Immunopharmacology
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  • FIGURE 52–1 Mechanisms of action of cyclosporine, tacrolimus, and sirolimus on T cells. Both cyclosporine <br /> and tacrolimus bind to immunophilins (cyclophilin and FK506-binding protein [FKBP], respectively), forming a complex that binds the phosphatase calcineurin and inhibits the calcineurin-catalyzed dephosphorylation essential to permit movement of the nuclear factor of activated T cells (NFAT) into the nucleus. In the nucleus, NFAT interacts with transcription factor AP-I (fos/jun), an interaction required for transcription of interleukin-2 (IL-2) and other growth and differentiation–associated cytokines (lymphokines). Sirolimus (rapamycin) works at a later stage in T-cell activation, downstream of the IL-2 receptor. Sirolimus also binds FKBP, but the FKBP-sirolimus complex binds to and inhibits the mammalian target of rapamycin (mTOR), a kinase involved in cell-cycle progression (proliferation). <br /> TCR, T-cell receptor.
  • FIGURE 52–1 Mechanisms of action of cyclosporine, tacrolimus, and sirolimus on T cells. Both cyclosporine <br /> and tacrolimus bind to immunophilins (cyclophilin and FK506-binding protein [FKBP], respectively), forming a complex that binds the phosphatase calcineurin and inhibits the calcineurin-catalyzed dephosphorylation essential to permit movement of the nuclear factor of activated T cells (NFAT) into the nucleus. In the nucleus, NFAT interacts with transcription factor AP-I (fos/jun), an interaction required for transcription of interleukin-2 (IL-2) and other growth and differentiation–associated cytokines (lymphokines). Sirolimus (rapamycin) works at a later stage in T-cell activation, downstream of the IL-2 receptor. Sirolimus also binds FKBP, but the FKBP-sirolimus complex binds to and inhibits the mammalian target of rapamycin (mTOR), a kinase involved in cell-cycle progression (proliferation). <br /> TCR, T-cell receptor.
  • Allopurinol is approximately 80% absorbed after oral administration and has a terminal serum half-life of 1–2 hours. Like uric acid, allopurinol is itself metabolized by xanthine oxidase, but the resulting compound, alloxanthine, retains the capacity to inhibit xanthine oxidase
  • FIGURE 16–10 Mechanisms of action of immunosuppressive drugs. Each major category of drugs used to prevent or to treat allograft rejection is shown along with the molecular targets of the drugs <br /> Reference: Cellular and Molecular Immunology-2012 by Abul K. Abbas <br />
  • Figure 33-8 Pathways of T-cell activation and site of action of immunosuppressive agents. ATG, antithymocyte globulin; AZA, <br /> azathioprine; IL, interleukin; MHC, major histocompatibility complex; MMF, mycoplasma membrane fraction; MTOR, mammalian target of rapamycin; NFAT, nuclear factor of activated T-cells; TCR, T-cell receptor. <br /> Reference: Cecil Essentials of Medicine 8ed 2010
  • 1) Immunisation of a mouse (2) Isolation of B cells from the spleen (3) Cultivation of myeloma cells (4) Fusion of myeloma and B cells (5) Separation of cell lines
  • (6) Screening of suitable cell lines (7) in vitro (a) or in vivo (b) multiplication (8) Harvesting
  • Sketches of mouse (top left), chimeric (top right) and humanized (bottom left) monoclonal antibodies. Human parts are shown in brown, non-human parts in blue
  • Color Atlas of Biochemistry (2005), 2Ed Bm Ocr 7.0-2.6 Lotb
  • Ofatumumab is a human IgG 1 monoclonal antibody directed against a different epitope on CD20 than rituximab. It is approved for patients with chronic lymphocytic leukemia (CLL) who are refractory to fludarabine and alemtuzumab. Ofatumumab binds to all B cells including B-CLL. It is thought to lyse B-CLL cells in <br /> the presence of complement and to mediate antibody-dependent cellular cytotoxicity. There is a slight risk of hepatitis B virus reactivation in patients taking ofatumumab. <br /> Panitumumab is a fully human IgG 2 kappa light chain monoclonal antibody. It is approved for the treatment of EGFRexpressing metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecancontaining chemotherapy regimens. Panitumumab binds to <br /> EGFR (similar to cetuximab), inhibiting epidermal growth factor from binding to its receptor, and prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases. It inhibits cell growth, induces apoptosis, decreases vascular growth factor production, and suppresses internalization of the EGFR. Although some dermatologic and infusion-related toxicities have been observed following infusion of panitumumab, the distinct advantage over cetuximab is that it is fully human, and therefore does not elicit HAMAs. This is the first FDA-approved monoclonal antibody produced from transgenic mice expressing <br /> the human immunoglobulin gene loci.
  • Ofatumumab is a human IgG 1 monoclonal antibody directed against a different epitope on CD20 than rituximab. It is approved for patients with chronic lymphocytic leukemia (CLL) who are refractory to fludarabine and alemtuzumab. Ofatumumab binds to all B cells including B-CLL. It is thought to lyse B-CLL cells in <br /> the presence of complement and to mediate antibody-dependent cellular cytotoxicity. There is a slight risk of hepatitis B virus reactivation in patients taking ofatumumab. <br /> Panitumumab is a fully human IgG 2 kappa light chain monoclonal antibody. It is approved for the treatment of EGFRexpressing metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecancontaining chemotherapy regimens. Panitumumab binds to <br /> EGFR (similar to cetuximab), inhibiting epidermal growth factor from binding to its receptor, and prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases. It inhibits cell growth, induces apoptosis, decreases vascular growth factor production, and suppresses internalization of the EGFR. Although some dermatologic and infusion-related toxicities have been observed following infusion of panitumumab, the distinct advantage over cetuximab is that it is fully human, and therefore does not elicit HAMAs. This is the first FDA-approved monoclonal antibody produced from transgenic mice expressing <br /> the human immunoglobulin gene loci.
  • VEGF:vascular endothelial growth factor <br /> <br /> Bevacizumab binds to VEGF and inhibits VEGF from binding to endothelial cells. It is an antiangiogenic drug that inhibits angiogenesis in tumors. It is approved for first line treatment of patients with metastatic colorectal cancer alone or in combination with 5-FU-based chemotherapy. It is also approved for treatment of non-small cell lung cancer, glioblastoma multiforme that has progressed after prior treatment, and metastatic kidney cancer when used with interferon-alpha. <br /> Since bevacizumab is antiangiogenic, it should not be administered until patients heal from surgery. Patients taking the drug should be watched for hemorrhage, gastrointestinal perforations, and wound healing problems. <br />
  • EGFR: epidermal growth factor receptor
  • Trastuzumab is a recombinant DNA-derived, humanized <br /> monoclonal antibody that binds to the extracellular domain of the <br /> human epidermal growth factor receptor HER-2/ neu . This antibody <br /> blocks the natural ligand from binding and down-regulates <br /> the receptor. Trastuzumab is approved for the treatment of <br /> HER-2 /neu -positive tumors in patients with breast cancer and <br /> patients with metastatic gastric or gastroesophageal junction adenocarcinoma. <br /> As a single agent it induces remission in about <br /> 15–20% of breast cancer patients; in combination with chemotherapy, <br /> it increases response rates and duration as well as 1-year <br /> survival.
  • Ofatumumab is a human IgG 1 monoclonal antibody directed against a different epitope on CD20 than rituximab. It is approved for patients with chronic lymphocytic leukemia (CLL) who are refractory to fludarabine and alemtuzumab. Ofatumumab binds to all B cells including B-CLL. It is thought to lyse B-CLL cells in <br /> the presence of complement and to mediate antibody-dependent cellular cytotoxicity. There is a slight risk of hepatitis B virus reactivation in patients taking ofatumumab. <br /> Panitumumab is a fully human IgG 2 kappa light chain monoclonal antibody. It is approved for the treatment of EGFRexpressing metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecancontaining chemotherapy regimens. Panitumumab binds to <br /> EGFR (similar to cetuximab), inhibiting epidermal growth factor from binding to its receptor, and prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases. It inhibits cell growth, induces apoptosis, decreases vascular growth factor production, and suppresses internalization of the EGFR. Although some dermatologic and infusion-related toxicities have been observed following infusion of panitumumab, the distinct advantage over cetuximab is that it is fully human, and therefore does not elicit HAMAs. This is the first FDA-approved monoclonal antibody produced from transgenic mice expressing <br /> the human immunoglobulin gene loci.
  • Yttrium is a chemical element with symbol Y and atomic number 39. It is a silvery-metallic transition metal chemically similar to the lanthanides
  • Figure 45–1 Sites of action of immunosuppressants. Available immunosuppressants inhibit the immune response by blocking that response at various sites. <br /> Ref: Clinical Drug Therapy 2003
  • Mechanism of type IV hypersensitivity (DTH). In the sensitization phase, the processed allergen (eg, from poison oak) is presented to CD4 TH1 cells by antigen-presenting cells in association with class II MHC. T cells are induced to express IL-2 receptors and are stimulated to proliferate and differentiate into memory TDTH cells. Secondary contact with antigen triggers the effector phase, in which memory TDTH cells release cytokines that attract and activate nonspecific inflammatory macrophages and neutrophils. These cells display increased phagocytic and microbicidal activities and release large quantities of lytic enzymes that cause extensive tissue damage. <br />
  • FIGURE 16–2 First- and second-set allograft rejection. Results of the experiments shown indicate that graft rejection displays the features of adaptive immune responses, namely, memory and mediation by lymphocytes. An inbred strain B mouse will reject a graft from an inbred strain A mouse with first-set kinetics (left panel). An inbred strain B mouse sensitized by a previous graft from an inbred strain A mouse will reject a second graft from an inbred strain A mouse with second-set kinetics (middle panel), demonstrating memory. An inbred strain B mouse injected with lymphocytes from another strain B mouse that has rejected a graft from a strain A mouse will reject a graft from a strain A mouse with secondset kinetics (right panel), demonstrating the role of lymphocytes in mediating rejection and memory. An inbred strain B mouse sensitized by a previous graft from a strain A mouse will reject a graft from a third unrelated strain with first-set kinetics, thus demonstrating another feature of adaptive immunity, specificity (not shown). Syngeneic grafts are never rejected (not shown). <br /> Reference: Cellular and Molecular Immunology-2012 by Abul K. Abbas <br />
  • FIGURE 16–8 Immune mechanisms of graft rejection. A, In hyperacute rejection, preformed antibodies reactive with vascular endothelium <br /> activate complement and trigger rapid intravascular thrombosis and necrosis of the vessel wall. <br /> Reference: Cellular and Molecular Immunology-2012 by Abul K. Abbas <br />
  • FIGURE 16–8 Immune mechanisms of graft rejection. B, In acute rejection, CD8+ T lymphocytes reactive <br /> with alloantigens on endothelial cells and parenchymal cells mediate damage to these cell types. Alloreactive antibodies formed after engraftment <br /> may also contribute to vascular injury. <br /> Reference: Cellular and Molecular Immunology-2012 by Abul K. Abbas <br />
  • FIGURE 16–8 Immune mechanisms of graft rejection. C, In chronic rejection with graft arteriosclerosis, injury to the vessel wall leads to intimal smooth muscle cell proliferation and luminal occlusion. This lesion may be caused by a chronic DTH reaction to alloantigens in the vessel wall. <br /> Reference: Cellular and Molecular Immunology-2012 by Abul K. Abbas <br />
  • FIGURE 16–1 People in the United States living with functioning organ grafts, 1999-2007. (Data from OPTN/SRTR Annual <br /> Report 2009. Available at: http://www.ustransplant.org/csr/current/fastfacts.aspx. Accessed April 2010.) <br /> Reference: Cellular and Molecular Immunology-2012 by Abul K. Abbas <br />
  • Color Atlas of Biochemistry (2005), 2Ed Bm Ocr 7.0-2.6 Lotb
  • FIGURE 7–23 Structure of cytokine receptors. A, Receptors for different cytokines are classified into families on the basis of conserved <br /> extracellular domain structures and signaling mechanisms. The cytokines or other ligands that bind to each receptor family are listed below the <br /> schematic drawings. WSXWS, tryptophan-serine-X-tryptophan-serine <br /> Cytokine receptors of the type I and type II receptor families engage signal transduction pathways that involve non-receptor tyrosine kinases called Janus kinases or <br /> JAKs and transcription factors called signal transducers and activators of transcription (STATs). <br /> TRAFs :TNF receptor associated factors, <br /> IRAK: IL-1R–associated kinase <br /> Reference: Cellular and Molecular Immunology-2012 by Abul K. Abbas
  • FIGURE 7–23 Structure of cytokine receptors. B, Groups of cytokine receptors share identical or highly homologous subunit <br /> chains. Selected examples of cytokine receptors in each group are shown. <br /> Cytokine receptors of the type I and type II receptor families engage signal transduction pathways that involve non-receptor tyrosine kinases called Janus kinases or <br /> JAKs and transcription factors called signal transducers and activators of transcription (STATs). <br /> TRAFs :TNF receptor associated factors, <br /> IRAK: IL-1R–associated kinase <br /> Reference: Cellular and Molecular Immunology-2012 by Abul K. Abbas

Immunopharmacology Immunopharmacology Presentation Transcript

  • Immunopharmacology By M.H.Farjoo M.D. , Ph.D. Shahid Beheshti University of Medical Science
  • Immunopharmacology  Classification  Immunosuppressive Antibodies  Hypersensitivity & Drug allergy  Clinical Uses  Transplantation  GVHD  Cytokines  Cytokine Inhibitors  Desensitization to Drugs  Drug Pictures
  • Classification  Immunophilin Ligands:  Cyclosporine  Tacrolimus (FK 506)  Sirolimus  Mycophenolate mofetil (MMF)  Thalidomide  Cytotoxic Agents:  Azathioprine  Cyclophosphamide  Other cytotoxic agents
  • Cyclosporine  Cyclosporine is a peptide antibiotic that blocks T cell activation.  It binds to cyclophilin, a member of a class of intracellular proteins called immunophilins.  Cyclosporine and cyclophilin form a complex that inhibits calcineurin.  calcineurin is a phosphatase necessary for the activation of a T-cell-specific transcription factor.  This transcription factor, NF-AT, is involved in the synthesis of interleukins (eg, IL-2) by activated T cells.
  • Cyclosporine Cont,d  There is interpatient variability in bioavailability which requires individual patient dosage adjustments.  Cyclosporine has efficacy in human organ transplantation and in the treatment of GVHD.  Toxicities are numerous: nephrotoxicity, hypertension, liver dysfunction and seizures.
  • Cyclosporine Cont,d  Tumors may arise after cyclosporine treatment because the drug induces TGF-β.  Cyclosporine has been used for transplants of the kidney, pancreas, liver and heart.  Cyclosporine with methotrexate, is a standard prophylactic regimen to prevent GVHD allogeneic transplants.
  • Tacrolimus (FK 506)  Tacrolimus is 10-100 times more potent than cyclosporine in inhibiting immune responses.  Tacrolimus is utilized for the same indications as cyclosporine.  Its toxic effects are similar to those of cyclosporine.
  • Sirolimus  Sirolimus (rapamycin) is derived from Streptomyces hygroscopicus  It binds FK506-binding protein, resulting in an active complex that blocks the molecular target of rapamycin (mTOR).  The mTOR is a key component in cell growth and proliferation, angiogenesis, and metabolism.  Thus, blockade of mTOR can lead to inhibition of interleukin-driven T-cell proliferation.
  • Sirolimus  Sirolimus is synergistic with cyclosporine.  Sirolimus has been used to prevent rejection of solid organ allografts.  Toxicities includes: profound myelosuppression (especially thrombocytopenia), hepatotoxicity, diarrhea, hypertriglyceridemia, and headache
  • Mycophenolate mofetil (MMF)  MMF is a derivative of mycophenolic acid, isolated from the mold Penicillium glaucum.  MMF inhibits T- and B-lymphocyte responses by inhibition of purines synthesis.  It is used in solid organ transplant for refractory rejection.  It is also used in combination with tacrolimus to prevent GVHD.  Toxicities include: GI disturbances, hypertension and reversible myelosuppression.
  • Thalidomide  Thalidomide inhibits angiogenesis and has anti- inflammatory and immunomodulatory effects.  Thalidomide is used in multiple myeloma and when combined with dexamethasone, the response rates are 90%.  The adverse effect profile of thalidomide is extensive. The most important toxicity is teratogenesis.  Thrombosis is sufficiently frequent that most patients are placed on warfarin.
  • Azathioprine  Azathioprine is a prodrug of mercaptopurine and functions as an antimetabolite.  These agents are prototypes of the antimetabolite group of cytotoxic immunosuppressive drugs.  Azathioprine and mercaptopurine interfere with purine metabolism at steps required for lymphoid cell proliferation.
  • Azathioprine Cont,d  Drug inactivation depends on xanthine oxidase so the dose should be reduced in patients receiving allopurinol.  It may cause hepatic dysfunction (very high ALP, mild jaundice) particularly in preexisting hepatic dysfunction.
  • Azathioprine Cont,d  Cellular immunity as well as serum antibody responses can be blocked by Azathioprine.  Azathioprine and mercaptopurine are benefitial in maintaining renal allografts.  The chief toxic effect of azathioprine and mercaptopurine is bone marrow suppression.
  • Cyclophosphamide  Cyclophosphamide destroys proliferating lymphoid cells.  Large doses of cyclophosphamide may causes pancytopenia and hemorrhagic cystitis.
  • Other cytotoxic agents  Hydroxychloroquine (antimalarial agent) decreases T- cell activation, used for rheumatoid arthritis and SLE.  Methotrexate is used in rheumatoid arthritis.
  • Immunosuppressive Antibodies  Hybridomas: consist of antibody-forming cells fused to plasmacytoma cells.  Hybrid cells produce the required antibody and can be subcloned for antibody production.  Humanization involves replacing most of the murine antibody with human regions while keeping only the variable regions intact.  Chimeric mouse-human antibodies have less complete replacement of the murine components.  the suffix "-umab" or "-zumab" is used for humanized antibodies, and "-imab" or "-ximab" for chimeric products.
  • 1) Immunisation of a mouse (2) Isolation of B cells from the spleen (3) Cultivation of myeloma cells (4) Fusion of myeloma and B cells (5) Separation of cell lines
  • (6) Screening of suitable cell lines (7) in vitro (a) or in vivo (b) multiplication (8) Harvesting
  • Sketches of mouse (top left), chimeric (top right) and humanized (bottom left) monoclonal antibodies. Human parts in brown, non-human parts in blue
  • Immunosuppressive Antibodies Cont,d  Consist of:  Monoclonal antibodies (MABS)  Antilymphocyte & antithymocyte antibodies  Immune globulin intravenous (IGIV)  Hyperimmune immunoglobulins  Rho (D) immune globulin
  • Monoclonal Antibodies (MABs)  Indications of MABs:  Antitumor  Delivery of Isotopes to Tumors  Immunosuppressants and Anti-Inflammatory  Anti-TNF-α MABs  Other Immunosuppressant MABs  Antiplatelet
  • Antitumor MABs.  Alemtuzumab (Campath, Lemtrada)  Bevacizumab (Avastin)  Cetuximab (Erbitux)  Ofatumumab (Not in Iran)  Panitumumab (Not in Iran)  Rituximab (Rituxan, MabThera and Zytux)  Trastuzumab (Herceptin)
  • Antitumor MABs  Alemtuzumab is used in chronic lymphocytic leukemia.  It may cause pancytopenia (risk of infection).  Bevacizumab binds to VEGF and inhibits angiogenesis in tumors.  It is used for metastatic colorectal cancer, non-small cell lung cancer, and metastatic kidney cancer.  Since it is antiangiogenic, it should NOT be used until patients heal from surgery.  Side effects are hemorrhage, GI perforations, and wound healing problems.
  •  Cetuximab targets EGFR and inhibits tumor cell growth by decreases in growth factor production, and increased apoptosis.  It is used in EGFR-positive metastatic colorectal cancer and head and neck cancer.  Rituximab is used for B-cell non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis.  It induces apoptosis in the malignant lymphoma cells. Antitumor MABs
  • Antitumor MABs  Trastuzumab is a recombinant DNA-derived, humanized monoclonal antibody.  It is used for breast cancer and gastric adenocarcinoma.  It induces remission in 15–20% of breast cancer patients, and increases 1-year survival.
  • MABs Used to Deliver Isotopes to Tumors  Arcitumomab (Not in Iran)  Capromab pendetide (Not in Iran)  Ibritumomab (Zevalin)  Tositumomab
  • MABs Used to Deliver Isotopes to Tumors  Ibritumomab is labeled with isotopic yttrium and is used in non-Hodgkin’s lymphoma.  Tositumomab is labeled with iodine 131 and is used in non-Hodgkin’s lymphoma.  Toxicities include severe cytopenias.
  •  Anti-TNF-α MABs  Adalimumab  Certolizumab pegol (Not in Iran)  Etanercept  Golimumab (Not in Iran)  Infliximab  Other Immunosuppressant MABs  Basiliximab and Daclizumab  Natalizumab  Omalizumab MABs Used as Immunosuppressants and Anti-Inflammatory Agents.
  •  They bind TNF-α, a proinflammatory cytokine.  This suppresses downstream inflammatory cytokines (IL-1, IL-6) involved in leukocyte activation.  An increased risk of infection or reactivation of TB, hepatitis B, and invasive systemic fungi is common to all of them.  Risk of malignancies (eg. lymphoma) is increased. Anti-TNF-α MABs
  •  Adalimumab, Etanercept and Infliximab are used in rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis.  Infliximab is also used for Crohn’s disease and ulcerative colitis. Anti-TNF-α MABs
  •  Basiliximab and Daclizumab are IL-2 antagonists, and are therefore immunosuppressive.  They are used for prophylaxis of rejection in renal transplant patients.  Natalizumab inhibits the adhesion of leukocytes to their receptor.  It is used in multiple sclerosis and Crohn’s disease.  Omalizumab is an anti-IgE antibody used in allergic asthma when inhaled corticosteroids are ineffective. Other Immunosuppressant MABs
  •  Abciximab binds to the activated platelets and prevents their aggregation.  It is used in percutaneous coronary intervention for the prevention of cardiac ischemic complications Antiplatelet MAB
  • Antilymphocyte & Antithymocyte Antibodies  Antilymphocyte globulin (ALG) and antithymocyte globulin (ATG) are used in transplantation.  The antiserum is obtained by immunization of horses or sheep with human lymphoid cells.  They play a definite role in the management of solid organ and bone marrow transplantation.
  • Immune Globulin Intravenous (IGIV)  Immunoglobulin (IgG) is prepared from pools of thousands of healthy donors.  No specific antigen is the target of the "therapeutic antibody.“  Its precise mechanism of action is still controversial  One expects that the pool of different antibodies will have a normalizing effect upon the patient's immune networks.  IGIV is effective in immunoglobulin deficiencies, autoimmune disorders, HIV disease and bone marrow transplants.
  • Hyperimmune Immunoglobulins  Hyperimmune immunoglobulin are IGIVs with high titers of antibodies against viruses or toxins.  Hyperimmune IGIVs are available for hepatitis B virus, rabies, tetanus, and digoxin overdose.  Intravenous administration of the hyperimmune globulins reduces risk or severity of infection.
  • Rho(D) Immune Globulin  Rho(D) immune globulin is a concentrated (15%) solution of human IgG.  Sensitization of Rh-negative mothers to the D antigen occurs usually at the time of birth of an Rho(D)- positive infant.  In subsequent pregnancies, maternal antibody is transferred to the fetus during the third trimester, leading to erythroblastosis fetalis.
  • Rho(D) Immune Globulin Cont,d  If an Rho(D) antibody is injected to the mother within 24-72 hours after the birth of an Rh-positive infant, the process is stopped.  Treatment is also often advised in miscarriages, ectopic pregnancies, or abortions.
  • Hypersensitivity & Drug allergy  Hypersensitivity can be classified as antibody- mediated or cell-mediated.  Three types of hypersensitivity are antibody-mediated (types I-III), while the fourth is cell-mediated (type IV).  Hypersensitivity occurs in two phases: the sensitization phase and the effector phase.  Sensitization occurs upon initial encounter with an antigen; the effector phase involves immunologic memory.
  • Hypersensitivity & Drug allergy Cont’d  Type I hypersensitivity results from cross-linking of membrane-bound IgE on basophils or mast cells by antigen.  Type II hypersensitivity results from the formation of Ag-Ab complexes (blood transfusion reaction).  Subsequent administration of the drug can lead to anaphylaxis (type I hypersensitivity).
  • Type II Reactions to Drugs  Examples include:  SLE following hydralazine or procainamide.  "lupoid hepatitis" due to cathartic sensitivity.  Autoimmune hemolytic anemia by methyldopa.  Thrombocytopenic purpura due to quinidine.  Agranulocytosis due to a variety of drugs.
  • Type II Reactions to Drugs Cont’d  Autoimmune reactions to drugs subside within several months after the drug is withdrawn.  Immunosuppressive therapy is warranted only when the autoimmune response is unusually severe.
  • Hypersensitivity & Drug allergy Cont’d  Type III hypersensitivity (Serum sickness) is due to the complement activation by Immune complexes.  In type III hypersensitivity, clinical symptoms occur 3 to 4 days after exposure to the antigen.  Type IV delayed-type hypersensitivity (DTH) occur 2-3 days after exposure to the antigen.  DTH induces a local inflammatory response that causes tissue damage by antigen-nonspecific cells, especially macrophages.
  • Type III Reactions to Drugs  Type II and type III hypersensitivities often overlap.  The clinical features include: urticarial and erythematous skin eruptions, arthralgia, glomerulonephritis, edema and fever.  The reactions last 6-12 days and subside once the offending drug is eliminated.
  • Type III Reactions to Drugs Cont’d  Glucocorticoids are useful in attenuating severe serum sickness reactions to drugs.  In severe cases plasmapheresis can be used to remove the offending drug and immune complexes.  The sulfonamides, penicillin, thiouracil, iodides and anticonvulsants all may initiate immune angiitis.  Stevens-Johnson syndrome is associated with sulfonamide therapy.
  • Hypersensitivity & Drug allergy Cont’d  In some drug reactions, several hypersensitivity responses may present simultaneously.  Some reactions to drugs may be mistakenly classified as allergic when they are actually genetic deficiency or idiosyncratic.  Two examples are:  Hemolysis due to primaquine in G6PD deficiency  Aplastic anemia caused by chloramphenicol.
  • Transplantation  Four types of rejection can occur in a solid organ transplant recipient:  Hyperacute: is due to preformed antibodies, (anti- blood group antibodies), occurs within hours, cannot be stopped with immunosuppressives.  Accelerated: is mediated by both antibodies and T cells, immunosuppressive drugs cannot stop it.
  • Transplantation Cont,d  Acute: Occurs within days to months and involves cellular immunity. Reversal of rejection is usually possible.  Chronic: Occurs after months or years and is characterized by fibrosis of the vasculature of the transplanted organ. It is treated as acute rejection.
  • Organ Immunopharmacologic Agents Used Response Renal Cyclosporine, azathioprine, prednisone, ALG, tacrolimus, basiliximab,3 daclizumab,3 sirolimus Very good Heart Cyclosporine, azathioprine, prednisone, ALG, tacrolimus, basiliximab, daclizumab, sirolimus Good Liver Cyclosporine, prednisone, azathioprine, tacrolimus, sirolimus Fair Bone marrow Cyclosporine, cyclophosphamide, prednisone, methotrexate, ALG Good Organ transplantation outcome
  • GVHD  Graft-versus-host disease (GVHD) is very common, occurring in the majority of patients who receive an allogeneic transplant.  GVHD occurs as donor T cells fail to recognize the patient's skin, liver, and gut (usually) as self.  Acute GVHD occurs within the first 100 days, and is manifested as a skin rash, severe diarrhea, or hepatotoxicity.
  • GVHD Cont,d  Patients generally progress to chronic GVHD (after 100 days) and require therapy for variable periods thereafter.  Patients generally can stop immunosuppression as GVHD resolves (1-2 years after their transplant).
  • Cytokines  The cytokines are a large and heterogeneous group of proteins with diverse functions.  Some play numerous roles in the function of the immune system and in the control of hematopoiesis.  Cytokines have antiproliferative, antimicrobial, and antitumor effects.
  • The cytokines Cytokine Properties Interferon-a (IFN-α) Antiviral, oncostatic, activates NK cells Interferon-b (IFN-β) Antiviral, oncostatic, activates NK cells Interferon-γ (IFN-γ) Antiviral, oncostatic, secreted by and activates or up- regulates TH1 cells, NK cells, CTLs, and macrophages Interleukin 1 to 32 (IL-1 to 32) Variable functions Tumor necrosis factor-α (TNF-α) Oncostatic, macrophage activation, proinflammatory Tumor necrosis factor-β (TNF-β) Oncostatic, proinflammatory, chemotactic Granulocyte colony- stimulating factor Granulocyte production Granulocyte-macrophage colony stimulating factor Granulocyte, monocyte, eosinophil production Macrophage colony- stimulating factor Monocyte production, activation Erythropoietin (epoetin, EPO) Red blood cell production Thrombopoietin (TPO) Platelet production
  • Cytokines Cont,d  Interferons (IFNs), are cytokines that are grouped into three families: IFN-α, IFN-β and IFN-γ.  The IFN-α and IFN-β families are type I that act on the same receptor. IFN- γ, a type II acts on a separate receptor.  IFNs, particularly IFN-γ, display immune-enhancing properties.
  • Cytokines Cont,d  IFNs also inhibit cell proliferation. In this respect, IFN- α and IFN-β are more potent than IFN-γ.  IFN-α is approved for the treatment of several neoplasms and for use in hepatitis B and C.  Toxicities of IFNs, which include fever, depression and myelosuppression can severely restrict their clinical use.
  • Cytokines Cont,d  Cancer therapy by TNF-α has been disappointing due to dose-limiting toxicities.  One exception is intra-arterial high-dose TNF-α for malignant melanoma and soft tissue sarcoma.  In these settings, response rates >80% have been noted.  The more recently discovered cytokines have been classified as interleukins (ILs) and numbered in the order of their discovery.
  • Cytokine Inhibitors  Cytokine inhibitors are used when cytokines are involved in the pathogenesis (septic shock).  Anakinra (not yet in Iran) is an IL-1 receptor antagonist, stemming the cascade of cytokines released.  Anakinra is used in rheumatoid arthritis untreated by other antirheumatic drugs.
  • Desensitization to Drugs  When certain drugs (penicillin, insulin) must be used even in the presence of known allergic sensitivity.  It is done by starting with very small doses and increasing the dose within hours to the full dose.  This practice must be performed under direct medical supervision, as anaphylaxis may occur before desensitization.  Patient is only desensitized during administration of the drug.
  • Lena delta in Russia (NASA satellite) 170 Km.
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