frustration. ADHD, or Attention Deficit Hyperactivity Disorder, is a chronic condition that requires consistent medication to manage effectively. This shortage has highlighted the critical role these medications play in the daily lives of those affected by ADHD. Contact : +1 (747) 209 – 3649 E-mail : sales@trinexpharmacy.com
TEST BANK For Community and Public Health Nursing: Evidence for Practice, 3rd...Donc Test
TEST BANK For Community and Public Health Nursing: Evidence for Practice, 3rd Edition by DeMarco, Walsh, Verified Chapters 1 - 25, Complete Newest Version TEST BANK For Community and Public Health Nursing: Evidence for Practice, 3rd Edition by DeMarco, Walsh, Verified Chapters 1 - 25, Complete Newest Version TEST BANK For Community and Public Health Nursing: Evidence for Practice, 3rd Edition by DeMarco, Walsh, Verified Chapters 1 - 25, Complete Newest Version Test Bank For Community and Public Health Nursing: Evidence for Practice 3rd Edition Pdf Chapters Download Test Bank For Community and Public Health Nursing: Evidence for Practice 3rd Edition Pdf Download Stuvia Test Bank For Community and Public Health Nursing: Evidence for Practice 3rd Edition Study Guide Test Bank For Community and Public Health Nursing: Evidence for Practice 3rd Edition Ebook Download Stuvia Test Bank For Community and Public Health Nursing: Evidence for Practice 3rd Edition Questions and Answers Quizlet Test Bank For Community and Public Health Nursing: Evidence for Practice 3rd Edition Studocu Test Bank For Community and Public Health Nursing: Evidence for Practice 3rd Edition Quizlet Test Bank For Community and Public Health Nursing: Evidence for Practice 3rd Edition Stuvia Community and Public Health Nursing: Evidence for Practice 3rd Edition Pdf Chapters Download Community and Public Health Nursing: Evidence for Practice 3rd Edition Pdf Download Course Hero Community and Public Health Nursing: Evidence for Practice 3rd Edition Answers Quizlet Community and Public Health Nursing: Evidence for Practice 3rd Edition Ebook Download Course hero Community and Public Health Nursing: Evidence for Practice 3rd Edition Questions and Answers Community and Public Health Nursing: Evidence for Practice 3rd Edition Studocu Community and Public Health Nursing: Evidence for Practice 3rd Edition Quizlet Community and Public Health Nursing: Evidence for Practice 3rd Edition Stuvia Community and Public Health Nursing: Evidence for Practice 3rd Edition Test Bank Pdf Chapters Download Community and Public Health Nursing: Evidence for Practice 3rd Edition Test Bank Pdf Download Stuvia Community and Public Health Nursing: Evidence for Practice 3rd Edition Test Bank Study Guide Questions and Answers Community and Public Health Nursing: Evidence for Practice 3rd Edition Test Bank Ebook Download Stuvia Community and Public Health Nursing: Evidence for Practice 3rd Edition Test Bank Questions Quizlet Community and Public Health Nursing: Evidence for Practice 3rd Edition Test Bank Studocu Community and Public Health Nursing: Evidence for Practice 3rd Edition Test Bank Quizlet Community and Public Health Nursing: Evidence for Practice 3rd Edition Test Bank Stuvia
Our backs are like superheroes, holding us up and helping us move around. But sometimes, even superheroes can get hurt. That’s where slip discs come in.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Promoting Wellbeing - Applied Social Psychology - Psychology SuperNotesPsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
Clinic ^%[+27633867063*Abortion Pills For Sale In Tembisa Central19various
Clinic ^%[+27633867063*Abortion Pills For Sale In Tembisa Central Clinic ^%[+27633867063*Abortion Pills For Sale In Tembisa CentralClinic ^%[+27633867063*Abortion Pills For Sale In Tembisa CentralClinic ^%[+27633867063*Abortion Pills For Sale In Tembisa CentralClinic ^%[+27633867063*Abortion Pills For Sale In Tembisa Central
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
9. History
Corticosteroid
cortisone - RA
1949 Philip Hench Early 1960s
AZA –kidney
allograft
rejection
1960s and 1970s
Cyclophos
phamide
Antilymphocyte
serum
Alexander C .Wiseman,Clin J Am Soc Nephrol 11: 332–343, February,
10. History
• Develop monoclonal antibodies (mAbs) use and the
discovery of the immunosuppressive effects of
cyclosporin A from fermentation extracts of the fungal
species Tolypocladium inflatum .
• Mammalian target of rapamycin (mTOR) pathways
Alexander C .Wiseman,Clin J Am Soc Nephrol 11: 332–343, February, 2
17. History
Corticosteroid
cortisone - RA
1949 Philip Hench Early 1960s
AZA –kidney
allograft
rejection
1960s and 1970s
Cyclophos
phamide
Antilymphocyte
serum
Alexander C .Wiseman,Clin J Am Soc Nephrol 11: 332–343, February,
2016
25. History
Corticosteroid
cortisone - RA
1949 Philip Hench Early 1960s
AZA –kidney
allograft
rejection
1960s and 1970s
Cyclophos
phamide
Antilymphocyte
serum
Clin J Am Soc Nephrol 11: 332–343, February,
2016
26. History
• Develop monoclonal antibodies (mAbs) use and the
discovery of the immunosuppressive effects of
cyclosporin A from fermentation extracts of the fungal
species Tolypocladium inflatum .
• Mammalian target of rapamycin (mTOR) pathways
Alexander C .Wiseman,Clin J Am Soc Nephrol 11: 332–343, February
29. n engl j med 351;26 www.nejm.org december 23, 2004
30. T Cell-Directed Therapy
• Agents Targeting Signal 1 (the interaction of the TCR
complex with an APC )
• Agents Targeting Signal 2 (the costimulatory signal
provided by additional T cell/APC interaction that
leads to full activation of the T cell)
• Agents that inhibit further downstream activation and
proliferation (typically driven by cytokine production)
Alexander C .Wiseman,Clin J Am Soc Nephrol 11: 332–343, Februar
42. Anti- CD 20 : Rituximab
• The first agent to target CD20, rituximab, is a chimeric anti-
CD20 mAb (30% murine and 70% human) that leads to B
cell depletion through a number of mechanisms, including
complement-dependent cytotoxicity, growth arrest, and
apoptosis .
45. Complement Inhibition (Eculizumab)
• Eculizumab is a humanized mAb to C5 that effectively
inhibits its cleavage to C5a and C5b.
• Because C5a is a neutrophil chemoattractant and
required to form the C5b-9 membrane attack
complex, inhibition of this enzymatic step results in
blockade of proin flammatory,
prothrombotic, and lytic functions of complement
47. Agents Targeting Chemokines and Cell Adhesion
• CCR5 receptor antagonist maraviroc used in the treatment
of HIV.
• CXCR4 antagonist plerixafor approved for hematopoietic stem cell
mobilization.
• CCR4 humanized mAb mogamulizumab approved for the treatment of
T cell lymphoma.
• Emapticap is an inhibitor to CCL2 (also known as monocyte
chemotactic protein 1), which has been studied in phase 1 and 2
trials in diabetic nephropathy .
48. Pooled Polyclonal Antibodies as
Immunosuppressive Agents
• Immune Globulins
mechanisms often cited include
(1) direct binding to natural antibodies, immunomodulatory
proteins (e.g., cytokines), or superantigens and pathogens
(2) inhibition of complement fixation on target tissues by acting
as a complement sink
(3) Fc receptor (FcR) binding and subsequent inhibition of the
FcR mediated recycling of native IgG
(4) stimulation of FcR-induced anti-inflammatory pathways
49. Pooled Polyclonal Antibodies as
Immunosuppressive Agents
• Polyclonal Antithymocyte Globulin
ATG products also have activity against B cells, monocytes, and
neutrophils to lesser degrees.
The primary mechanism of action of ATGs is lymphocyte depletion,
predominantly by complement-dependent lysis and T cell activation–
induced apoptosis
59. Panackel C, Ganjoo N, Saif R, Jacob M.,IMA Kerala Medical Journal. 2016 Mar 30;9(1):
60. n engl j med 351;26 www.nejm.org december 23, 2004
61. n engl j med 351;26 www.nejm.org december 23, 2004
Editor's Notes
FIGURE 9-1 Activation of naive and effector T cells by antigen. Antigens that are transportedby dendritic cells to lymph nodes are recognized by naive T lymphocytes that recirculate through these lymphnodes. The T cells are activated to differentiate into effector cells, which may remain in the lymphoid organsto help B lymphocytes or migrate to sites of infection, where the effector cells are again activated by antigensand perform their various functions, such as macrophage activation.
FIGURE 17-6 Activation of alloreactive T cells. A, In the case of direct allorecognition, donor dendritic cells in the allograft migrate tosecondary lymphoid tissues, where they present allogeneic MHC molecules to host T cells. In the case of indirect allorecognition, recipient dendriticcells that have entered the allograft transport donor MHC proteins to secondary lymphoid tissues and present peptides derived from these MHCproteins to alloreactive host T cells. In both cases, the T cells become activated and differentiate into effector cells. B, The alloreactive effector T cellsmigrate into the allograft, become reactivated by alloantigen, and mediate damag
FIGURE 9-2 Phases of T cell responses. Antigen recognition by T cells induces cytokine (e.g., IL-2) secretion, particularly in CD4+ T cells, clonal expansion as a result of cell proliferation, and differentiation of the T cells into effector cells or memory cells. In the effector phase of the response, the effector CD4+ T cells respond to antigen by producing cytokines that have several actions, such as the recruitment and activation of leukocytes and activation of B lymphocytes, while CD8+ CTLs respond by killing other cells.
FIGURE 9-3 Functions of costimulators in T cell activation. A, The resting APC (typically dendritic cells presenting self antigens) expresses fewor no costimulators and fails to activate naive T cells. (Antigen recognition without costimulation may make T cells unresponsive [tolerant]; we will discussthis phenomenon in Chapter 15.) B, Microbes and cytokines produced during innate immune responses activate APCs to express costimulators, such as B7molecules. The APCs (usually presenting microbial antigens) then become capable of activating naive T cells. Activated APCs also produce cytokines such as IL-12,which stimulate the differentiation of naive T cells into effector cells. CD28 Antigen recognition T cell response NaiveT cell B7 IL-2 CD28Unactivated (costimulatordeficient) APC Activated APCs: increased expression of costimulators, secretion of cytokinesCytokines (e.g., IL-12) No response or tolerance T cell survival, proliferatio
FIGURE 9-4 Mechanisms of T cell costimulation by CD28. CD28 engagement induces signaling pathways that enhance or work together with TCR signals to stimulatethe expression of survival proteins, cytokines, and cytokine receptors; to promote cell proliferation; and to induce differentiation toward effector and memory cells by activating various transcription factors (not shown, see Chapters 10 and 11). These differentiation events may be secondary to the increased clonal expansion and may also involve increased production of various transcription factors
Immunosuppressive agents have a long history, with a recent acceleration in growth in number. After the discovery by Nobel Prize awardee Philip Hench that the corticosteroid cortisone had significant antiinflammatory effects in patients with rheumatoid arthritis (RA) in 1949 , azathioprine (AZA) was an effective immunosuppressive agent in the prevention of kidney allograft rejection in the early 1960s
The 1960s and 1970s were marked by a borrowing of cyclophosphamide from the developing field of cancer chemotherapy for use in immune diseases and transplantation, whereas the use of antilymphocyte serum as a lymphocyte-depleting agent gained favor in the developing field of kidney transplantation
two key developments were the technology to develop monoclonal antibodies (mAbs) for human therapeutic use and the discovery of the immunosuppressive effects of cyclosporin A from fermentation extracts of the fungal species Tolypocladium inflatum (The 1990s were a period of significant immunosuppressive drug development, because increased insight into B and T cell development, activation, and proliferation, cytokine and chemokine signaling, and complement activation led to targeted therapeutics, particularly mAbs that could later be humanized (
Effects on the immune system are alsonumerous but most clearly related to inhibition of all cytokine transcription by blocking transcription factors, such asNF-kb and activator protein-1 (56). This has numerousdownstream effects, such as (1) depletion of T cells becauseof inhibition of IL-2, inhibition of Th1 differentiation, andinduction of apoptosis, (2) eosinophil apoptosis (either directly or by inhibition of IL-5), and (3) macrophage dysfunction because of inhibition of IL-1 and TNF-a. Its effecton neutrophil function is modest; however, neutrophil migration to sites of inflammation is impaired, bone marrowsecretion of neutrophils is increased, and apoptosis is decreased, all of which contribute to leukocytosis (57). Similarly, B cells are not significantly inhibited by corticosteroids,with only mild decreases in Ig production. Its side effectprofile is well appreciated clinically and frequently malignedas a chronic therapy
Immunosuppressive agents have a long history, with a recent acceleration in growth in number. After the discovery by Nobel Prize awardee Philip Hench that the corticosteroid cortisone had significant antiinflammatory effects in patients with rheumatoid arthritis (RA) in 1949 , azathioprine (AZA) was an effective immunosuppressive agent in the prevention of kidney allograft rejection in the early 1960s
The 1960s and 1970s were marked by a borrowing of cyclophosphamide from the developing field of cancer chemotherapy for use in immune diseases and transplantation, whereas the use of antilymphocyte serum as a lymphocyte-depleting agent gained favor in the developing field of kidney transplantation
Salvage pathway and de novo pathway . osuppressive properties. Information on the thiopurine nucleotides has often been derived from studies in which 6MP wasadministered. BecauseAZA is rapidly converted into 6MP,l5< 1 7 , 307 31 however, similar metabolites and modesof action are expectedfor both. Several sitesof inhibition of purine synthesis have been identified for the thiopurines3 in both the de novo pathway, which involves synthesis of purine ribonucleotidesfrom small-molecular-weight precursor^,^' and in the salvage pathway,which involves direct reaction of a purine base with a phosphoribo~yltransferase~~(Figure 3).
Mycophenolate mofetil MMF, CellCept is a prodrug of mycophenolic acid MPA , an inhibitor of inosine Ž w. Ž .monophosphate dehydrogenase IMPDH . This is the rate-limiting enzyme in de novo synthesis of guanosine nucleotides. T- Ž .and B-lymphocytes are more dependent on this pathway than other cell types are. Moreover, MPA is a fivefold more potentinhibitor of the type II isoform of IMPDH, which is expressed in activated lymphocytes, than of the type I isoform ofIMPDH, which is expressed in most cell types. MPA has therefore a more potent cytostatic effect on lymphocytes than onother cell types. This is the principal mechanism by which MPA exerts immunosuppressive effects.Three other mechanisms may also contribute to the efficacy of MPA in preventing allograft rejection and otherapplications. First, MPA can induce apoptosis of activated T-lymphocytes, which may eliminate clones of cells respondingto antigenic stimulation. Second, by depleting guanosine nucleotides, MPA suppresses glycosylation and the expression ofsome adhesion molecules, thereby decreasing the recruitment of lymphocytes and monocytes into sites of inflammation andgraft rejection. Third, by depleting guanosine nucleotides MPA also depletes tetrahydrobiopterin, a co-factor for theinducible form of nitric oxide synthase iNOS . MPA therefore suppresses the production by iNOS of NO, and consequent Ž .tissue damage mediated by peroxynitrite.CellCeptw suppresses T-lymphocytic responses to allogeneic cells and other antigens. The drug also suppresses primary,but not secondary, antibody responses. The efficacy of regimes including CellCeptw
Mycophenolate. Mycophenolate is an inhibitor of IMPDH,the rate-limiting enzyme of guanine nucleotide synthesiscritical for de novo purine synthesis and thus, DNA synthesis. T cells (and B cells) are dependent on the de novo pathway for DNA synthesis. Similar to AZA, primary sideeffects are gastrointestinal and hematopoetic. Its efficacyin the prevention of rejection compared with AZA togetherwith better tolerability than mTOR inhibitors have led to itsuse as the primary antimetabolite in transplantation
Leflunomide is a pyrimidine antagonist thatblocks DNA synthesis and cell cycling from S to G2 phase.Its specific mechanism of action entails inhibition of the keyrate–limiting enzyme dihydro-orotate dehydrogenase critical for de novo pyrimidine synthesis
Cytotoxic Agents (Cyclophosphamide) as Immunosuppressive Agents A brief mention of cyclophosphamide is necessary given its use as an immunosuppressant in life-threatening or severe rheumatologic and renal diseases, including ANCA-related vasculitis, lupus nephritis, and other systemic vasculidites.Cyclophosphamide is an alkylating agent that is toxic to all human cells to differing degrees, with hematopoetic cells forming a particularly sensitive target (104). Primary toxicities, such as bladder toxicity, gonadal toxicity, and later malignancy, have led to attempts to minimize exposure(,250–300 mg/kg cumulative dose to avoid gonadal oxicity and ,360 mg/kg cumulative dose to minimize therisk of malignancy), attempts to use intermittent intravenous rather than daily oral therapy to minimize exposure, and search for alternative agents (for example, mycophenolate mofetil in lupus nephritis and rituxan in ANCA-related vasculitis)
Immunosuppressive agents have a long history, with a recent acceleration in growth in number. After the discovery by Nobel Prize awardee Philip Hench that the corticosteroid cortisone had significant antiinflammatory effects in patients with rheumatoid arthritis (RA) in 1949 , azathioprine (AZA) was an effective immunosuppressive agent in the prevention of kidney allograft rejection in the early 1960s
The 1960s and 1970s were marked by a borrowing of cyclophosphamide from the developing field of cancer chemotherapy for use in immune diseases and transplantation, whereas the use of antilymphocyte serum as a lymphocyte-depleting agent gained favor in the developing field of kidney transplantation
two key developments were the technology to develop monoclonal antibodies (mAbs) for human therapeutic use and the discovery of the immunosuppressive effects of cyclosporin A from fermentation extracts of the fungal species Tolypocladium inflatum (The 1990s were a period of significant immunosuppressive drug development, because increased insight into B and T cell development, activation, and proliferation, cytokine and chemokine signaling, and complement activation led to targeted therapeutics, particularly mAbs that could later be humanized (
Therapeutic agents that target T cell function can be separated into those that inhibit signal 1 (the interaction of theT cell receptor [TCR] complex with an antigen-presentingcell [APC] either carrying antigen or in the case of transplantation, acting as antigen itself) and its resulting intracellularsignaling and those that inhibit signal 2 (the costimulatorysignal provided by additional T cell/APC interaction thatleads to full activation of the T cell) (Figure 2). Agents thatinhibit further downstream activation and proliferation (occasionally referred to as signal 3) are typically driven bycytokine production and signaling and will be discussed inlater sections
anti-TCR Agents. Inhibition of the first point of antigenpresentation (the MHC/TCR complex) has been an attractive target in transplant immunosuppression. The murineanti-CD3 mAb Muromonab-CD3 (OKT3) was the first mAbapproved as a drug for human use in 1986 for the prevention of rejection in renal, heart, and liver transplants (9). Ittargeted the CD3 subunit of the TCR complex and led torapid elimination of functional T cells. It is now no longerin production because of waning utilization, primarily because of significant side effects related to the mitogenicityassociated with its murine source. This early experienceled to the development of humanized forms of antiTCR–based agents in an effort to reduce this mitogenicityas well as other anti-TCR mAbs that targeted other receptor subunits (10–12). These next generation therapeuticswere subsequently forwarded for the treatment of newonset diabetes and as induction agents in kidney transplantation but have been hindered by ongoing safetyand efficacy issues.
Calcineurin Inhibitors (Cyclosporin and Tacrolimus).After initial TCR binding, a calcineurin-dependent signaling pathway is induced that leads to initial T cell gene transcription necessary for additional activation. Two commonly used calcineurin inhibitors (CNIs; cyclosporin and tacrolimus)and one investigational agent (voclosporin) inhibit the ability of calcineurin to dephosphorylate nuclear factor (NF) of activated T cells (NFAT), required for translocation from cytoplasm to nucleus, and prevent calcineurin-dependent gene transcription (13,14). In the early 1980s, cyclosporin transformed the field of transplantation with dramatic reductions in acute rejection rates, and it has been shown to be effective in a number of immune diseases, including a number of glomerulopathies(15,16). In the late 1990s, tacrolimus was introduced in kidney transplantation and over time, has shown to be more potent in reducing the rates of acute rejection
Costimulation Blockade by CD80/86:CD28 Targeting (Abatacept and Belatacept). The interaction of CD80/86 on the APC with CD28 on the T cell (costimulation) is required for optimal T cell activation. After upregulation and the generation of an effective immune response, the T cell expresses the cell surface molecule cytotoxic T lymphocyte–associated protein 4 (CTLA4), which competitively binds to CD80/86 and downregulates the T cell response. To mimic this downregulatory effect, human IgG heavy chains were linked with CTLA4 to create a fusion protein for clinical use . evelopment of another CTLA4-Ig with significantlyhigher affinity for CD80/86 for transplantation (belatacept)
Costimulation Blockade by CD154:CD40 Targeting (AntiCD40 mAb). The CD154 (also known as CD40L; present on activated T cells): CD40 (on APCs) interaction is a critical step in T cell costimulatory signaling, because this interaction leads to the upregulation of CD80/86 on APCs. Targeting the induced surface molecule CD154 on activated T cells was a focus of drug development until it was recognized that CD154 was also present on platelets, and agents binding this cell surface molecule led to an increasein thrombotic events in both primate and early-phase human trials (29). Attention has, thus, turned to targeting CD40.A number of mAbs against CD40 are in development, with a fully human anti-CD40 (ASKP1240; Astellas) under study in phase 2 clinical trials in kidney transplantation
B Cell Targeting - Anti-CD20 Targeting: Rituximab, Ocrelizumab, Ofatumumab, and Veltuzumab
- Anti-CD22 Targeting: Epratuzumab
Targeting B Cell Differentiation : Belimumab and Atacicept
CD20 is a transmembrane protein present on pre-B and mature B lymphocytes, but it is not present on stem cells, normal plasma cells, or other cell lines. Its role in B cell development includes regulation of activation for cell cycling and B cell differentiation
The first agent to target CD20, rituximab, is a chimeric anti-CD20 mAb (30% murine and 70% human) that leads to B cell depletion through a number of mechanisms, including complement-dependent cytotoxicity, growth arrest, and apoptosis
against plasma cells, and thus, for diseases in which plasma cell maturation and antibody production are felt to be a primary pathogenic mechanism, these previous agents are expected to have limited efficacy. Critical to the function of highly metabolic cells, such as plasma cells, is the ability to regulate the degradation of proteins through the proteasome, which is present in all eukaryotic cells. Inhibition of the proteasome leads to inhibition of cell cycling and induction of apoptosis. Bortezomib is a proteasome inhibitor that was found to be particularly effective in treatment of the plasma cell dyscrasia multiple myeloma and indicated by the FDA forthe treatment of advanced myeloma in 2003
Inhibitionof the complement cascade increases the risk of serious infection from encapsulated bacteria; thus, vaccination for Neisseriameningitis, Streptococcus pneumonia, and Haemophilus influenzatype b should be performed before therapy.
Specific Cytokine Inhibition
IL-2 Receptor Antagonist (Basiliximab).
Targeting TNF-a.
IL-1 Inhibition (Anikinra, Rilonacept, and Canakinumab).
IL-6 Inhibition (Tocilizumab)
IL-17 Inhibition (Secukinumab). Non specific Cytokine Inhibition
Corticosteroids.
Janus Kinase Inhibition (Tofacitinib).
chemokine receptor antagonists include theCCR5 receptor antagonist maraviroc used in the treatmentof HIV, the CXCR4 antagonist plerixafor approved for hematopoietic stem cell mobilization, and the CCR4 humanized mAb mogamulizumab approved for the treatment ofT cell lymphoma. Relevant to nephrology practice, emapticapis an inhibitor to CCL2 (also known as monocyte chemotactic protein 1), which has been studied in phase 1 and 2trials in diabetic nephropathy
antibodies to human lymphocyte antigens have been created by a number of techniques: by immunizing rabbits withhuman thymocytes (Thymoglobulin), immunizing horses with human thymocytes (Atgam), or immunizing rabbits with lymphocytes from a Jurkat T cell leukemia line(Fresenius antithymocyte globulin [ATG]). The resulting IgG fraction from sera is then purified and pasteurized foruse. The resulting antibodies are polyclonal (i.e., all cell surface molecules presented on the infused thymocytesmay lead to a humoral response in the immunized source, and the final preparation contains a vast array of diverse antibodies to various antigens)
Similar to cyclosporin A, sirolimus (previously called rapamycin) was discovered and developed as an antifungal, but it was found to have antineoplastic and immunosuppressive properties, the mechanisms of which were only later appreciated and described as mammalian target of rapamycin (mTOR) pathways
In lymphoid cells, the mTOR pathway leads to cell cycle progression from G1 to S phase and proliferation in responseto cytokine stimulation, including but not limited to IL-2 receptor binding (Figure 4). Inhibitors of mTOR that are clinically available include sirolimus, everolimus, and temsirolimus; owever, mTOR signaling is not isolated to lymphocytes, and this intracellular signaling pathway has been described in monocytes/macrophages, dendritic cells, natural killer cells, and endothelial cells (8). Thus, inhibition of mTOR may be expected to lead to a number of clinically relevant effects related to its antiproliferative, antiviral, anti-inflammatory, and antitumor effects as well as a diverse side effect profile (88). mTOR inhibitors have been evaluated for their ability to inhibitcyst growth in autosomal dominant polycystic kidney disease, with conflicting and modest results in large multicentertrials
The first compound inhibiting mammalian target of rapamycin (mTOR), sirolimus (rapamycin),was identified in the 1970s from a soil bacterium collected on Easter Island (Rapa Nui) (Figure 1) [1].Sirolimus showed antifungal, antitumor, and immunosuppressive effects , wo targets of rapamycin (TOR)1 and TOR2 in the yeast cells in 1991 Sirolimus and its analogues (rapalogues) exert their effects by inhibiting mTORC1 anddownstream phosphorylation of its substrates.