School of Medicine Universitas Sumatera Utara

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1 Immuno-modulatormodulator Prof.AznanLelo,dr,PhD SpFK,dr.Datten Bangun MSc,SpFK Dept. Pharmacology & Therapeutic School of Medicine Universitas Sumatera Utara 13 Mei 2009, KBK-FK USU, Medan

2 Introduction : - Patients with autoimmune disease, and patients who received transplanted tissue or organs, require therapy with immunosuppressive drugs. ± 50 years ago, started with : - Corticosteroids - Antimetabolites - Alkylating agents..

3 Over the past 20 years,the field of immunosuppression has shifted to specific inhibitors of immunity that affect distinct immune pathways. This is important because: = greater efficacy = reduced toxicity = more insight are gained into the operation of the immune system

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5 Immune Problems Major Histocompatibility Complex (MHC) is the major concern. Rejections: -. Antibody mediated -. T cells mediated HIV/AIDS Chronic infection Malignancy Organ transplantation

6 Simplified Schematic of an Immune Response Class I APC Class II Cytokines Costim. Mol. CD8 + T cells CD4 + T cells proliferation & differentiation CD8 + cytolytic T cells proliferation & differentiation CD4 + immune cells (delayed hypersensitivity) IL-4,-5,-6 Protein antigens B cells Plasma cells MHC class II/peptides APCs APC=Antigen Presenting Cell proliferation & differentiation antibody production

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9 Immunostimulator Immunostimulators are agents that increase the immune responses. Natural 1. Vaccine BCG 1. Chloroquine 2. Interferon 2. Levamisol 3. Interleukin 3. Isoprinosine 4. Phyllantus niruri (Meniran) 5. Tincture Echinacea 6.Andrographis paniculata (Sambiloto) paniculata (Sambiloto) Synthetic 4. Phyllantus niruri (Meniran) 5. Tincture Echinacea

10 BCG (Bacille Calmette-Guerin) Vaccine against tuberculosis Mechanism of action: unknown, may be activate macrophages, NK cells, B cells, and various T cells in vitro and in vivo Indication: treatment and prophylaxis of bladder carcinoma (in situ) Side effects: fever, nausea, vomiting, cough and reddish of skin

11 Cytokines General properties of cytokines. A large and heterogeneous of protein with many functions.-- pleiotropic Synthesized within lymphoreticular cells. different cell make different cytokines. Immunoregulatory. regulate specific immune response. stimulate hematopoiesis. facilitate immune response & activate inflammatory response Similar to hormone. Short lived. Bind to specific receptor on target cells. Rarely work alone. Chemotaxis The first group discovered,the Interferon,were followed by the Colony- Stimulating Factors(CSFs)

12 Cytokines Role of cytokines in disease Bacterial septic shock Cancer Inflammatory Autoimmune eg. IFN-α : treatment of neoplasm IFN-β β : treatment t t of multiple l sclerosis IFN-γ : chronic granulomatous CSFs : regulate the proliferation and differentiation of bone-marrow progenitor cells

13 Mechanism of Action of Cytokines

14 Mechanism of Action of Cytokines

15 Interferon IFNs interact with cell receptor to produce a wide variety of effects that depend on the cell and IFNs types. Interferon Alfa = natural lymphokin Beta Mechanism of Action Activate: macrophage Tcell NK cell B cell Ab Indication Antiviral Hepatitis C anti-inflammatory action Multiple-Sclerosis (MS) repairing the destroyed BBB in MS patient Gamma activate macrophages Anti-viral, = immune interferon Anti-tumor, tumor kidney Ca Chronic granulomatous

16 Chloroquine Quinolin derivative Mechanism of action: inhibit DNA Polymerase and RNA Polymerase. inhibit fusion of macrophage irreversibly inhibit NO synthesis Indication: rheumatoid arthritis, psoriasis Side effects: ototoxic

17 Levamisole Anti parasitic agent, imidazothiazole synthetic Mechanism of action: not well understood d Stimulates antibody formation to various antigens, stimulating T-cell activation and proliferation, potentiate monocyte and macrophage functions, including phagocytosis, chemotaxis and increases motility and adherence of neutrophil Indication: rheumatoid arthritis, viral infection and systemic lupus erythematosus Side effects: nausea, vomiting, urticaria and agranulocytosis

18 Other Immunomodulator Isoprinosine purine synthetic Old drug for herpes, genital warts, influenza, tumors, hepatitis B Has an adjuvant effect Mechanism of action :? Increased of NK cell cytotoxicity and T cell and monocyte functional activities.

19 Other Immunomodulator 1.Phyllantus niruri (Meniran) Traditional herb Increases production of IFN-γ γ & TNF-α Used as adjuvant in patient with HIV infection & TB therapy. 2.Echinacea tincture Traditional herb, Echinae purpurea (ruddeckia). Anti-oxidant

20 Other Immunomodulator Andrographis paniculata (Sambiloto) Traditional herb, used for treatment of dysentery, diarrhea, or malaria. Increased Macrophage Migration Index (MMI) and Lymphocytes proliferation. Legal drugs for HIV infection in Germany.

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22 General Principles of Immunosuppression Primary immune responses are more easily suppressed than secondary (memory) Different immunosuppressants have different effects on different immune reactions Suppression is more likely achieved if therapy begins before exposure to the immunogen---- as in Rh(-) mother with Rh(+) infant.

23 Ideal Immunosuppressant Strongly immunosuppressive i Specific, no overall immunosuppression Anti-infection ability Low Toxicity for Vital Organs Low cost Long in vivo bioactivity it Easy to use

24 The use of immunosuppresant in the rejection of a transplanted organ - alloimmunity :- transplant rejection - graft versus host disease in several diseases in which an autoimmune component may contribute t to the pathogenesis: various connective tissue diseases such as vasculitis or systemic lupus erythematosus, certain type of glomerulonephritis, chronic active hepatitis, psoriasis, Crohn n disease and some haematological disorders

25 Currently used Immunosuppressants Category Cytotoxic Agents anti-metabolite DNA alkylating agent inhibits dihydrofolate reductase inhibits IMP dehydrogenase Steroids Biological Agents Fungus Products Monoclonal antibodies (TNF-alfa Antibodies, Interleukins-2 Receptor Antibodies) Azathioprine Cyclophosphamide Methotrexate Mycophenolate mofetil Drugs Prednisone, Methylprednisolone, Dexamethasone, etc ALG (anti-lymphocyte globulins), ATG (anti-thymocyte globulins), OKT3 Cyclosporine, Tacrolimus (FK506), Sirolimus, Rapamicin, Mycophenolate mofetil, 15- Deoksispergualin Infliximab, Adalimumab, Etanercept Daclizumab and Basiliximab Muromonab-CD3

26 Cytotoxic Agents Category anti-metabolite DNA alkylating agent inhibits dihydrofolate reductase inhibits IMP dehydrogenase Drugs Azathioprine 6-mercaptopurine Cyclophosphamide Methotrexate Mycophenolate mofetil Cytotoxic drugs act on rapidly dividing cells. Prevention of lymphocyte prolifertion and transformation Prevention of antibody and lymphokine synthesis

27 Uses of cytotoxic agents Azathioprine; with cyclosporine and/or prednisone for organ transplant rejection and severe RA Mycophenolate mofetil; with cyclosporine and prednisone for renal transplants Cyclophosphamide; for BMT Methotrexate; GVHD prophylaxis p

28 Mechanisms of Glucocorticoid Action 1. Inhibit the production of pro-inflammatory cytokines 2. Promote the production of inflammatory cytokines like double-edged sword 3. Induce apoptosis in inflammatory cells 4. Interfere with cytokine signals Newton, Thorax 2000;55:

29 Use of Glucocorticoid as Immunosuppressant Most widely used effective anti-inflammatory inflammatory drugs Used with other immunophilin inhibitors to prevent transplant rejection and GVHD(Graft-versus-Host Disease natural glucocorticoids not used due to mineralocorticoid activity Prednisone and prednisolone are used orally at moderate to high doses; Very high doses of methylprednisolone used i.v. during acute organ rejection Used before and after anti-thymocyte Abs to inhibit allergic reactions

30 Glucocorticoid effects related to immunosuppressioni Reduced immune cell content of lymph nodes, spleen and blood lymphopenia, monocytopenia, eosinopenia, but neutrophilia Interference with APC, T-cell and macrophage functions

31 Clinical Concerns with Corticosteroids Growth inhibition in pediatric i transplants t Cataracts (10% incidence) Bone disease (inhibition of osteoblastic activity, decreased calcium absorption, increased urinary calcium excretion) Diabetes (insulin-resistance, gluconeogenesis) Hyperlipidemia (40-60% posttransplant accelerated atherogenesis, increased incidence if combined with calcineurin inhibitors and sirolimus) Hypertension (60-80% in transplant patients) Increased cardiovascular risk factors Predisposition to infection (decr. PMN, T cell activity. Cushing syndrome

32 Antibiotic products Calcineurin inhibitors (TCR activation blockers) Cyclosporine commonly used with prednisone and other immunosuppressants to prevent allograft rejections in renal, hepatic and cardiac transplants, and in RA and psoriasis use is delayed post-transplantation due to neurotoxicity it concerns Tacrolimus (FK506) is approved for prevention of solid-organ organ allograft rejection, and eczema (topical) treatment begins prior to surgery, and is maintained well afterwards TCR=T Cell Receptor

33 Calcineurin inhibitors : Cyclosporine, Tacrolimus and Rapamycin CsA and FK506 act on T-cells to inhibit T-cell receptor activation and induction of cytokines CsA may also inhibit IgE-stimulated t mast cell degranulation and stimulate TGF-α expression Rapamycin acts to inhibit lymphocyte response to cytokines Rapamycin and analogues are also used to sensitize cancer cells to chemotherapeutic reagents Transforming Growth Factor

34 Cyclosporine Fungi: Tolypocladium inflatum gams Mechanism of action Bind to imunophilin and then inhibit calcineurin activity, production of limphokin and interleukin release---<<<<< Pharmacokinetics Bioavailability il 20-50%, Tmax: 3-4hrs, half-life: lflif 24 hrs Hepatic metabolism CYP3A4 Excretion: bile and urine Indication Transplantasi organ: 4-24 hrs prior to surgery: 15 mg/kg/d and for 2 weeks, and then the dose reduced untill 3-10 mg/kg/d. Rheumatoid arthritis : 2,5-4 mg/kg/d Psoriasis : 2,5-4 mg/kg/d Side effects Nephrotoxic and hepatotoxic Hypertension, hyperkalemia, tremor Pancreatitis, peptic ulcer, nausea, vomiting and fever

35 Mechanism of action of cyclosporine Cyclosporin Imunophilin (cyclophillin) Cyclosporin-imunophilin complex Activate T cell receptor, then enhance Ca concentration Calcineurin activation ( - ) Akibatnya defosforilasi f i NFATc bergerak dari sitoplasma ke nukleus NFATc link to other nucleus components Activate gen to encode cytokine Cytokine release Immune respons

36 Structure Tacrolimus (Prograf) macrolide (structure like erythromycin) Mechanism similiar to cyclosporine except binds to different protein that inhibits calcineurin (a phosphatase enzyme involved in gene transcription i of IL-2, gamma interferon and other cytokines) Bioavailability: =given by IV infusion or orally =used concomitantly with corticosteroids Adverse Effects: =nephrotoxicity, increased risk of hypersensitivity, y hyperglycemia, y GI complaints, hypertension, neurotoxicity(tremor,headache, motor disturbances, seizures) and lymphomas

37 FKBP= FK-binding protein NFAT= Nuclear Factor of Activated T cells CaN = Calcineurin

38 Monoclonal antibodies Monoclonal antibodies are developed to overcome: Immune disease Rheumatoid arthritis, SLE Malignancy Lymphoma, breast cancer, etc TNF-alfa Antibodies Infliximab, Adalimumab, Etanercept Interleukins-2 Receptor Antibodies Daclizumab, Basiliximab, Muromonab-CD3 Trastuzumab Rituximab Palivizumab

39 Key Actions Attributed to TNFα

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42 TNF Antagonists: TNF Antagonists: Characteristics Characteristics i Adalimumab 1 Etanercept 2 Infliximab 3,4 Structure Human mab TNF receptor-igg1 Chimeric i mab Fusion Protein Binding target TNF TNF, Lymphotoxin TNF Binding affinity it x x Half-life ~14 days days 8-10 days Administration sc sc iv Preparation Liquid Lyo Lyo Dose 40 mg 25 mg 3-10 mg/kg eow q2w q4-8w Use Alone or with other Alone With MTX only DMARDs, incl MTX (or with MTX - US)

43 Bioactive Immunosuppressants Anti-thymocyte thymocyte antibodies 3 types available all derived from non-human sources Rh(D) immune globulin-- Rh(-) mother with Rh(D)+ infant OKT3, OKT4, Anti-CD20, anti-tnf, anti- ICAMs, and CTLA4-Ig Repeated blood transfusion; transfusion of apoptotic cells

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