school of medicine universitas sumatera...
Post on 11-May-2018
214 Views
Preview:
TRANSCRIPT
Immuno modulatorImmuno-modulator
Prof.AznanLelo,dr,PhD SpFK,dr.Datten Bangun MSc,SpFK
Dept. Pharmacology & Therapeutic
School of MedicineUniversitas Sumatera Utara
13 Mei 2009, KBK-FK USU, Medan
Introduction :Patients with autoimmune disease- Patients with autoimmune disease, and patients who received
l d itransplanted tissue or organs, require therapy with immunosuppressive drugs.
± 50 years ago, started with :- CorticosteroidsCorticosteroids- Antimetabolites- Alkylating agentsAlkylating agents..
Over the past 20 years,the field of immunosuppression has shifted to specificimmunosuppression has shifted to specific inhibitors of immunity that affect distinct immune pathwaysaffect distinct immune pathways.
This is important because:= greater efficacy greater efficacy= reduced toxicity= more insight are gained into the= more insight are gained into the
operation of the immune system
Immune ProblemsImmune Problems• Major Histocompatibility Complex (MHC)Major Histocompatibility Complex (MHC)
is the major concern.• Rejections: -. Antibody mediatedj y
-. T cells mediated• HIV/AIDS• HIV/AIDS• Chronic infection
M li• Malignancy• Organ transplantation
Simplified Schematic of I R
proliferation & diff ti ti
an Immune Response
Class I
CD8+ T cells CD8+ cytolytic T cellsdifferentiation
CD4+ T cells CD4+ immune cellsAPC
Class II
proliferation & differentiation
(delayed hypersensitivity)CytokinesCostim. Mol.
IL 4 5 6Protein antigens B cells Plasma cells
proliferation & differentiation
IL-4,-5,-6
MHC class II/peptidesAPCs
antibodyproduction
differentiation
APC=Antigen Presenting Cell
ImmunostimulatorImmunostimulators are agents that increase the immune responses.
Natural Synthetic1 Vaccine BCG 1 Chloroquine
increase the immune responses.
1. Vaccine BCG 1. Chloroquine2. Interferon 2. Levamisol3 Interleukin 3 Isoprinosine3. Interleukin 3. Isoprinosine4. Phyllantus niruri (Meniran)
4. Phyllantus niruri (Meniran)
5. Tincture Echinacea
5. Tincture Echinacea
Andrographis paniculata (Sambiloto)6.Andrographis paniculata (Sambiloto)
BCG (Bacille Calmette-Guerin)BCG (Bacille Calmette Guerin)• Vaccine against tuberculosisg• Mechanism of action: unknown, may be activate
– macrophages, – NK cellsNK cells, – B cells, and – various T cells
• in vitro and• in vitro and • in vivo
• Indication: treatment and prophylaxis of bladder carcinoma (in situ)carcinoma (in situ)
• Side effects: fever, nausea, vomiting, cough and reddish of skin
CytokinesGeneral properties of cytokinesGeneral properties of cytokines.• A large and heterogeneous of protein with many
functions.-- pleiotropic• Synthesized within lymphoreticular cells• Synthesized within lymphoreticular 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 receptor on target cells.p p g• Rarely work alone.• Chemotaxis
The first group discovered,the Interferon,were followed by the Colony-Stimulating Factors(CSFs)
CytokinesRole of cytokines in disease
B t i l ti h k• Bacterial septic shock• Cancer• Inflammatory• AutoimmuneAutoimmune
eg. IFN-α : treatment of neoplasm IFN β t t t f lti l l iIFN-β : treatment of multiple sclerosisIFN-γ : chronic granulomatousCSFs : regulate the proliferation and differentiation
of bone-marrow progenitor cells
InterferonIFNs interact with cell receptor to produce a wide variety of effects thatIFNs interact with cell receptor to produce a wide variety of effects thatdepend on the cell and IFNs types.
Interferon Mechanism of Action Indication
Alfa= natural lymphokin
Activate:• macrophage • T cell NK cell
Antiviral Hepatitis C
T cell NK cell• B cell Ab
Beta • anti-inflammatory action• repairing the destroyed
Multiple-Sclerosis (MS)• repairing the destroyed
BBB in MS patient
Gamma activate macrophages • Anti-viral, • Anti tumor kidney Ca= immune interferon • Anti-tumor, kidney Ca• Chronic
granulomatous
ChloroquineChloroquine
• Quinolin derivative• Quinolin derivative• Mechanism of action:
– inhibit DNA Polymerase and RNA Polymerase. i hibi f i f h– inhibit fusion of macrophage
– irreversibly inhibit NO synthesis• Indication: rheumatoid arthritis, psoriasis• Side effects: ototoxic
Levamisole• Anti parasitic agent, imidazothiazole synthetic
M h i f ti t ll d t d• Mechanism of action: not well understood– Stimulates antibody formation to various antigens, – stimulating T-cell activation and proliferation, g– 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 agranulocytosisagranulocytosis
Other ImmunomodulatorOther Immunomodulator
IsoprinosineIsoprinosine• purine synthetic
Old d f h it l t• 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.T cell and monocyte functional activities.
Other Immunomodulator1.Phyllantus niruri (Meniran)Traditional herbTraditional herb • Increases production of
– IFN-γ &IFN γ & – TNF-α
• Used as adjuvant in patient with HIV infection & TB jtherapy.
2.Echinacea tinctureTraditional herb, Echinae purpurea (ruddeckia).Anti-oxidantAnti oxidant
Other ImmunomodulatorAndrographis paniculata (Sambiloto)
Other Immunomodulatorg p p ( )
• Traditional herb used for treatment of• Traditional herb, used for treatment of dysentery, diarrhea, or malaria.I d• Increased – Macrophage Migration Index (MMI) and – Lymphocytes proliferation.
• Legal drugs for HIV infection in Germany.
General Principles of ImmunosuppressionImmunosuppression
• Primary immune responses are more easilyPrimary immune responses are more easily suppressed than secondary (memory)
• Different immunosuppressants have differentDifferent immunosuppressants have different effects on different immune reactions
• Suppression is more likely achieved if therapy pp y pybegins before exposure to the immunogen----
as in Rh(-) mother with Rh(+) infant.
Ideal ImmunosuppressantIdeal Immunosuppressant
St l i i• Strongly immunosuppressive• Specific, no overall immunosuppression• Anti-infection ability• Low Toxicity for Vital OrgansLow Toxicity for Vital Organs• Low cost
L i i bi ti it• Long in vivo bioactivity• 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 t t ib t t th th icomponent may contribute to the pathogenesis:
– 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– some haematological disorders
Currently used ImmunosuppressantsCategory Drugs
Cytotoxic Agentsanti-metabolite Azathioprine
DNA alkylating agent Cyclophosphamideinhibits dihydrofolate reductase Methotrexatey
inhibits IMP dehydrogenase Mycophenolate mofetil
Steroids Prednisone, Methylprednisolone, Dexamethasone etcDexamethasone, etc
Biological Agents ALG (anti-lymphocyte globulins), ATG (anti-thymocyte globulins), OKT3
F ng s Prod cts Cyclosporine Tacrolimus (FK506) SirolimusFungus Products Cyclosporine, Tacrolimus (FK506), Sirolimus,Rapamicin, Mycophenolate mofetil, 15-Deoksispergualin
Monoclonal antibodies Infliximab Adalimumab EtanerceptMonoclonal antibodies(TNF-alfa Antibodies, Interleukins-2 Receptor Antibodies)
Infliximab, Adalimumab, EtanerceptDaclizumab and BasiliximabMuromonab-CD3
Cytotoxic AgentsCategory Drugs
anti-metabolite Azathioprine6-mercaptopurine
DNA alkylating agent Cyclophosphamideinhibits Methotrexate
dihydrofolate reductaseMethotrexate
inhibits Mycophenolate mofetilIMP dehydrogenase
Mycophenolate mofetil
Cytotoxic drugs act on rapidly dividing cells.y g y gPrevention of lymphocyte prolifertion and transformationPrevention of antibody and lymphokine synthesis
Uses of cytotoxic agentsUses of cytotoxic agents
• Azathioprine; with cyclosporine and/orAzathioprine; with cyclosporine and/or prednisone for
organ transplant rejection and– organ transplant rejection and – severe RA
M h l t f til ith l i• Mycophenolate mofetil; with cyclosporine and prednisone for renal transplants
• Cyclophosphamide; for BMT• Methotrexate; GVHD prophylaxis p p y
Mechanisms of Glucocorticoid ActionMechanisms of Glucocorticoid Action
1. Inhibit the production of ppro-inflammatory cytokines
2 P t th d ti2. Promote the production of inflammatory cytokines
like double-edged sword
3. Induce apoptosis in inflammatory cellsinflammatory cells
4. Interfere with cytokine signalsg
Newton, Thorax 2000;55:603-613
Use of Glucocorticoid as I tImmunosuppressant
• Most widely used effective anti-inflammatory drugsMost widely used effective 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 atPrednisone 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 reactionsallergic reactions
Glucocorticoid effects related to i iimmunosuppression
• 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 CorticosteroidsG th i hibiti i di t i t l t• Growth inhibition in pediatric transplants
• Cataracts (10% incidence)• Bone disease (inhibition of osteoblastic activity, decreased ( y,
calcium absorption, increased urinary calcium excretion)• Diabetes (insulin-resistance, gluconeogenesis)• Hyperlipidemia (40 60% posttransplant accelerated• 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 activityPredisposition to infection (decr. PMN, T cell activity.• Cushing syndrome
Calcineurin inhibitors(TCR activation blockers)
Antibioticproducts
(TCR activation blockers)
• Cyclosporine y p– commonly used with prednisone and other
immunosuppressants to prevent allograft rejections in renal hepatic and cardiac transplants and in RAin renal, hepatic and cardiac transplants, and in RA and psoriasis
– use is delayed post-transplantation due to t i itneurotoxicity concerns
• Tacrolimus (FK506) – is approved for prevention of solid-organ allograftis approved for prevention of solid organ allograft
rejection, and eczema (topical)– treatment begins prior to surgery, and is maintained
well afterwardswell afterwards
TCR=T Cell Receptor
Calcineurin inhibitors :Cyclosporine Tacrolimus and RapamycinCyclosporine, Tacrolimus and Rapamycin
• CsA and FK506 act on T-cells to inhibit T-cell receptor activation and induction of cytokinesC A l i hibit I E ti l t d t ll• CsA may also inhibit IgE-stimulated mast cell degranulation and stimulate TGF-α expressionR i t t i hibit l h t• Rapamycin acts to inhibit lymphocyte response to cytokines
• Rapamycin and analogues are also used to• Rapamycin and analogues are also used to sensitize cancer cells to chemotherapeutic reagentsreagents
Transforming Growth Factor
Cyclosporine• Fungi: Tolypocladium inflatum gams• Mechanism of actionMechanism of action
– Bind to imunophilin and then inhibit calcineurin activity, production of limphokin and interleukin release---<<<<<
• PharmacokineticsBi il bilit 20 50% T 3 4 h h lf lif 24 h– Bioavailability 20-50%, Tmax: 3-4 hrs, half-life: 24 hrs
– Hepatic metabolism CYP3A4– Excretion: bile and urine
• IndicationIndication– 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/dRheumatoid 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
Mechanism of action of cyclosporineImunophilin (cyclophillin)Cyclosporin
C l i i hili lCyclosporin-imunophilin complex
Activate T cell receptor, then enhance Ca concentration
( - )
Akib t d f f il i NFAT b k d i it l k kl
Calcineurin activation
Akibatnya defosforilasi NFATc bergerak dari sitoplasma ke nukleus
NFATc link to other nucleus components
Activate gen to encode cytokine
C t ki lCytokine release
Immune respons
Tacrolimus (Prograf)Tacrolimus (Prograf)StructureStructure
macrolide (structure like erythromycin)MechanismMechanism
similiar to cyclosporine except binds to different protein that inhibits calcineurin (a phosphatase enzyme i l d i i i f I 2 i finvolved in gene transcription of IL-2, gamma interferon and other cytokines)
Bioavailability: =given by IV infusion or orallyBioavailability: =given by IV infusion or orally=used concomitantly with cortico-steroids
Ad Eff tAdverse Effects:=nephrotoxicity, increased risk of
hypersensitivity, hyperglycemia, GI complaints, yp y yp g y phypertension, neurotoxicity(tremor,headache, motor disturbances, seizures) and lymphomas
Monoclonal antibodiesMonoclonal antibodies• Monoclonal antibodies are developed to overcome:p
– Immune disease• Rheumatoid arthritis, SLE
– Malignancyg y• Lymphoma, breast cancer, etc
• TNF-alfa Antibodies – Infliximab, Adalimumab, EtanerceptInfliximab, Adalimumab, Etanercept
• Interleukins-2 Receptor Antibodies– Daclizumab, Basiliximab, Muromonab-CD3
Trast mab• Trastuzumab• Rituximab• Palivizumab
TNF Antagonists: Ch i iTNF Antagonists: CharacteristicsCharacteristicsTNF Antagonists: Characteristics
S H Ab TNF I G1 Chi i Ab
Adalimumab1 Etanercept2 Infliximab3,4
Structure Human mAb TNF receptor-IgG1 Chimeric mAb Fusion Protein
Binding target TNF TNF, Lymphotoxin TNF
Bi di ffi it 2 3 1010 1010 1 8 109Binding affinity 2.3x1010 1010 1.8x109
Half-life ~14 days 3-5.5 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 onlyDMARDs, incl MTX (or with MTX - US)
Bioactive ImmunosuppressantsBioactive Immunosuppressants
• Anti-thymocyte antibodiesAnti thymocyte antibodies– 3 types available
• all derived from non-human sources
• Rh(D) immune globulin-- Rh(-) motherwith Rh(D)+ infantwith Rh(D) infant
• OKT3, OKT4, Anti-CD20, anti-TNF, anti-ICAMs, and CTLA4-IgICAMs, and CTLA4 Ig
• Repeated blood transfusion; transfusion of apoptotic cellsapoptotic cells
top related