Immunopharmacology2010.12

Types of DrugsImmunosuppressants (important!)ImmunostimulantsImmunomodulatorsInduction of tolerance (tolerogens)CytokinesHematopoetic growth factorsAntibodies targeting key cell receptors/ligands

Simplified schematic of an immune responseClass IMHC class II/peptidesAPCsProtein antigensCD8+ T cellsCD4+ T cellsB cellsPlasma cellsCD8+ cytolytic T cells CD4+ immune cells(delayed hypersensitivity)antibodyproductionproliferation & differentiationIFNg, IL-2CytokinesCostim. Mol.IL-4,-5,-6proliferation & differentiationAPCClass IIproliferation & differentiation

Antigenantigenpresenting cell (macrophage,dendritic cell)

CD4T helpercellprimedCD4T helpercellCD8 T cellcytotoxicT cellsplasmacells12344IL-1IL-2IL-2IL-2Major steps in immune responsesB cell

Antigenantigenpresenting cell

CD4T helpercellprimedCD4T helpercellCD8 T cellcytotoxicT cellsplasmacells12344IL-1IL-2IL-2cytokines Sites of action of immunosuppressive drugsXXXXXABDDECX

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

Purpose of immunosuppressive drugs

Prevention of organ transplant rejection

Treatment of autoimmune diseases

Multiple SclerosisLupus Rheumatoid Arthritis Crohns DiseaseType I Diabetes 1

Glucocorticoidsreducing 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

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

Newton, Thorax 2000;55:603-613 Mechanisms of Glucocorticoid ActionInhibit the production of proinflammatory cytokines

Promote the production of inflammatory cytokines

Induce apoptosis in inflammatory cells

4. Interfere with cytokine signals

Glucocorticoid-sensitive sites of the immune responseMHC Class I/peptidesAPCsMHC Class II/peptidesAPCsProtein antigenCD8 T-cellCD4 T-cell(helper T-cells)B-cellPlasma cellCD8 cytolytic T-cellsCD4 immune cell(delayed hypersensitivity)antibodyproductionproliferation & differentiationproliferationIL-2IL-1IL-1, -4,-5,-6proliferation & differentiationGCXXGCXX

Clinical usesAutoimmune diseasesIdiopathic thrombocytopenic purpura ()Autoimmune hemolytic anemia Acute glomerulonephritisAcquired factor XIII antibodies and bleeding syndrome Organ transplantationPrevention of cell proliferationinduced by coronary stents

Cyclosporin isolated from the fungus Tolypocladium inflatum () isolated from a soil sample obtained by Sandoz scientists at Hardangervidda, Norway in 1969

Immunophilin ligands Cyclosporinepeptide antibioticCyclosporine cyclophilin complex inhibiting cytoplasmic phosphatase, calcineurinnecessary for the activation of a T-cell-specific transcription factor

FK Binding proteinsirolimusmTortacrolimusCyclosporinecyclophilinCalcineurinCytokine SignalingNFAT TranslocationGenes lead to T cell Activation IL-2Targets of Immunosuppressants

Mechanism of Action of Helper T-cell blockersXXFrom Hardman and Limbird, The Pharmacological Basis of Therapeutics

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

Immunological Rejection Major Histocompatibility Complex () MHC

Rejections: Antibody mediated T cells mediated

Hyperacute rejectione.g., Blood type mismatchAcute Graft RejectionDirect recognition of allogeinic MHC; rejection about 10 daysChronic rejectionTake many months to years. Due to failure of immunosuppressants

Clinical usesgraft-versus-host disease after hematopoietic stem cell transplantationselected autoimmune disorders

Tacrolimusmacrolide antibiotic23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis.

Tacrolimusbinding to the immunophilin FK-binding protein inhibiting the cytoplasmic phosphatase, calcineurin10-100 times more potent than cyclosporine used in organ and stem cell transplantation

Sirolimus Structuremacrolide similiar to tacrolimusMechanismbinds 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

FK Binding proteinsirolimusmTORtacrolimusCyclosporineimmunophilinCalcineurinCytokine SignalingNFAT TranslocationGenes lead to T cell Activation IL-2Targets of Immunosuppressants

Consequences of mTOR actionLymphocyte cell proliferation & differentiationT cellsB cellsAntibody productionMesenchymal cell proliferationVascular smooth muscle cellsEndothelial cellsFibroblasts

SirolimusInhibits mammalian target of rapamycin (mTOR) mTOR is a protein kinase that plays pivotal role in IL-2 receptor responsesIL-2 binds to its receptor on T cells and leads to mTOR activationmTOR initiates cascade of events (including cyclin dependent kinases) that promote T lymphocyte proliferation and differentiationInhibition of mTOR blocks IL-2 dependent cell-cycle progression at G1S phase transition

Mycophenolate mofetilPenicillium glaucum inhibiting T- and B-lymphocyte responsesVery often used now alternative to cyclosporine, solid organ transplant patientslupus nephritis, rheumatoid arthritis, and some dermatologic disorders

Cytotoxic agentsAzathioprineprodrug of mercaptopurinefunctions as an antimetabolite

Cytotoxic agentsCyclophosphamideautoimmune disorders (including systemic lupus erythematosus)acquired factor XIII antibodies and bleeding syndrome autoimmune hemolytic anemia antibody-induced pure red cell aplasia Wegeners granulomatosis

Immunosuppressants Inhibiting T Cell ActivationDrugGlucortiocoids

Cyclosporine and Tacrolimus

Sirolimus

Mycophenolate MofetilTargetGRE 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)

Monoclonal antibody1975, hybridoma technology by Milstein and Kohlerantibody-forming cells fused to immortal plasmacytoma cells[()]Pure and mass antibody possibleAntilymphocyte & Antithymocyte AntibodiesMuromonab-CD3 against T-cell surface proteins

Inhibitors of immune responseA- 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)

ImmunostimulantsThymic HormonesImprove primary immune deficiency in childrenSynthetic StimulantsLevamisole stimulates phagocytosis and T cell production of cytokinesAdjuvants of bacterial originBacille de Calmette Guerin (BCG, ) is viable strain of Mycobacterium bovis that enhances macrophage activityBCG used for bladder cancer and melanomas

hepatitis B vaccinea small glycoprotein, hepatitis B surface antigen (HBsAg)child's immune system recognizes HBsAg as foreign produces antibodieswhen 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.

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.