School of Medicine Universitas Sumatera Utara

CD4+ T cells CD4+ immune cells APC ... antibody production A P C =An tigen Pr esenting Ce ll. ... Beta • anti-inflammatory action...

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Immuno modulator Immuno-modulator 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

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

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

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

Simplified Schematic of an Immune I Response R proliferation & diff differentiation ti ti

CD8+ T cells

CD8+ cytolytic T cells

Class I

APC

proliferation & differentiation

Class II

CD4+ T cells

Cytokines Costim. Mol.

CD4+ immune cells (delayed hypersensitivity)

IL 4 5 6 IL-4,-5,-6 Protein antigens

B cells

MHC class II/peptides APCs APC=Antigen Presenting Cell

Plasma cells proliferation & differentiation

antibody production

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

1. Chloroquine 1 2. Levamisol 3 Isoprinosine 3. 4. Phyllantus niruri (Meniran) 5. Tincture Echinacea

BCG (Bacille Calmette-Guerin) Calmette Guerin) • Vaccine against g tuberculosis • Mechanism of action: unknown, may be activate – – – –

macrophages, NK cells, 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

Cytokines General properties of cytokines cytokines. • A large and heterogeneous of protein with many functions.--Æ pleiotropic • Synthesized within lymphoreticular cells cells. – different cell make different cytokines.

• Immunoregulatory. g y

– regulate specific immune response. – stimulate hematopoiesis. – facilitate immune response & activate inflammatory response

• • • • •

Similar to hormone. Short lived. Bind to specific p receptor p on target g cells. Rarely work alone. Chemotaxis

The first group discovered,the Interferon,were followed by the ColonyStimulating Factors(CSFs)

Cytokines Role of cytokines in disease • Bacterial B t i l septic ti shock h k • Cancer • Inflammatory • Autoimmune eg. IFN-α : treatment of neoplasm IFN β : treatment IFN-β t t t off multiple lti l sclerosis l i IFN-γ : chronic granulomatous CSFs

: regulate the proliferation and differentiation of bone-marrow progenitor cells

Mechanism of Action of Cytokines

Mechanism of Action of Cytokines

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

Mechanism of Action Activate: • macrophage • T cell Æ NK cell • B cell Æ Ab

Indication Antiviral Hepatitis C

Beta

• anti-inflammatory action Multiple-Sclerosis (MS) • repairing the destroyed BBB in MS patient

Gamma

activate macrophages

= immune interferon

• Anti-viral, • Anti-tumor, Anti tumor kidney Ca • Chronic granulomatous

Chloroquine • Quinolin derivative • Mechanism of action: – inhibit DNA Polymerase and RNA Polymerase. – inhibit i hibi ffusion i off macrophage h – irreversibly inhibit NO synthesis

• Indication: rheumatoid arthritis, psoriasis • Side effects: ototoxic

Levamisole • Anti parasitic agent, imidazothiazole synthetic • Mechanism M h i off action: ti nott wellll understood d t d – Stimulates antibody formation to various antigens, – stimulating g 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

Other Immunomodulator Isoprinosine • purine synthetic • Old d drug ffor h herpes, genital it l warts, t influenza, tumors, hepatitis B • Has an adjuvant effect • Mechanism of action : ? – –

Increased of NK cell cytotoxicity and T cell and monocyte functional activities.

Other Immunomodulator 1.Phyllantus niruri (Meniran) Traditional herb • Increases production of – IFN IFN-γγ & – TNF-α • Used as adjuvant j in patient with HIV infection & TB therapy.

2.Echinacea tincture Traditional herb, Echinae purpurea (ruddeckia). Anti oxidant Anti-oxidant

Other Immunomodulator Andrographis g p paniculata p (Sambiloto) ( ) • Traditional herb herb, used for treatment of dysentery, diarrhea, or malaria. • Increased I d – Macrophage Migration Index (MMI) and – Lymphocytes proliferation.

• Legal drugs for HIV infection in Germany.

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

Ideal Immunosuppressant • • • • • • •

Strongly St l immunosuppressive i i Specific, no overall immunosuppression Anti-infection ability Low Toxicity for Vital Organs Low cost L Long i vivo in i bioactivity bi ti it Easy to use

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 componentt may contribute t ib t to t the th pathogenesis: th i – various connective tissue diseases such as • vasculitis or • systemic lupus erythematosus,

– – – – –

certain type of glomerulonephritis, chronic active hepatitis, p , psoriasis, Crohn’n disease and some haematological disorders

Currently used Immunosuppressants Category

Drugs

Cytotoxic Agents anti-metabolite Azathioprine DNA alkylating agent Cyclophosphamide y reductase Methotrexate inhibits dihydrofolate inhibits IMP dehydrogenase Mycophenolate mofetil

Steroids

Prednisone, Methylprednisolone, Dexamethasone etc Dexamethasone,

Biological Agents

ALG (anti-lymphocyte globulins), ATG (anti-thymocyte globulins), OKT3

F ng s Products Fungus Prod cts

Cyclosporine, Tacrolimus (FK506) Cyclosporine (FK506), Sirolimus Sirolimus, Rapamicin, Mycophenolate mofetil, 15Deoksispergualin

Monoclonal antibodies

Infliximab, Adalimumab, Infliximab Adalimumab Etanercept Daclizumab and Basiliximab Muromonab-CD3

(TNF-alfa Antibodies, Interleukins-2 Receptor Antibodies)

Cytotoxic Agents Category anti-metabolite DNA alkylating agent inhibits dihydrofolate reductase inhibits IMP dehydrogenase

Drugs Azathioprine 6-mercaptopurine Cyclophosphamide Methotrexate Mycophenolate mofetil

Cytotoxic y drugs g act on rapidly y dividing g cells. Prevention of lymphocyte prolifertion and transformation Prevention of antibody and lymphokine synthesis

Uses of cytotoxic agents • Azathioprine; with cyclosporine and/or prednisone for – organ transplant rejection and – severe RA

• M Mycophenolate h l t mofetil; f til with ith cyclosporine l i and prednisone for renal transplants • Cyclophosphamide; for BMT • Methotrexate; GVHD prophylaxis p p y

Mechanisms of Glucocorticoid Action 1. Inhibit the p production of pro-inflammatory cytokines 2 Promote 2. P t the th production d ti of inflammatory cytokines Æ like double-edged sword

3. Induce apoptosis in inflammatory cells 4. Interfere with cytokine signals g Newton, Thorax 2000;55:603-613

Use of Glucocorticoid as I Immunosuppressant t • Most widely used effective anti-inflammatory anti 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

Glucocorticoid effects related to i immunosuppression i • Reduced immune cell content of lymph nodes, spleen and blood – lymphopenia, monocytopenia, eosinopenia, but neutrophilia

• Interference with APC, T-cell and macrophage functions

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

Antibiotic products

Calcineurin inhibitors (TCR activation blockers)

• Cyclosporine y p – commonly used with prednisone and other immunosuppressants to prevent allograft rejections in renal renal, hepatic and cardiac transplants transplants, and in RA and psoriasis – use is delayed post-transplantation due to neurotoxicity t i it concerns

• Tacrolimus (FK506) – is approved for prevention of solid-organ solid organ allograft rejection, and eczema (topical) – treatment begins prior to surgery, and is maintained well afterwards TCR=T Cell Receptor

Calcineurin inhibitors : Cyclosporine Tacrolimus and Rapamycin Cyclosporine, • CsA and FK506 act on T-cells to inhibit T-cell receptor activation and induction of cytokines • CsA C A may also l iinhibit hibit IIgE-stimulated E ti l t d mastt cellll degranulation and stimulate TGF-α expression • Rapamycin R i acts t tto inhibit i hibit llymphocyte h t response to cytokines • Rapamycin and analogues are also used to sensitize cancer cells to chemotherapeutic reagents Transforming Growth Factor

Cyclosporine •



Fungi: Tolypocladium inflatum gams Mechanism of action – Bind to imunophilin and then inhibit calcineurin activity, production of limphokin and interleukin release---<<<<<



Pharmacokinetics – Bi Bioavailability il bilit 20 20-50%, 50% T Tmax: 3 3-4 4h hrs, h half-life: lf lif 24 h 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 2,5 5-4 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

Mechanism of action of cyclosporine Cyclosporin

Imunophilin (cyclophillin)

C l Cyclosporin-imunophilin i i hili complex l Activate T cell receptor, then enhance Ca concentration Calcineurin activation (-) Akib t Akibatnya defosforilasi d f f il i NFATc NFAT bergerak b k dari d i sitoplasma it l ke k nukleus kl NFATc link to other nucleus components Activate gen to encode cytokine C t ki release Cytokine l Immune respons

Tacrolimus

(Prograf)

FStructure Fmacrolide (structure like erythromycin) FMechanism Fsimiliar to cyclosporine except binds to different protein that inhibits calcineurin (a phosphatase enzyme i involved l d in i gene transcription i i off IL-2, I 2 gamma iinterferon f and other cytokines) Bioavailability: =given by IV infusion or orally =used concomitantly with corticosteroids Ad Adverse Eff Effects: t =nephrotoxicity, increased risk of hypersensitivity, yp y hyperglycemia, yp g y GI complaints, p hypertension, neurotoxicity(tremor,headache, motor disturbances, seizures) and lymphomas

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

Monoclonal antibodies • Monoclonal antibodies are developed p to overcome: – Immune disease • Rheumatoid arthritis, SLE

– Malignancy g y • Lymphoma, breast cancer, etc

• TNF-alfa Antibodies – Infliximab, Adalimumab, Etanercept

• Interleukins-2 Receptor Antibodies – Daclizumab, Basiliximab, Muromonab-CD3

• Trastuzumab Trast mab • Rituximab • Palivizumab

Key Actions Attributed to TNFα

TNF Antagonists: TNF Antagonists: Characteristics Ch Characteristics i i Adalimumab1

Etanercept2

Infliximab3,4

H Human mAb Ab

TNF receptor-IgG1 I G1 Fusion Protein

Chi Chimeric i mAb Ab

Binding target

TNF

TNF, Lymphotoxin

TNF

Bi di affinity Binding ffi it

2.3x10 2 3 1010

1010

1.8x10 1 8 109

Half-life

~14 days

3-5.5 days

8-10 days

sc

sc

iv

Preparation

Liquid

Lyo

Lyo

Dose

40 mg eow

25 mg q2w

3-10 mg/kg q4-8w

Alone or with other DMARDs, incl MTX

Alone (or with MTX - US)

With MTX only

S Structure

Administration

Use

Bioactive Immunosuppressants • Anti Anti-thymocyte thymocyte antibodies – 3 types available • all derived from non-human sources

• Rh(D) immune globulin--ÆRh(-) mother with Rh(D)+ Rh(D) infant • OKT3, OKT4, Anti-CD20, anti-TNF, antiICAMs, and CTLA4 CTLA4-Ig Ig • Repeated blood transfusion; transfusion of apoptotic cells