BRM is a successful biopharmaceutical company formed in 1996 by Dennis Guberski and Dr. Arthur Like of the University of Massachusetts Medical School (UMass). Over the course of 20 years the founders developed proprietary diabetes research models under the sponsorship of the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK). BRM licensed this intellectual property portfolio from UMass in 1998 and since that time has used these proprietary tools to become one of the leading sources of customized preclinical contract research specializing in type 1 and type 2 diabetes.
This document provides an overview of immunodeficiency. It defines immunodeficiency and discusses primary and secondary immunodeficiencies. It describes the immune system and its four arms. It discusses various types of primary immunodeficiencies that affect B cells, T cells, phagocytes, and complement pathways. It also discusses common variable immunodeficiency and selective IgA deficiency. Secondary immunodeficiencies caused by AIDS, cancer, diabetes, transplantation, autoimmune diseases, steroids, asplenia, and aging are summarized. Tests for evaluating immunodeficiency and treatment options are briefly outlined.
Malaria vaccines cum antimalaria drugs, by bdollarbernard bahaah
This presentation slides give an upto date information on antimalaria drugs and vaccines. It can be used for academic purpose or some other purpose. It highlights some of the successes and potentials of antimalaria drugs.
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.
Immunosuppression involves reducing the activation of the immune system through medications, surgery, radiation or other means. The document discusses the history of immunosuppression and developments in transplantation including the identification of cortisone and research on the immune system. It outlines current methods of immunosuppression including calcineurin inhibitors, mTOR inhibitors, antimetabolites, corticosteroids, depleting antibodies and fusion proteins. The mechanisms, types and treatment of allograft rejection such as hyperacute, acute and chronic rejection are also summarized.
This document lists over 60 potential factors that are known to cause false positive HIV antibody test results. These factors include naturally occurring antibodies, viral infections like hepatitis B, autoimmune diseases, organ transplants, blood transfusions, and various medical treatments. False positives can also be caused by cross-reactivity with antibodies against other viruses or proteins as well as certain laboratory testing issues. Proper screening and confirmatory testing is necessary to avoid incorrect HIV diagnoses due to false positive initial test results from these many different sources.
CTLA-4: IMMUNE CHECKPOINT BLOCKADE THERAPY,,,, THE 2018 NOBEL PRIZE WINNING STUDY IN THE FIELD OF PHYSIOLOGY/ MEDICINE,,, JOINTLY AWARDED TO JAMES P. ALLISON OF USA and TASAKU HONJU OF JAPAN .
This document summarizes management of liver transplant rejection. It discusses causes of allograft failure including primary nonfunction, vascular complications, and biliary complications. It also discusses the types, causes, clinical picture, diagnosis, prevention and management of rejection. The types of rejection include hyperacute, acute, and chronic rejection. Management involves immunosuppressant drugs like calcineurin inhibitors cyclosporine and tacrolimus, as well as sirolimus. Rejection is diagnosed through liver biopsy and treated initially with corticosteroids or other immunosuppressants.
1. Transplant rejection occurs when the recipient's immune system attacks the transplanted organ or graft, recognizing it as foreign. It can involve cell-mediated immunity or circulating antibodies.
2. Graft versus host disease occurs when immune cells from the donor engraft in the recipient and attack the recipient's body, seeing it as foreign. It is a risk for allogenic stem cell or solid organ transplants from a donor.
3. Treatment for rejection and GVHD involves immunosuppressive drugs like steroids, ATG, mycophenolate, and antibodies targeting immune cells and cytokines.
This document provides an overview of immunodeficiency. It defines immunodeficiency and discusses primary and secondary immunodeficiencies. It describes the immune system and its four arms. It discusses various types of primary immunodeficiencies that affect B cells, T cells, phagocytes, and complement pathways. It also discusses common variable immunodeficiency and selective IgA deficiency. Secondary immunodeficiencies caused by AIDS, cancer, diabetes, transplantation, autoimmune diseases, steroids, asplenia, and aging are summarized. Tests for evaluating immunodeficiency and treatment options are briefly outlined.
Malaria vaccines cum antimalaria drugs, by bdollarbernard bahaah
This presentation slides give an upto date information on antimalaria drugs and vaccines. It can be used for academic purpose or some other purpose. It highlights some of the successes and potentials of antimalaria drugs.
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.
Immunosuppression involves reducing the activation of the immune system through medications, surgery, radiation or other means. The document discusses the history of immunosuppression and developments in transplantation including the identification of cortisone and research on the immune system. It outlines current methods of immunosuppression including calcineurin inhibitors, mTOR inhibitors, antimetabolites, corticosteroids, depleting antibodies and fusion proteins. The mechanisms, types and treatment of allograft rejection such as hyperacute, acute and chronic rejection are also summarized.
This document lists over 60 potential factors that are known to cause false positive HIV antibody test results. These factors include naturally occurring antibodies, viral infections like hepatitis B, autoimmune diseases, organ transplants, blood transfusions, and various medical treatments. False positives can also be caused by cross-reactivity with antibodies against other viruses or proteins as well as certain laboratory testing issues. Proper screening and confirmatory testing is necessary to avoid incorrect HIV diagnoses due to false positive initial test results from these many different sources.
CTLA-4: IMMUNE CHECKPOINT BLOCKADE THERAPY,,,, THE 2018 NOBEL PRIZE WINNING STUDY IN THE FIELD OF PHYSIOLOGY/ MEDICINE,,, JOINTLY AWARDED TO JAMES P. ALLISON OF USA and TASAKU HONJU OF JAPAN .
This document summarizes management of liver transplant rejection. It discusses causes of allograft failure including primary nonfunction, vascular complications, and biliary complications. It also discusses the types, causes, clinical picture, diagnosis, prevention and management of rejection. The types of rejection include hyperacute, acute, and chronic rejection. Management involves immunosuppressant drugs like calcineurin inhibitors cyclosporine and tacrolimus, as well as sirolimus. Rejection is diagnosed through liver biopsy and treated initially with corticosteroids or other immunosuppressants.
1. Transplant rejection occurs when the recipient's immune system attacks the transplanted organ or graft, recognizing it as foreign. It can involve cell-mediated immunity or circulating antibodies.
2. Graft versus host disease occurs when immune cells from the donor engraft in the recipient and attack the recipient's body, seeing it as foreign. It is a risk for allogenic stem cell or solid organ transplants from a donor.
3. Treatment for rejection and GVHD involves immunosuppressive drugs like steroids, ATG, mycophenolate, and antibodies targeting immune cells and cytokines.
Immune check point inhibitors and adverse effectsSCGH ED CME
Immune checkpoint inhibitors can cause immune-related adverse events by removing inhibitory checkpoints and excessively activating the immune system. Common adverse effects include dermatitis in over 50% of patients, enterocolitis in under 20%, hepatitis in under 10%, and endocrinopathies. Symptoms usually onset several months after treatment. Management involves stopping the immune checkpoint inhibitor and administering corticosteroids in most cases. Life-threatening hyperimmunity is possible so consulting the oncologist and other specialists is important.
Macrophage Activation Syndrome (MAS) is caused by excessive activation and multiplication of macrophages and cytotoxic T cells, leading to massive inflammation. In MAS, these immune cells overproduce cytokines that cause a "cytokine storm" and the macrophages begin destroying normal blood cells. This can cause a sudden drop in blood cell counts and become life-threatening. MAS shares similarities to hemophagocytic lymphohistiocytosis, a genetic disease where cytotoxic cells cannot properly kill infected cells. MAS most commonly occurs in systemic juvenile idiopathic arthritis and is diagnosed based on signs of infection, low blood cell counts, high ferritin levels, and liver dysfunction. Treatment involves high-dose corticosteroids,
Biological Goals for Novel Immune CheckpointsPaul D. Rennert
Immune Checkpoint discovery yielded remarkable therapeutics (anti-CTLA4, anti-PD-1) but has more recently stalled out. Here I explore some of the issues the field has uncovered. Presented at the ICI-IO conference in March 2019. F
This document summarizes immunostimulant drugs and immunotherapy. It describes the innate and adaptive immune response and lists immunostimulant microbial products like BCG that boost immune function. Immunostimulant drugs include cytokines, thalidomide, and levamisole. Immunotherapy methods covered are active and passive vaccination, adoptive cell transfer, and cell-based vaccination. The document provides details on specific immunostimulant drugs and their uses and side effects.
This document discusses a case presentation of a 2-year-old boy named D. George who has been brought in by his parents due to concerns about recurrent infections. The boy has a history of frequent upper respiratory infections and ear infections, and has been hospitalized twice for infections. The document provides background on primary immunodeficiency diseases and different aspects of the immune system to help evaluate the child's condition and determine if he has an immunodeficiency.
Paul Frohna is Chief Medical Officer of Bioniz Therapeutics where he oversees clinical and regulatory strategy and operations for the company’s platform of multi-cytokine inhibitors that are in development for alopecia areata, cutaneous T cell lymphoma, and a variety of other autoimmune diseases
Presentation by Michael A. Brehm, Ph.D., Assistant Professor, Diabetes Center of Excellence, Program in Molecular Medicine, University of Massachusetts Medical School, at the JDRF New England Chapter's 14th Annual Spring Research Briefing on Tuesday, April 9, 2013.
This document discusses primary immunodeficiency diseases (PIDs) in children. It begins with an overview of immune system development in children and the typical age-related changes in immunoglobulin levels. It then covers the classification of PIDs including combined immunodeficiencies affecting both B and T cells, predominantly antibody/B cell deficiencies, predominantly T cell deficiencies, and other types. Specific combined immunodeficiencies like severe combined immunodeficiency are described in more detail regarding their genetic causes and clinical manifestations. Secondary causes of recurrent infections in children are also reviewed.
Immune Based Therapies for HIV Richard Trauger, phdSearch For A Cure
Presentation on Immune Based Therapies and their implications for HIV treatment presented at the Fenway Health Center, Boston, MA for the public education conference An End To AIDS - How A State Bill Can Change Everything conducted by SearchForACure.org, the Fenway Health
Center, and the MA Dept. of Public Health
The document summarizes the evolution of malarial drugs from the first drug quinine derived from tree bark in the 1800s to current efforts to develop new drugs. It describes the malaria parasite life cycle and challenges in treating different species and stages. A variety of drug classes have been developed that target various stages, from blood stages to dormant liver stages. However, resistance develops rapidly when drugs are used as monotherapy. Current efforts focus on new drug discovery, revisiting old drugs, and exploring drugs from other fields. Combination therapies and targeting transmission stages may help eliminate malaria.
IVIg has several mechanisms of action including modulating B cells, T cells, complement, cytokines, cell migration, and superantigens. It can inhibit antibody production, B cell differentiation, and the formation of membrane attack complexes. IVIg also reduces pro-inflammatory cytokines and modulates T cell responses, endothelial cell function, and chemokine receptors. The specific mechanisms involved depend on the autoimmune disease being treated.
The immunotherapy of cancer: past, present & the next frontierThe ScientifiK
The immunotherapy of cancer has progressed through several phases from past to present:
1) Early attempts focused on vaccines and cytokines with limited success and understanding.
2) Anti-CTLA4 therapy showed the first durable responses in metastatic melanoma.
3) Anti-PD-1 therapy was found to be superior to anti-CTLA4, with better responses and tolerability. This established that overcoming immunosuppression is key.
4) Combination strategies are now the focus, exploring combinations of immunotherapies or with targeted/chemotherapies to extend responses. Biomarkers like PD-L1 are being used to identify patients most likely to benefit from anti-PD-1
The document discusses drug resistance against malaria parasites. It covers the life cycle of malaria parasites, symptoms of malaria, common areas where malaria occurs, and how malaria is transmitted. It then discusses various antimalarial drugs used for treatment, including mechanisms of action and resistance. Resistance occurs through mutations in genes encoding for drug targets in the parasite or efflux pumps. Maintaining compliance with combination drug therapies can help delay the emergence of resistance.
The document provides information on antiretroviral drugs used to treat HIV/AIDS. It discusses how HIV works, how it is transmitted, the stages of HIV infection, and how antiretroviral drugs target different stages of the viral lifecycle. It also summarizes several commonly used antiretroviral drugs, including their mechanisms of action, contraindications, warnings, and adverse effects.
Elite controllers of HIV infection are able to naturally control HIV through cell-mediated immunity without antiretroviral therapy. Key factors contributing to their elite status include certain HLA polymorphisms, highly functional HIV-specific CD8+ T cells, strong mucosal immunity, beneficial NK cell interactions with HLA alleles, and balanced regulatory T cell and Th17 cell responses that prevent immune activation. Their immune responses also feature polyfunctional CD8+ T cells, HIV-specific CD4+ T cell responses, and antimicrobial factors like defensins from dendritic cells that inhibit HIV at multiple stages of its life cycle.
ProImmune Antigen Characterization Summit Johanna Olweusamandacturner
Johanna Olweus, Dept Immunology, Institute for Cancer Research, Radiumshospitalet, Oslo, Norway, presents at the ProImmune Antigen Characterization and Biomarker Discovery Summit, January 2011.
Cancer immunotherapy: finding allies among the "allos"
Mecanismos moleculares relacionados con la fisiopatología de la diabetes mel...Angelo Venegas Vera
La resistencia a la insulina y la secreción anormal de insulina son los principales componentes de la diabetes mellitus tipo 2. El documento describe varios genes relacionados con un mayor riesgo de desarrollar diabetes tipo 2, como los genes IRS1, CAPN10 y PPARG2, los cuales están involucrados en la disfunción de las células beta pancreáticas y la respuesta a la insulina. También se mencionan otros factores moleculares como el GLP-1 y sus efectos en la homeostasis de la glucosa.
This document provides information on carbohydrate counting for diabetes management. It defines carbohydrate counting as a method to calculate grams of carbohydrates consumed. The goals are to maintain consistent carb intake, increase dietary flexibility, and manage blood glucose. Carbohydrates are broken down into glucose and absorbed into the bloodstream. Foods like fruits, starches, grains and milk contain carbs. Counting carbs involves identifying carb-containing foods and determining servings equal to 15 grams of carbs. Tools like mobile apps, food labels and visual guides can help estimate carb amounts. Physical activity also impacts blood sugar, so carb intake may need adjustment based on activity level and intensity.
Use of Glycated Hemoglobin (A1C) in the Diagnosis ofType 2 Diabetes Mellitus...Shahid Nawaz
The Canadian Diabetes Association reviewed the use of glycated hemoglobin (A1C) for diagnosing diabetes and recommends adding it as a diagnostic criterion. An A1C level of 6.5% or higher confirms a diagnosis of diabetes. A1C testing has advantages over glucose tests as it can be done at any time and reflects average glucose levels over several months. However, A1C levels may be affected by certain medical conditions and ethnic groups. The document provides guidelines on using A1C for diagnosis and confirms the use of traditional glucose tests remain valid options.
Immune check point inhibitors and adverse effectsSCGH ED CME
Immune checkpoint inhibitors can cause immune-related adverse events by removing inhibitory checkpoints and excessively activating the immune system. Common adverse effects include dermatitis in over 50% of patients, enterocolitis in under 20%, hepatitis in under 10%, and endocrinopathies. Symptoms usually onset several months after treatment. Management involves stopping the immune checkpoint inhibitor and administering corticosteroids in most cases. Life-threatening hyperimmunity is possible so consulting the oncologist and other specialists is important.
Macrophage Activation Syndrome (MAS) is caused by excessive activation and multiplication of macrophages and cytotoxic T cells, leading to massive inflammation. In MAS, these immune cells overproduce cytokines that cause a "cytokine storm" and the macrophages begin destroying normal blood cells. This can cause a sudden drop in blood cell counts and become life-threatening. MAS shares similarities to hemophagocytic lymphohistiocytosis, a genetic disease where cytotoxic cells cannot properly kill infected cells. MAS most commonly occurs in systemic juvenile idiopathic arthritis and is diagnosed based on signs of infection, low blood cell counts, high ferritin levels, and liver dysfunction. Treatment involves high-dose corticosteroids,
Biological Goals for Novel Immune CheckpointsPaul D. Rennert
Immune Checkpoint discovery yielded remarkable therapeutics (anti-CTLA4, anti-PD-1) but has more recently stalled out. Here I explore some of the issues the field has uncovered. Presented at the ICI-IO conference in March 2019. F
This document summarizes immunostimulant drugs and immunotherapy. It describes the innate and adaptive immune response and lists immunostimulant microbial products like BCG that boost immune function. Immunostimulant drugs include cytokines, thalidomide, and levamisole. Immunotherapy methods covered are active and passive vaccination, adoptive cell transfer, and cell-based vaccination. The document provides details on specific immunostimulant drugs and their uses and side effects.
This document discusses a case presentation of a 2-year-old boy named D. George who has been brought in by his parents due to concerns about recurrent infections. The boy has a history of frequent upper respiratory infections and ear infections, and has been hospitalized twice for infections. The document provides background on primary immunodeficiency diseases and different aspects of the immune system to help evaluate the child's condition and determine if he has an immunodeficiency.
Paul Frohna is Chief Medical Officer of Bioniz Therapeutics where he oversees clinical and regulatory strategy and operations for the company’s platform of multi-cytokine inhibitors that are in development for alopecia areata, cutaneous T cell lymphoma, and a variety of other autoimmune diseases
Presentation by Michael A. Brehm, Ph.D., Assistant Professor, Diabetes Center of Excellence, Program in Molecular Medicine, University of Massachusetts Medical School, at the JDRF New England Chapter's 14th Annual Spring Research Briefing on Tuesday, April 9, 2013.
This document discusses primary immunodeficiency diseases (PIDs) in children. It begins with an overview of immune system development in children and the typical age-related changes in immunoglobulin levels. It then covers the classification of PIDs including combined immunodeficiencies affecting both B and T cells, predominantly antibody/B cell deficiencies, predominantly T cell deficiencies, and other types. Specific combined immunodeficiencies like severe combined immunodeficiency are described in more detail regarding their genetic causes and clinical manifestations. Secondary causes of recurrent infections in children are also reviewed.
Immune Based Therapies for HIV Richard Trauger, phdSearch For A Cure
Presentation on Immune Based Therapies and their implications for HIV treatment presented at the Fenway Health Center, Boston, MA for the public education conference An End To AIDS - How A State Bill Can Change Everything conducted by SearchForACure.org, the Fenway Health
Center, and the MA Dept. of Public Health
The document summarizes the evolution of malarial drugs from the first drug quinine derived from tree bark in the 1800s to current efforts to develop new drugs. It describes the malaria parasite life cycle and challenges in treating different species and stages. A variety of drug classes have been developed that target various stages, from blood stages to dormant liver stages. However, resistance develops rapidly when drugs are used as monotherapy. Current efforts focus on new drug discovery, revisiting old drugs, and exploring drugs from other fields. Combination therapies and targeting transmission stages may help eliminate malaria.
IVIg has several mechanisms of action including modulating B cells, T cells, complement, cytokines, cell migration, and superantigens. It can inhibit antibody production, B cell differentiation, and the formation of membrane attack complexes. IVIg also reduces pro-inflammatory cytokines and modulates T cell responses, endothelial cell function, and chemokine receptors. The specific mechanisms involved depend on the autoimmune disease being treated.
The immunotherapy of cancer: past, present & the next frontierThe ScientifiK
The immunotherapy of cancer has progressed through several phases from past to present:
1) Early attempts focused on vaccines and cytokines with limited success and understanding.
2) Anti-CTLA4 therapy showed the first durable responses in metastatic melanoma.
3) Anti-PD-1 therapy was found to be superior to anti-CTLA4, with better responses and tolerability. This established that overcoming immunosuppression is key.
4) Combination strategies are now the focus, exploring combinations of immunotherapies or with targeted/chemotherapies to extend responses. Biomarkers like PD-L1 are being used to identify patients most likely to benefit from anti-PD-1
The document discusses drug resistance against malaria parasites. It covers the life cycle of malaria parasites, symptoms of malaria, common areas where malaria occurs, and how malaria is transmitted. It then discusses various antimalarial drugs used for treatment, including mechanisms of action and resistance. Resistance occurs through mutations in genes encoding for drug targets in the parasite or efflux pumps. Maintaining compliance with combination drug therapies can help delay the emergence of resistance.
The document provides information on antiretroviral drugs used to treat HIV/AIDS. It discusses how HIV works, how it is transmitted, the stages of HIV infection, and how antiretroviral drugs target different stages of the viral lifecycle. It also summarizes several commonly used antiretroviral drugs, including their mechanisms of action, contraindications, warnings, and adverse effects.
Elite controllers of HIV infection are able to naturally control HIV through cell-mediated immunity without antiretroviral therapy. Key factors contributing to their elite status include certain HLA polymorphisms, highly functional HIV-specific CD8+ T cells, strong mucosal immunity, beneficial NK cell interactions with HLA alleles, and balanced regulatory T cell and Th17 cell responses that prevent immune activation. Their immune responses also feature polyfunctional CD8+ T cells, HIV-specific CD4+ T cell responses, and antimicrobial factors like defensins from dendritic cells that inhibit HIV at multiple stages of its life cycle.
ProImmune Antigen Characterization Summit Johanna Olweusamandacturner
Johanna Olweus, Dept Immunology, Institute for Cancer Research, Radiumshospitalet, Oslo, Norway, presents at the ProImmune Antigen Characterization and Biomarker Discovery Summit, January 2011.
Cancer immunotherapy: finding allies among the "allos"
Mecanismos moleculares relacionados con la fisiopatología de la diabetes mel...Angelo Venegas Vera
La resistencia a la insulina y la secreción anormal de insulina son los principales componentes de la diabetes mellitus tipo 2. El documento describe varios genes relacionados con un mayor riesgo de desarrollar diabetes tipo 2, como los genes IRS1, CAPN10 y PPARG2, los cuales están involucrados en la disfunción de las células beta pancreáticas y la respuesta a la insulina. También se mencionan otros factores moleculares como el GLP-1 y sus efectos en la homeostasis de la glucosa.
This document provides information on carbohydrate counting for diabetes management. It defines carbohydrate counting as a method to calculate grams of carbohydrates consumed. The goals are to maintain consistent carb intake, increase dietary flexibility, and manage blood glucose. Carbohydrates are broken down into glucose and absorbed into the bloodstream. Foods like fruits, starches, grains and milk contain carbs. Counting carbs involves identifying carb-containing foods and determining servings equal to 15 grams of carbs. Tools like mobile apps, food labels and visual guides can help estimate carb amounts. Physical activity also impacts blood sugar, so carb intake may need adjustment based on activity level and intensity.
Use of Glycated Hemoglobin (A1C) in the Diagnosis ofType 2 Diabetes Mellitus...Shahid Nawaz
The Canadian Diabetes Association reviewed the use of glycated hemoglobin (A1C) for diagnosing diabetes and recommends adding it as a diagnostic criterion. An A1C level of 6.5% or higher confirms a diagnosis of diabetes. A1C testing has advantages over glucose tests as it can be done at any time and reflects average glucose levels over several months. However, A1C levels may be affected by certain medical conditions and ethnic groups. The document provides guidelines on using A1C for diagnosis and confirms the use of traditional glucose tests remain valid options.
There are three main types of diabetes: Type 1, Type 2, and gestational diabetes. Type 1 diabetes occurs when the immune system attacks and destroys the insulin-producing cells in the pancreas. It accounts for 5-10% of diabetes cases and treatment requires lifelong insulin administration via injections or pump. Psychological impacts of Type 1 diabetes can include depression, stress, low self-esteem, and social anxiety. Higher levels of depression, stress, and social anxiety are associated with poorer diabetes management and control. Social support from family, friends, and medical providers is important for helping adolescents cope with Type 1 diabetes.
This document provides an introduction to nutrition and proteins. It defines nutrition as the science of food and its relationship to health. Nutrients include proteins, carbohydrates, fats, vitamins and minerals. Proteins are composed of amino acids and are important for growth, tissue repair, enzyme production and other bodily functions. Common sources of protein include foods from animals like meat and dairy, and plants like pulses, cereals and nuts. The document also outlines protein and nutrient requirements for different age groups and discusses protein metabolism and deficiency diseases.
Este documento describe la fisiopatología de la diabetes mellitus tipo 1. Explica que es una enfermedad autoinmune causada por la destrucción de las células beta del páncreas que producen insulina. Los factores genéticos como los antígenos HLA y los ambientales como ciertos virus pueden contribuir al desarrollo de la enfermedad. La destrucción de las células beta ocurre por un proceso autoinmune mediado por citoquinas e inmunoglobulinas que atacan antígenos de las células beta.
This document discusses Type 1 Diabetes, its causes, symptoms, diagnosis, and treatment. Type 1 Diabetes is an autoimmune disease where the body's immune system attacks and destroys the insulin-producing beta cells in the pancreas. Common symptoms include frequent urination, excessive thirst, hunger, weight loss, fatigue, and blurred vision. It is diagnosed through blood tests showing high blood glucose levels. While there is no cure, maintaining normal blood sugar levels through insulin treatment and diet can help people with Type 1 Diabetes live normal lives, though regular monitoring is needed to prevent potential complications.
Type 1 diabetes mellitus is an autoimmune disease characterized by the destruction of insulin-producing beta cells in the pancreas. It accounts for approximately 10% of diabetes cases. The incidence of type 1 diabetes is increasing worldwide. Genetic factors confer susceptibility, but environmental triggers such as certain viral infections are also implicated in disease pathogenesis. The destruction of beta cells is mediated by an immune response involving T cells and autoantibodies. Over time this leads to absolute insulin deficiency. Type 1 diabetes is typically treated with lifelong insulin therapy.
1. Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia resulting from defects in insulin secretion or action.
2. There are several types of diabetes including type 1, type 2, gestational diabetes, and other rare forms.
3. Type 1 diabetes is an autoimmune disease where the immune system attacks and destroys the insulin-producing beta cells in the pancreas. It accounts for approximately 10% of diabetes cases.
The document discusses the pathophysiology of AIDS, autoimmune diseases, and hypersensitivity reactions. It provides details on the diagnosis, pathogenesis, and treatment of AIDS, describing how HIV infects and destroys CD4 cells, leading to immunosuppression. Mechanisms of several autoimmune diseases like Graves' disease and rheumatoid arthritis are examined, focusing on how lymphocytes fail to recognize the body's own cells and tissues, resulting in autoimmune responses.
The passage discusses the pathogenesis of diabetes complications. It states that glucose is highly reactive and damages tissues when insulin is deficient. The complications are divided into short term metabolic issues like diabetic ketoacidosis and long term angiopathy issues involving the microvasculature and macrovasculature. The pathogenesis involves excess glucose damaging insulin independent tissues through mechanisms like increased sorbitol, activation of protein kinase C, and formation of advanced glycation end products.
1. Biomedical Research Models, Inc. developed an inbred rat strain called the Multiple Autoimmune Disease (MAD) rat that is susceptible to developing multiple autoimmune diseases. This study characterized the MAD rat model of type 1 diabetes (T1D).
2. The study found that Toll-like receptor (TLR) ligands like polyinosinic-polycytidylic acid (poly I:C) could reliably induce T1D in MAD rats, while the TLR ligand CpG did not induce diabetes. Poly I:C induced T1D in a dose-dependent manner.
3. T1D could be induced in MAD rats up to 34 days of age but the penetrance diminished at
This document discusses infections in immunocompromised patients. It begins by describing the various microbes that can cause infection, including bacteria, parasites, fungi and viruses. It then discusses the different types of underlying immune defects that determine infection risk, such as humoral versus cell-mediated defects. The document outlines various factors that influence the risk of infection, including the level of immunosuppression, transplant organ, graft-versus-host disease, exposures, and immune-modulating medications. It presents several case examples of infections in immunocompromised patients.
This document summarizes leishmaniasis, a parasitic disease caused by Leishmania parasites and transmitted by sand flies. It is endemic in parts of Africa, Asia, Europe, and Latin America. There are several clinical forms including visceral leishmaniasis (the most serious form affecting internal organs), cutaneous leishmaniasis (affecting skin), and mucocutaneous leishmaniasis (affecting skin and mucous membranes). Symptoms, diagnosis, treatment, and complications are described for each form. Visceral leishmaniasis is usually fatal without treatment and can cause long-term immunity after recovery.
MDR/XDR TB poses a serious global public health threat. MDR TB is resistant to rifampicin and isoniazid, while XDR TB is also resistant to fluoroquinolones and second-line injectable drugs. Factors contributing to drug resistance include improper treatment, non-compliance, and exposure to drug-resistant TB patients. Diagnosis and treatment of drug-resistant TB is challenging due to long turnaround times for drug susceptibility testing and toxic second-line drug regimens of up to 2 years. Proper diagnosis, treatment monitoring, and surgical intervention where needed are critical to control the spread of drug-resistant TB.
This document discusses the pathogenesis of various types of diabetes mellitus. It begins with an overview of definitions, epidemiology, diagnosis, and classification of diabetes. It then discusses the regulation of glucose homeostasis by insulin and the pathogenesis of type 1 and type 2 diabetes in more depth. For type 1 diabetes, it describes the genetic susceptibility factors, environmental triggers, and mechanisms of beta cell destruction by the immune system. For type 2 diabetes, it discusses genetic and environmental risk factors like obesity, and the key metabolic defects of insulin resistance and beta cell dysfunction that characterize the disease. It also reviews genetic defects that can cause diabetes.
The document discusses various primary immunodeficiency syndromes including T cell deficiencies like DiGeorge syndrome and X-linked hyper IgM syndrome. It also covers combined B- and T-cell immunodeficiencies such as severe combined immunodeficiency disease (SCID) as well as acquired immunodeficiency diseases and diseases of immune dysregulation including hemophagocytic lymphohistiocytosis (HLH), X-linked lymphoproliferative syndrome, and HIV/AIDS. Treatment options discussed include bone marrow transplantation, gene therapy, and highly active antiretroviral therapy. Outcomes for children with immunodeficiencies depend on timely diagnosis, adequate treatment and surveillance, and the underlying disease.
Combined T cells And Bcell Deficiency - SCIDGirish Kumar K
- Severe combined immunodeficiency (SCID) is a genetic disorder characterized by the absence of both T cells and B cells, resulting in impaired cell-mediated and humoral immunity.
- SCID can be caused by defects in cytokine receptors, genes involved in lymphocyte development and differentiation, or enzymes involved in purine metabolism.
- Patients with SCID present with recurrent and persistent infections by various pathogens. The diagnosis of SCID is suggested by very low lymphocyte counts and confirmed by functional tests of lymphocytes. Bone marrow transplantation or gene therapy can cure SCID in many cases.
This document discusses tuberculosis (TB), including its epidemiology, causative agent, pathogenesis, diagnosis, and treatment. Some key points:
- TB is caused by the bacterium Mycobacterium tuberculosis and spreads through airborne droplets when infected individuals cough, sneeze, talk or spit. It can infect the lungs (pulmonary TB) or other organs (extra-pulmonary TB).
- Diagnosis involves microscopic examination of sputum samples for acid-fast bacilli, culture testing, and more recently PCR and gene-based tests. India's Revised National Tuberculosis Control Programme (RNTCP) is based on the WHO DOTS strategy to improve cure rates and case detection.
OHH Unit 3 Biological and ergonomical hazards 1.pptABHINANDHKA1
Biological and ergonomical hazards in an occupation. ergonomics means rules of work. In this work is fit to the worker instead of fitting the worker to a job.
Biological agents are bacteria, Fungi, Prions and Virus etc. By implementing the hierarchy of control measures, it can be mitigated upto an optimal limit,
India has a high burden of diabetes, with over 61 million diabetic patients. Type 1 diabetes incidence is increasing, with around 78,000 children developing it annually. Genetic and environmental factors contribute to type 1 diabetes risk. Vaccination for type 1 diabetes aims to induce regulatory T-cells to prevent immune destruction of insulin-producing beta cells. While antigens and clinical trials show promise, challenges remain in identifying biomarkers, developing animal models, and determining optimal combinations or adjunct therapies.
This document provides information on HIV/AIDS, including its history, epidemiology, definition, characteristics, transmission, pathogenesis, clinical manifestations by system, opportunistic infections, diagnosis, and treatment. Some key points are:
- HIV was first identified in the 1980s and has since infected over 38 million people worldwide. India has the third largest epidemic with over 2 million cases.
- Advanced HIV is defined as CD4 count <350 or WHO stage 3/4 disease. AIDS is defined as CD4 <200 or WHO stage 4 disease.
- HIV is transmitted sexually, through blood/blood products, or mother-to-child. It primarily targets CD4 cells and causes immunosuppression.
- Clinical
Similar to Type 1 Diabetes Pre-Clinical Research (20)
BRM has developed proprietary rat strains which are translatable models for the characterization of type 1 and type 2 diabetes as well as immune-related diseases. Its technical competencies include design and conducting studies in autoimmunity (type 1 diabetes, lupus, Rheumatoid Arthritis and Multiple Sclerosis), metabolic disease (type 2 diabetes, metabolic syndrome, obesity, dyslipidemia, liver and kidney function), virology, neurodegenerative diseases, diabetic complications (retinopathy, neuropathy, nephropathy, and encephalopathy including Alzheimer’s disease) specialized animal model development and the production and care of multiple species.
BRM is a successful biopharmaceutical company formed in 1996 by Dennis Guberski and Dr. Arthur Like of the University of Massachusetts Medical School (UMass). Over the course of 20 years the founders developed proprietary diabetes research models under the sponsorship of the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK). BRM licensed this intellectual property portfolio from UMass in 1998 and since that time has used these proprietary tools to become one of the leading sources of customized preclinical contract research specializing in type 1 and type 2 diabetes.
- The MAD rat strain was developed to be susceptible to multiple autoimmune diseases. This study characterized the susceptibility of MAD rats to adjuvant-induced arthritis (AIA), a model of rheumatoid arthritis.
- MAD rats were found to be highly sensitive to developing inflammatory arthritis after AIA induction. Symptoms progressed from small to large joints similarly to human rheumatoid arthritis.
- A novel finding was the appearance of skin nodules coinciding with arthritis, resembling early rheumatoid nodules in humans. Treatment with dexamethasone inhibited arthritis while methotrexate partially inhibited it.
BRM's Capabilities in Virology, Viral Immunology and Pathology: HSV-1, HSV-2, Influenza, RSV, LCMV, and CMV. For more information, please visit our website at www.BRMCRO.com.
"The LEW.1WR1 rat is the only model so far that exhibits a low incidence of spontaneous diabetes that can be increased by perturbation. By far the most extensively studied of the models are the two BB rat strains, but all of them have provided interesting information. There are to date no rat models based on the insertion of transgenes, though genetic complementation has been used elegantly to identify the genetic defect in Komeda rats."
BRM has experience developing preclinical models for systemic lupus erythematosus (SLE) including the NZB/W F1 and MRL/lpr mouse models. These mice develop anti-dsDNA antibodies and progressive glomerulonephritis similar to human SLE. BRM has validated methods for measuring disease outcomes like proteinuria, antibody levels, immune cell profiles, and histopathology in these mice. They have also demonstrated prevention and remission of lupus symptoms in NZB/W F1 mice using treatments like anti-CD40L monoclonal antibody.
Authoring a personal GPT for your research and practice: How we created the Q...Leonel Morgado
Thematic analysis in qualitative research is a time-consuming and systematic task, typically done using teams. Team members must ground their activities on common understandings of the major concepts underlying the thematic analysis, and define criteria for its development. However, conceptual misunderstandings, equivocations, and lack of adherence to criteria are challenges to the quality and speed of this process. Given the distributed and uncertain nature of this process, we wondered if the tasks in thematic analysis could be supported by readily available artificial intelligence chatbots. Our early efforts point to potential benefits: not just saving time in the coding process but better adherence to criteria and grounding, by increasing triangulation between humans and artificial intelligence. This tutorial will provide a description and demonstration of the process we followed, as two academic researchers, to develop a custom ChatGPT to assist with qualitative coding in the thematic data analysis process of immersive learning accounts in a survey of the academic literature: QUAL-E Immersive Learning Thematic Analysis Helper. In the hands-on time, participants will try out QUAL-E and develop their ideas for their own qualitative coding ChatGPT. Participants that have the paid ChatGPT Plus subscription can create a draft of their assistants. The organizers will provide course materials and slide deck that participants will be able to utilize to continue development of their custom GPT. The paid subscription to ChatGPT Plus is not required to participate in this workshop, just for trying out personal GPTs during it.
PPT on Direct Seeded Rice presented at the three-day 'Training and Validation Workshop on Modules of Climate Smart Agriculture (CSA) Technologies in South Asia' workshop on April 22, 2024.
Mending Clothing to Support Sustainable Fashion_CIMaR 2024.pdfSelcen Ozturkcan
Ozturkcan, S., Berndt, A., & Angelakis, A. (2024). Mending clothing to support sustainable fashion. Presented at the 31st Annual Conference by the Consortium for International Marketing Research (CIMaR), 10-13 Jun 2024, University of Gävle, Sweden.
Travis Hills of MN is Making Clean Water Accessible to All Through High Flux ...Travis Hills MN
By harnessing the power of High Flux Vacuum Membrane Distillation, Travis Hills from MN envisions a future where clean and safe drinking water is accessible to all, regardless of geographical location or economic status.
(June 12, 2024) Webinar: Development of PET theranostics targeting the molecu...Scintica Instrumentation
Targeting Hsp90 and its pathogen Orthologs with Tethered Inhibitors as a Diagnostic and Therapeutic Strategy for cancer and infectious diseases with Dr. Timothy Haystead.
Sexuality - Issues, Attitude and Behaviour - Applied Social Psychology - Psyc...PsychoTech 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!
Describing and Interpreting an Immersive Learning Case with the Immersion Cub...Leonel Morgado
Current descriptions of immersive learning cases are often difficult or impossible to compare. This is due to a myriad of different options on what details to include, which aspects are relevant, and on the descriptive approaches employed. Also, these aspects often combine very specific details with more general guidelines or indicate intents and rationales without clarifying their implementation. In this paper we provide a method to describe immersive learning cases that is structured to enable comparisons, yet flexible enough to allow researchers and practitioners to decide which aspects to include. This method leverages a taxonomy that classifies educational aspects at three levels (uses, practices, and strategies) and then utilizes two frameworks, the Immersive Learning Brain and the Immersion Cube, to enable a structured description and interpretation of immersive learning cases. The method is then demonstrated on a published immersive learning case on training for wind turbine maintenance using virtual reality. Applying the method results in a structured artifact, the Immersive Learning Case Sheet, that tags the case with its proximal uses, practices, and strategies, and refines the free text case description to ensure that matching details are included. This contribution is thus a case description method in support of future comparative research of immersive learning cases. We then discuss how the resulting description and interpretation can be leveraged to change immersion learning cases, by enriching them (considering low-effort changes or additions) or innovating (exploring more challenging avenues of transformation). The method holds significant promise to support better-grounded research in immersive learning.
When I was asked to give a companion lecture in support of ‘The Philosophy of Science’ (https://shorturl.at/4pUXz) I decided not to walk through the detail of the many methodologies in order of use. Instead, I chose to employ a long standing, and ongoing, scientific development as an exemplar. And so, I chose the ever evolving story of Thermodynamics as a scientific investigation at its best.
Conducted over a period of >200 years, Thermodynamics R&D, and application, benefitted from the highest levels of professionalism, collaboration, and technical thoroughness. New layers of application, methodology, and practice were made possible by the progressive advance of technology. In turn, this has seen measurement and modelling accuracy continually improved at a micro and macro level.
Perhaps most importantly, Thermodynamics rapidly became a primary tool in the advance of applied science/engineering/technology, spanning micro-tech, to aerospace and cosmology. I can think of no better a story to illustrate the breadth of scientific methodologies and applications at their best.
ESA/ACT Science Coffee: Diego Blas - Gravitational wave detection with orbita...Advanced-Concepts-Team
Presentation in the Science Coffee of the Advanced Concepts Team of the European Space Agency on the 07.06.2024.
Speaker: Diego Blas (IFAE/ICREA)
Title: Gravitational wave detection with orbital motion of Moon and artificial
Abstract:
In this talk I will describe some recent ideas to find gravitational waves from supermassive black holes or of primordial origin by studying their secular effect on the orbital motion of the Moon or satellites that are laser ranged.
ESR spectroscopy in liquid food and beverages.pptxPRIYANKA PATEL
With increasing population, people need to rely on packaged food stuffs. Packaging of food materials requires the preservation of food. There are various methods for the treatment of food to preserve them and irradiation treatment of food is one of them. It is the most common and the most harmless method for the food preservation as it does not alter the necessary micronutrients of food materials. Although irradiated food doesn’t cause any harm to the human health but still the quality assessment of food is required to provide consumers with necessary information about the food. ESR spectroscopy is the most sophisticated way to investigate the quality of the food and the free radicals induced during the processing of the food. ESR spin trapping technique is useful for the detection of highly unstable radicals in the food. The antioxidant capability of liquid food and beverages in mainly performed by spin trapping technique.
2. Diabetes Mellitus is Not a
Single Disease
ABSOLUTE
INSULIN
DEFICIENCY
TYPE 2 (NIDDM)
MODY
(Maturity Onset
Diabetes of the Young) TYPE 1b (IDDM)
TYPE 1a (IDDM)
LADA
(Latent Autoimmune
Diabetes in Adults)
RELATIVE
INSULIN
DEFICIENCY
DIABETES
SPECTRUM
HYPERGLYCEMIA
4. Genetics, Environment and T1A Diabetes
• The environment seems to be important in
human T1Diabetes
• Monozygotic twin with the disorder: ~50%
concordance
• The incidence of type 1 diabetes is increasing
• Finland, Sardinia, the Baltic States, Poland
• Is this genetics, environment, or both?
5. Candidate Environmental Agents
• Toxins
• e.g. nitrosoureas
• Diet
• e.g. cow milk protein
• Toll-like receptor ligands (e.g. LPS)
• Infection
• e.g. mumps, rubella, measles
• “Hygiene”
6. Epidemiology of Type 1A Diabetes
• Seasonal Variation
• Lower incidence in Finnish boys in June with a
spike in November-December
• Correlations of Type 1A diabetes onset with:
• Coxsackie B
• Mumps
• Rubella
• CMV,EBV, Retrovirus are less clearly associated
7. Viruses and Human T1D
• Epidemiological studies suggest association
• “Causality” is unproven
• No evidence of direct viral infection of islets
• Other putative mechanisms include:
• Bystander T-cell activation
• Molecular mimicry
• T cell activation by viral superantigen
12. The Diabetes Prone BB Rat
• Oldest Model of Spontaneous Type 1
Diabetes
• Evidence for Autoimmunity
• Pancreatic insulitis
• Class II MHC associated (RT1u)
• T cell dependent
• Preventable by immunosuppression
• Transferable to adoptive recipients
• Autoantibodies
• Lymphocytic thyroiditis
13. Tolerance in the Presence of
Genetic Susceptibility
A
AA
R
β
Autoimmunity
CD4+ART2+ Treg Transfusion
A
A R
R
RA
β
Tolerance
BBDP/Wor Rat
14. Environmental Considerations
• Viruses have been shown to alter the tempo of diabetes among
BBDP/Wor rats
• Some viruses delay the onset of diabetes
• (SDAV,LCMV and Sendai)
• Others accelerate (RCMV)
• Incidence of diabetes in virus free colony ~85%
• In BBDR rats virus can induce resistant rats to develop
autoimmune disease
• Hashimoto’s Thyroiditis
• Type 1 Diabetes
• No spontaneous diabetes among virus free rats
15. • Parvovirus in the BBDR Rat
• Kilham’s rat virus (KRV)
• Single stranded DNA virus
• 3 overlapping structural proteins, VP1, VP2 and VP3
• 2 overlapping nonstructural proteins, NS1 and NS2
• Parvovirus B19 associated with autoimmune
rheumatoid arthritis in humans (Simpson et al 1984
Science 223:1425)
• BBDR rats are an animal model for Rheumatoid
Arthritis (Watson et al. 1990 J.Exp.Med 172:1331)
16. Susceptibility and Mechanism
of Parvovirus Induced Diabetes
• Protocol
• 21-25 day old male and female animals
• 1 x 107 PFU KRV i.p. on day 0
• Monitor plasma glucose and body weight
• Experimental data demonstrates that the virus
• working through TLR-9
• creates and immune imbalance
17. Diabetes in Parvovirus (KRV)
infected BBDR Rats
Days After Infection
0 10 20 30 40
CumulativeDiabetes-Free
Survival(%)
0
20
40
60
80
100
KRV Alone (N=24)
18. Immunological Balance
Tolerance and Autoimmunity in BB rats
A
AA
R
β
Autoimmunity
CD4+ART2+ Transfusion
“Treg” Cells
A
A R
R
RA
β
Tolerance
ART2+ Treg Depletion
Virus Infection
BBDP BBDR
TLR Ligation
19. Diabetes in Parvovirus vs. H-1
Infected BBDR Rats
Days After Infection
0 10 20 30 40
CumulativeDiabetes-Free
Survival(%)
0
20
40
60
80
100
KRV Alone (N=24)
H-1 Alone (N=6)
21. BBDR Summary 1
• BBDR rats show virus-specific susceptibility
to the triggering of T1D
• Virus-induced Treg modulation may be one
mechanism of viral induction of diabetes
22. Innate Immune Responses
Trigger T1D in Rats
• Adaptive Immunity
• Pathogen-specific defense
• Involves the MHC and T Cell Receptor
• Long lasting immunity
• Innate Immunity
• First line of defense
• Activation of immune responses through toll-like
receptors (TLRs) that recognize pathogen
associated molecular patterns (PAMPs)
23. Hypothesis and Method
• Innate immune responses produced by TLR
ligation will induce T1D in resistant rats
• Polyinosinic:polycytidylic acid (poly I:C)
– A synthetic double-stranded polyribonucleotide
– Ligand of toll-like receptor 3 (TLR3)
– Strong inducer of cytokines
– A simple tool for testing multiple strains
24. TLR3 Ligation Can Induce Diabetes
Strain RT1 B/D Diabetes
MAD (LEW.1WR1) u 22/22
BBDR u 20%-100%
PVG.RT1u u 26/30
LEW.1AR1 u 4/20
PVG.R8 u 6/9
LEW.1AR1-iddm u 0/10
WF u 1/22
WAG u 1/9
Treatment with poly I:C alone for 2-3 weeks; insulitis data concordant
Data from Ellerman and Like, Tirabassi et al., and Hedrich et al.
25. Synergy: Diabetes After Virus Infection
and Activation of Innate Immunity
Days After Infection
0 10 20 30 40
CumulativeDiabetes-Free
Survival(%)
0
20
40
60
80
100
KRV Alone (N=24)
KRV after Poly I:C (N=6)
H-1 Alone (N=6)
H-1 after Poly I:C (N=10)
26. Parvovirus (KRV) Itself May Act via TLR9
Stimulus
CpG KRV Poly I:C
IL-12p40(%ofControl)
0
20
40
60
80
100
0.1 µg/ml
1 µg/ml
10 µg/ml
The ability of spleen cells to respond to KRV by producing IL12-p40
is inhibited by iCpG, an inhibitor of TLR9 (Dr. D Zipris)
27. BBDR Summary 2
• Innate immune activation can trigger T1D in
many but not all rat strains with a high risk
MHC haplotype
• Innate immune activation can synergize with
viral infection to increase the penetrance of
T1D
• One diabetogenic virus, KRV, may act in part
via activation of TLR9
28. New Model of Type1 Diabetes
The MAD Rat (LEW.1WR1)
• Recombinant inbred congenic strain
• Same MHC class II RT1B/Du haplotype required for autoimmune
diabetes in BB, Komeda, and LEW.1AR1/Ztm-iddm rats
• In the colony of rats maintained at BRM, Inc.:
• Spontaneous diabetes absent from acquisition in 1989 until 1999
• Now occurs at low frequency (0.5-3%)
• Develop autoimmune insulitis and diabetes when treated with
poly I:C, a ligand of toll-like receptor 3 (TLR3)
29. Extending the Scope of Viral Triggers:
The MAD Rat
• The BBDR + KRV combination is not unique
• LEW.1WR1 Rats
– MHC-Congenic LEW rats
– High risk MHC class II RT1B/Du haplotype
– Normal immunological phenotype
– Diabetes occurs at consistently but at low
frequency (~2.5%)
30. Hypothesis
• Given its genetic predisposition to
spontaneous T1D:
• Viral infection will trigger T1D in
MAD rats
31. Rat Cytomegalovirus
(RCMV)
• Beta-herpesvirus homologous to human
cytomegalovirus
• Persistent and latent infections
• No reported associated diseases
• Stocks are prepared from salivary glands
32. Relevance to Human Disease
• Human Cytomegalovirus (HCMV)
• Associated with autoimmune diseases
• Ubiquitous pathogen causing unapparent infections in
immunocompetent individuals
• Peptide from HCMV protein stimulate CD4+ T cells
that recognize GAD
• Organ transplantation
• Currently no effective vaccine
35. Diabetogenicity of five TLR
agonists in MAD rats
Group Test
Article
TLR Induction
of
Diabetes
Induction
Of
Arthritis
Gender
Bias
1 Poly I:C (primarily HMW) TLR3 ++++
No ♀ = ♂
2 LMW poly I:C (purified) TLR3 ++++
3 HMW poly I:C (purified) TLR3 ++++
4 Zymosan TLR2 +++
5 R848 TLR7 ++
6 CpG oligodeoxynucleotide TLR9 -
The dosing regimen was 3 times weekly by intraperitoneal injection beginning
at 21-24 days of age. Compounds were administered to 6 female and 6 male
rats at each dose of compound. Animals were treated over a 30 day period and
were monitored for diabetes from 7 to 40 days after the initiation of treatments
37. RCMV accelerates diabetes onset
in Diabetes Prone BB rats
0 5
0
20
40
60
80
100
30 40 50 60 70 80 90 100 110 120
RCMV/mock
infection
+ RCMV
- RCMV
RCMV INFECTED (n = 47)
CONTROLS (n = 29)
Age (days)
%DiabeticBB-DPrats
p = .0043
(Kaplan-Meier Log Rank)
van der Werf et al 2003: Clin Dev Immunol. 10:153
Hillebrands et al 2003: Clin Dev Immunol 10:133
38. Virus N Diabetes Virus N Diabetes
None 6 0 (0%) H-1 20 0 (0%)
Parvo 32 11 (34%) Coxsackie B4 18 0 (0%)
RCMV 38 14 (37%) Vaccinia 10 0 (0%)
Triggering of T1D in MAD Rats
is Virus-Specific
Latency to onset 16-30 Days
Dose of virus varied from 104 to 107 PFU
39. RCMV Infected Cells in Salivary Glands
But Not in Pancreatic Islets
Immunohistochemistry for RCMV early antigen (mAb 8)
Salivary Gland (mAb8) Islet (H&E) Islet mAb8
40. Conclusions
Virus Triggering of T1D in Resistant Rats
• T1D can be triggered in the rat by:
– Specific viral infections
– Two infections that are synergistic
– TLR ligation
– Certain viruses only in an immune system “pre-
activated” by TLR ligation
41. Topic 2
Prevention by Immunization
• If viral infections do promote diabetes onset
in susceptible rats with normal immune
systems…
• Then immunization may prevent the disease
43. Maternal Immunization Protects Weanling
MAD Rats from Virus-Induced Diabetes
0
CumulativeDiabetes-Free
Survival(%)
0
20
40
60
80
100
Days After Infection
10 20 30
Pups born to RCMV+KRV
Immunized Dam (N=10)
KRV+RCMV co-infection
Ordinary pups (N=10)
Pups born to RCMV
Immunized Dam (N=26)
Ordinary pups (N=13)
RCMV
44. Conclusion
• Maternal immunization can provide effective
and specific protection from virus-induced
diabetes in weanling rats
• Diabetes may be preventable by vaccines that
target candidate pathogens
• Rats like the MAD can be used to test diabetes
vaccination strategies
45. T-1D RAID Programs
• Rapid Access to Interventional Development for Type 1
diabetes
• BRM responded to two USPHS RFP’s in June of 2005.
• Our requested budgets totaled > $11.3 MM
• BRM was notified in December 2005 that it was
technically competent and within the Competitive
Range for Both RFP’s
– Only company competing for both contracts
46. T-1D RAID Programs
• Rapid Access to Interventional Development for Type 1
diabetes
• Preclinical Studies of Efficacy in Animal Models of
Type 1 Diabetes (Pathogenesis) N01-DK-6-2909
– BRM Awarded $4.9Million Contract 2006-2012
– Selected over a Top 25 Research Institute
47. T1D RAID Process
Potential therapeutics
submitted by US scientists
5 selected yearly by T1D RAID board
Successful compounds screened
and identified by BRM
Entry into TrialNet
New successful drug identified
48. Trials to Prevent or Treat Type 1 Diabetes:
Clinical Considerations
Tight glycemic control is correlated with C-peptide
preservation in type 1 diabetes clinical trials.
Interventions are more likely to succeed if done early, while
some beta cell function is preserved.
49. NOD Model Problem 1:
Treatment of diabetes
in new onset NOD mice
Diabetic NODs are treated with poorly-
characterized insulin pellets or by insulin
injection resulting in variable or inadequate
glycemic control.
Poor control may contribute to rapid beta cell
demise or loss of functionality, and therefore a
poorer response to immune interventions
designed to reverse disease may be observed.
50. NOD Model Problem 1:
Solutions
Contract is developing better ways to
control glycemia in NOD diabetic mice
Contract is developing ways to predict
imminent diabetes in order to intervene
prior to beta cell loss.
51. Interventions to Maximize Success
• Tight glycemic control of diabetic animals for periods
of 3-6 weeks
– Provides immune modulatory therapies maximum
opportunity for success
• Contract is developing ways to predict imminent
diabetes to intervene prior to complete beta cell loss
52. Model Standardization
• Use optimized rodent models for standardized
preclinical testing of agents to prevent or reverse
diabetes
– Testing in multiple models (mice and rats)
– Development of standardized testing protocols
– Development of insulin treatment protocols for
reversal studies
53. Example Testing Schemes
Treat 21-110 days
Treat 21-160 days
Follow 50 days
Preventative Protocol
Read-outs
Preventative/Reversal Protocol
Treat when turns diabetic
Treat 2 nondiabetic littermates Read-outs
Pulse Protocol
Read-outs
54. Year BRM Jackson
2006 68% 65%
2007 (at 27 weeks) 86% 95%
2008 (at 23 weeks) 75% 75%
Incidence of Diabetes Among NOD Mice
55. Therapeutic Evaluations in the
NOD Mouse Study Designs
Reversal
Initiate treatment after
frank diabetes onset.
Insulin therapy to
maintain euglycemia.
Late Prevention
Initiate treatment to
animals with impaired
GTT prior to frank
diabetes. Insulin therapy
not used.
Early Prevention
Initiate treatment prior to
disease onset. Insulin therapy
not used.
56. Control and Prediction
• Contract is developing better ways to control
glycemia in NOD diabetic mice (and BB rat)
• Contract is developing ways to predict imminent
diabetes to intervene prior to complete beta cell loss
57. Using the GTT test to predict
diabetes onset (Protocol 2)
• Impaired glucose tolerance (IGT) expected to
be early manifestation of impending diabetes
– Perform GTT (ip injected glucose) on fasted
nondiabetic female mice at 12, 14, or 16 weeks of
age, then follow for 30 days for diabetes onset
– Analyze AUC of animals that became diabetic or
remained non-diabetic
– Determine the best parameters for prediction
59. NOD Mice with Impaired Glucose
Tolerance Develop Diabetes
GTT performed on animals at 14 weeks of age.
IGTT= Impaired Glucose Tolerance, NGTT= Normal Glucose Tolerance.
9/19 animals with IGTT turned diabetic within 30 days after test.
4/31 animals with NGTT turned diabetic within 30 days after test.
60. GTT Conclusions
• GTT has high predictive value for diabetes
when performed at 14 weeks of age
Sensitivity Specificity Pos. Pred. Value
14 Weeks 0.69 0.73 0.47
63. Metabolic Control in NOD Mice
• Factors to consider
– Total daily dose (2- 4 Units) 25 g mouse
– Type of Insulin
– Frequency of dosing QD, BID, TID
– % of daily dose administered each injection
– Injection time relative to “fed state”
• Many pilots done to test insulin formulation
(Humulin 50/50, Humulin 70/30, PZI), dose,
use of diluted insulin and BID dosing
64. Continuous Insulin Release to Control
Blood Glucose in Diabetic NOD Mice
• Continuous release of insulin using Alzet osmotic
pumps
– Implant subcutaneously
– Use Humulin R at 0.2, 0.3, 0.4U/day
– Monitor BG daily, with an intensive (every 3 hours)
24 h monitoring on Days 3, 7 and 14
• Continuous release insulin controls blood
glucose rapidly with few glycemic excursions
65. Daily Blood Glucose Averages
0
100
200
300
400
500
600
0 5 10 15 20
BloodGlucose(mg/dL)
Day Post Pump Insertion
0.2U
0.3U
0.4U
Mice implanted subcutaneously with pumps releasing 0.2-0.4U Humulin R/day.
Daily blood glucose measured approx. 8-9 hours after lights on.
N=6 for 0.2 and 0.3U groups; N=12-15 for 0.4U group.
66. Intensive BG Monitoring – 0.4U
Mice implanted subcutaneously with pumps releasing 0.4U Humulin R/day.
BG measured every 3 hours for 24 hours on Days 3, 7 and 14 post pump insertion.
N=15 for Days 3 and 7; N=12 for Day 14.
0
100
200
300
400
500
600
0 2 4 6 8 10 12 14 16 18 20 22 24
BloodGlucose(mg/dL)
Hour in Study
3 Day
7 Day
14 Day
67. Intensive BG Monitoring – 0.3U
0
100
200
300
400
500
600
0 2 4 6 8 10 12 14 16 18 20 22 24
BloodGlucose(mg/dL)
Hour in Study
3 Day
7 Day
14 Day
Mice implanted subcutaneously with pumps releasing 0.3U Humulin R/day.
BG measured every 3 hours for 24 hours on Days 3, 7 and 14 post pump insertion.
N=15 for Days 3 and 7; N=12 for Day 14
68. Daily Blood Glucose Mean +/- SEM
0
100
200
300
400
500
600
-1 1 2 3 4 5 6 7 8 9 10 11 12 13 14
BloodGlucose(mg/dL)
Days Post Pump Insertion
.2U .25U .3U Diluent
Mice implanted subcutaneously with 1002 Alset pumps releasing 0.2-0.3U Humulin R/day.
Daily blood glucose measured approx. 5-7 hours after lights on.
N=12 for 0.2U and 0.25U groups; N=14 for 0.3U group; N=7 for Diluent group.
69. Day 3 Intensive BG (Mean +/- SEM)
0.0
100.0
200.0
300.0
400.0
500.0
600.0
3 3.5 4
BloodGlucose(mg/dl)
Days Post Pump Insertion
.2U .25U .3U Diluent
Mice implanted subcutaneously with 1002 Alset pumps releasing 0.2-0.3U Humulin R/day.
Daily blood glucose measured 3 days post insertion over 24 hours.
N=12 for 0.2U and 0.25U groups; N=14 for 0.3U group; N=7 for Diluent group.
70. Day 7 Intensive BG (Mean +/- SEM)
0.0
100.0
200.0
300.0
400.0
500.0
600.0
7 7.5 8
BloodGlucose(mg/dl)
Days Post Pump Insertion
.2U .25U .3U Diluent
Mice implanted subcutaneously with 1002 Alset pumps releasing 0.2-0.3U Humulin R/day.
Daily blood glucose measured 7 days post insertion over 24 hours.
N=12 for 0.2U and 0.25U groups; N=14 for 0.3U group; N=7 for Diluent group.
71. Day 14 Intensive BG (Mean +/- SEM)
0.0
100.0
200.0
300.0
400.0
500.0
600.0
14 14.5 15
BloodGlucose(mg/dl)
Days Post Pump Insertion
.2U .25U .3U Diluent
Mice implanted subcutaneously with 1002 Alset pumps releasing 0.2-0.3U Humulin R/day.
Daily blood glucose measured 14 days post insertion over 24 hours.
N=12 for 0.2U and 0.25U groups; N=14 for 0.3U group; N=7 for Diluent group.