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Immunopharmacology 2010.12

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Shanghai Jiao Tong University Types of Drugs Immunosuppressants (important!) Immunostimulants Immunomodulators Induction of tolerance (tolerogens) Cytokines Hematopoetic growth factors Antibodies targeting key cell receptors/ligands

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Shanghai Jiao Tong University Simplified schematic of an immune response Class I MHC class II/peptides APCs Protein antigens CD8 + T cells CD4 + T cells B cells Plasma cells CD8 + cytolytic T cells CD4 + immune cells (delayed hypersensitivity) antibody production proliferation & differentiation IFN , IL-2 Cytokines Costim. Mol. IL-4,-5,-6 proliferation & differentiation APC Class II proliferation & differentiation

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Shanghai Jiao Tong University Antigen antigen presenting cell (macrophage, dendritic cell) CD4 T helper cell primed CD4 T helper cell CD8 T cell cytotoxic T cells plasma cells 1 2 3 4 4 IL-1 IL-2 Major steps in immune responses B cell

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Shanghai Jiao Tong University Antigen antigen presenting cell CD4 T helper cell primed CD4 T helper cell CD8 T cell cytotoxic T cells plasma cells 1 2 3 4 4 IL-1 IL-2 cytokines Sites of action of immunosuppressive drugs X X X X X A B DD E C X

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Shanghai Jiao Tong University

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The cell-mediated arm of the immune response involves the ingestion and digestion of antigen by antigen-presenting cells such as macrophages. Activated TH cells secrete IL-2, which causes proliferation and activation of cytotoxic T lymphocytes, and TH1 and TH2 cell subsets. TH1 cells also produce IFN- and TNF- , which can directly activate macrophages and NK cells. The humoral response is triggered when B lymphocytes bind antigen via their surface immunoglobulin. They are then induced by TH2-derived IL-4 and IL-5 to proliferate and differentiate into memory cells and antibody-secreting plasma cells. Regulatory cytokines such as IFN- and IL-10 down-regulate TH2 and TH1 responses, respectively. Immune response

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Shanghai Jiao Tong University Purpose of immunosuppressive drugs Prevention of organ transplant rejection Treatment of autoimmune diseases Multiple Sclerosis Lupus Rheumatoid Arthritis Crohns Disease Type I Diabetes 1

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Shanghai Jiao Tong University Glucocorticoids reducing the size and lymphoid content of the lymph nodes and spleen interfering with the cell cycle of activated lymphoid cells lowering the effective concentration of specific antibodies

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Shanghai Jiao Tong University

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Newton, Thorax 2000; 55:603-613 Biology of glucocorticoids

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Shanghai Jiao Tong University Newton, Thorax 2000;55:603-613 Mechanisms of Glucocorticoid Action 1.Inhibit the production of proinflammatory cytokines 2.Promote the production of inflammatory cytokines 3.Induce apoptosis in inflammatory cells 4. Interfere with cytokine signals

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Shanghai Jiao Tong University Glucocorticoid-sensitive sites of the immune response MHC Class I/peptides APCs MHC Class II/peptides APCs Protein antigen CD8 T-cell CD4 T-cell (helper T-cells) B-cell Plasma cell CD8 cytolytic T-cells CD4 immune cell ) (delayed hypersensitivity) antibody production proliferation & differentiation proliferation IL-2 IL-1 IL-1, -4,-5,-6 proliferation & differentiation GC X X X X

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Shanghai Jiao Tong University Clinical uses Autoimmune diseases Idiopathic thrombocytopenic purpura ( ) Autoimmune hemolytic anemia Acute glomerulonephritis Acquired factor XIII antibodies and bleeding syndrome Organ transplantation Prevention of cell proliferation induced by coronary stents

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Shanghai Jiao Tong University Cyclosporin isolated from the fungus Tolypocladium inflatum ( ) isolated from a soil sample obtained by Sandoz scientists at Hardangervidd a, Norway in 1969

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Shanghai Jiao Tong University Immunophilin ligands Cyclosporine peptide antibiotic Cyclosporine cyclophilin complex inhibiting cytoplasmic phosphatase, calcineurin necessary for the activation of a T-cell-specific transcription factor

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Shanghai Jiao Tong University FK Binding protein sirolimus mTor tacrolimus Cyclosporine cyclophilin Calcineurin Cytokine Signaling NFAT Translocation Genes lead to T cell Activation IL-2 Targets of Immunosuppressants

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Shanghai Jiao Tong University Mechanism of Action of Helper T-cell blockers X X From Hardman and Limbird, The Pharmacological Basis of Therapeutics

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Shanghai Jiao Tong University

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Clinical uses organ transplantation: Body parts: Facial, Limbs, Organs: Heart, kidney, liver, small intestine, lung, Tissues: Islets, hair follicles, bone, bone marrow, cornea, Cells: Stem cells, lymphocytes

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Immunological Rejection Major Histocompatibility Complex ( ) MHC Rejections: Antibody mediated T cells mediated Hyperacute rejection e.g., Blood type mismatch Acute Graft Rejection Direct recognition of allogeinic MHC; rejection about 10 days Chronic rejection Take many months to years. Due to failure of immunosuppressants

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Shanghai Jiao Tong University Clinical uses graft-versus-host disease after hematopoietic stem cell transplantation selected autoimmune disorders

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Shanghai Jiao Tong University Tacrolimus macrolide antibiotic 23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis.

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Shanghai Jiao Tong University Tacrolimus binding to the immunophilin FK-binding protein inhibiting the cytoplasmic phosphatase, calcineurin 10-100 times more potent than cyclosporine used in organ and stem cell transplantation

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Shanghai Jiao Tong University Sirolimus _ Structure _macrolide similiar to tacrolimus _ Mechanism _binds to immunophilin protein that binds to a key regulatory kinase required for T cell activation _(new unique mechanism to inhibit T lymphocyte activation by IL-2) _different site of action than cyclosporine and tacrolimus

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Shanghai Jiao Tong University FK Binding protein sirolimus mTOR tacrolimus Cyclosporine immunophilin Calcineurin Cytokine Signaling NFAT Translocation Genes lead to T cell Activation IL-2 Targets of Immunosuppressants

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Shanghai Jiao Tong University Consequences of mTOR action _ Lymphocyte cell proliferation & differentiation _T cells _B cells _ Antibody production _ Mesenchymal cell proliferation _Vascular smooth muscle cells _Endothelial cells _Fibroblasts

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Shanghai Jiao Tong University Sirolimus _ Inhibits mammalian target of rapamycin (mTOR) _mTOR is a protein kinase that plays pivotal role in IL-2 receptor responses _IL-2 binds to its receptor on T cells and leads to mTOR activation _mTOR initiates cascade of events (including cyclin dependent kinases) that promote T lymphocyte proliferation and differentiation _Inhibition of mTOR blocks IL-2 dependent cell-cycle progression at G1S phase transition

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Shanghai Jiao Tong University Mycophenolate mofetil Penicillium glaucum inhibiting T- and B-lymphocyte responses Very often used now alternative to cyclosporine, solid organ transplant patients lupus nephritis, rheumatoid arthritis, and some dermatologic disorders

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Shanghai Jiao Tong University Cytotoxic agents Azathioprine prodrug of mercaptopurine functions as an antimetabolite

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Shanghai Jiao Tong University Cytotoxic agents Cyclophosphamide autoimmune disorders (including systemic lupus erythematosus ) acquired factor XIII antibodies and bleeding syndrome autoimmune hemolytic anemia antibody-induced pure red cell aplasia Wegeners granulomatosis

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Shanghai Jiao Tong University Immunosuppressants Inhibiting T Cell Activation Drug Glucortiocoids Cyclosporine and Tacrolimus Sirolimus Mycophenolate Mofetil Target GRE of DNA (regulate gene transcription, inhibit transcription) Calcineurin (inhibit the phosphatase required for IL-2 transcription) Protein kinase involved in cell-cycle progression (inhibits mTOR and inhbits IL-2 signaling) Inosine monophosphate dehydrogenase (inhibits de novo guanine nucleotide synthesis)

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Shanghai Jiao Tong University Monoclonal antibody 1975, hybridoma technology by Milstein and Kohler antibody-forming cells fused to immortal plasmacytoma cells[ ( )] Pure and mass antibody possible Antilymphocyte & Antithymocyte Antibodies Muromonab-CD3 against T-cell surface proteins

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Shanghai Jiao Tong University Inhibitors of immune response Inhibitors of immune response A- Immune Globulin (antigen recognition) B- Corticosteroids (IL-1 production, cell proliferation) C- Cyclosporine, Tacrolimus, (1L-2 gene expr.), Sirolimus (IL-2 signal transduction) D- Rapamycin, Mycophenolate (T cell prolif.), Azathioprine, Cyclophosphamide (all cell prolif.) E- OKT3 (Muromonab-CD3) (monoclonal antibody to CD3 on T cell)

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Shanghai Jiao Tong University Immunostimulants Thymic Hormones Improve primary immune deficiency in children Synthetic Stimulants Levamisole stimulates phagocytosis and T cell production of cytokines Adjuvants of bacterial origin Bacille de Calmette Guerin (BCG, ) is viable strain of Mycobacterium bovis that enhances macrophage activity BCG used for bladder cancer and melanomas

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Shanghai Jiao Tong University hepatitis B vaccine a small glycoprotein, hepatitis B surface antigen (HBsAg) child's immune system recognizes HBsAg as foreign produces antibodies when infected with hepatitis B virus the antibodies recognize the protein and stimulate the immune system to produce large quantities of specific antibodies that attach to and destroy the virus and prevent the disease.

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Shanghai Jiao Tong University vaccination a child receives vaccination, most often before leaving the hospital after birth. the second and third HBV immunizations are administered by the age of 18 months, in conjunction with other routine childhood vaccinations.