Mpt Immunomodulator

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    Dr. Hj. Rika Yuliwulandari, PhD

    IMMUNOMODULATOR

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    I. Immune System Overview

    II. History of Immunology

    III. Current Treatment Techniques

    Immunosuppressants

    Immunostimulants Immunization

    OVERVIEW

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    Non-specific (Basically just recognizesforeign vs native)

    First line of defense Activation (endotoxin, MAF)

    Phagocytosis (m,neutrophils, All types of White Blood

    Cells (Leukocytes), Dendritic Cells

    Lysis (NK)

    Lysis (Complement cascade)

    Antigen specific

    MHC restricted antigen

    presentation

    Humoral (antibody)

    Cell-mediated (T cells)

    DTH: Lymphokines

    produced by Ag-stimulated T cellsrecruit/activate m.

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    IMMUNE RESPONSE

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    Innate Immunity Adaptive Immunity

    No Immunologic

    memory4

    CHARACTERISTICS OF

    INNATE AND ADAPTIVE IMMUNITY

    Antigen independent

    No time lag

    Not antigen specific

    Antigen dependentA lag period

    Antigen specific

    Development

    of memory

    CMI and Humoral

    (Ab) immunity)

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    Allografts from different individuals

    Xenograft from different species

    Tissue rejection may occur byTHcells recognizingdifferent MHC II, aid TC to destroy graft(recognize MHC I)

    TH cells also release cytokines, cue macrophages

    Graft vs host disease (bone marrow transplants)

    EXAMPLE OF IMMUNOLOGIC CASES

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    Transplantation Rejection

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    Disease that leads to inflammation ofthe joints and surrounding tissues

    Can affect organs

    The immune system confuses healthytissue with foreign and begins toattack itself

    Occurs at any age, usually affectswomen more than men

    Affects joints on both sides equally

    Wrists, fingers, knees, feet, ankles

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    RHEUMATOID ARTHRITIS

    http://www.scienceclarified.com/images/uesc_01_img0050.jpg

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    Autoimmune disease

    Symptoms:

    Chest pain, fatigue, fever,

    general discomfort, hair loss,mouth sores, sensitivity tosunlight, skin rash, swollenlymph nodes, arrhythmias,blood in urine, abdominal pain,coughing up blood, patchy skin

    colors

    Other form: lupus nephrititis

    Can cause kidney failure andlead to dialysis

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    SYSTEMIC LUPUS ERYTHEMATOSUS

    http://www.taconichills.k12.ny.us/webquests/noncomdisease/lupuspic.jpg

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    Type I diabetes mellitus

    Multiple sclerosis

    Asthma

    Allergies

    OTHER IMMUNOLOGICAL

    DISEASES

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    Drugs that suppress the immune system

    Suppression overcomes rejection of organ/tissue transplantation and reduces effects ofautoimmune diseases

    Drugs that stimulate the immune systemStimulation enhances activity of immune system against infectious agents and neoplastic cells

    TWO CATEGORIES

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    Immunosuppressioninvolves downregulating immunesystem activity

    Tolerancethe idea that a body can be taught not to rejectsomething

    Immunostimulationinvolves upregulating immune systemactivity

    Immunizationactive or passive

    TREATMENT STRATEGIES

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    T-cell blockers/Calcineurin inh

    Glucocorticoids

    Cytotoxic drugs

    Antibody reagents

    CYCLOSPORINETACROLIMUSSIROLIMUS

    CORTICOSTEROIDSCYCLOPHOSPHAMIDEAZATHIOPRINEMYCOPHENOLATE

    MOFETIL

    METHOTREXATE

    ANTIBODIES11

    IMMUNOSUPPRESSIVE AGENTS

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    T-CELL BLOCKER

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    Most effective immunosuppressivedrugs

    Target intracellular signallingpathways

    Blocks induction of cytokine genes cyclosporine and tacrolimus act on

    helper T-cells: inhibit T-cellreceptor-activated induction of IL-2

    cyclosporine may also inhibit IgE-stimulated mast cell degranulation andstimulate TGF- expression

    sirolimus inhibits T-cell activationand proliferation and IL-2induction

    Structure

    T-CELL BLOCKERS/CALCINEURIN INH: CYCLOSPORINE,

    TACROLIMUS, AND SIROLIMUS

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    Tacrolimusa.k.a. FK-506

    Cyclosporin A

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    CsA and FK506 mechanism

    of action

    Complex with bindingprotein (CpN, FKBP)inhibits calcineurin (CaN)

    CaN is required for de-phosphorylation andnuclear translocation ofNFAT (nuclear factor ofactivated T cells)

    CaN inhibition, blocksNFAT resulting ininhibition of IL-2 gene

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    Oral bioavailability low and variable (20 -50%cyclosporine; 6 - 56% tacrolimus)

    new cyclosporine microemulsion gives more consistent absorption

    Almost all excreted in bile after liver metabolism byCYP3A enzymesbioavailability subject to drug interactions that can increase or decrease blood levels

    ABSORPTION AND METABOLISM OFCYCLOSPORINE, TACROLIMUS

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    Pharmacokinetics

    variable, incomplete oral absorption extensive hepatic metabolism, excreted in bile

    used alone or in combination with prednisone and azathioprine (or other

    antineoplastic drugs)

    Adverse Effects

    nephrotoxicity, hepatotoxicity, hirsutism, neurotoxicity

    Drug interactions due to induction and inhibition of hepatic cytochromeP450

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    Cyclosporine commonly used with prednisone and otherimmunosuppressants to prevent allograft rejections in renal,hepatic and cardiac transplants, and in treatment of RA andpsoriasis

    Tacrolimus is approved for prevention of solid-organ allograftrejection, and eczema (topical)

    USES OF CALCINEURIN INHIBITORS(T-CELL BLOCKERS)

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    Nephrotoxicity (C>T)

    Neurotoxicity (T>C)

    GI problems (T)

    Hypertension (C>>T)

    Hyperkalemia (T)

    Hyperglycemia and onset of diabetes

    especially with glucocorticoids (T>C)Increased incidence of infections and secondary tumors

    least of immunosuppressants

    TOXIC EFFECTS OF CYCLOSPORINE ANDTACROLIMUS

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    SIROLIMUS AND EVEROLIMUS: NEW T-CELLBLOCKERS WITH DIFFERENT ACTIVITY

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    Pre-drug sirolimus bindsFKBP, but the complexinhibits mTOR kinase

    mTOR activates p70S6K

    mTOR inhibition preventsactivity of p34cdc2 whichcomplexes with cyclin E,thus preventing eliminationof p27Kip which is anegative regulator of cdks

    and eIF-4FResults in inhibition of cellcycle proogression at G1 toS phase

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    similar poor bioavailability as cyclosporine and tacrolimus, muchlonger half-life; 62 h vs. 18 and 12 h

    same metabolism (CYP3A) and potential drug interactions

    used for prophylaxis of organ transplant rejection in combinationwith a calcineurin inhibitor and glucocorticoids

    toxicities include:hyperlipidemia, lymphocoele, anemia, leukopenia,

    thrombocytopenia, fever, GI effects, hyper- or hypokalemia

    SIROLIMUSAND EVEROLIMUS: NEW T-CELL BLOCKERS

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    GLUCOCORTICOID

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    IMMUNOSUPPRESSION

    GLUCOCORTICOIDS

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    Prednisone

    Dexamethasone

    Cortisol

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    Used with other immunosuppressants to prevent transplantrejection and GVHD (synergistic effect/lower toxicity).

    natural glucocorticoids not used due to mineralocorticoid activityprednisone and prednisolone are used orally at high -moderate doses; Very high doses of methylprednisolone

    used i.v. during acute organ rejection

    Used before and after antithymocyte Abs to inhibit allergicreactions

    GLUCOCORTICOID USES IN IMMUNOSUPPRESSION

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    GLUCOCORTICOID-SENSITIVE SITES OF IMMUNE

    RESPONDING

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    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-1

    IL-1, -4,-5,-6

    proliferation &

    differentiation

    GCX

    XGC

    X

    X

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    Reduced immune cell content inlymph nodes, spleen and blood

    lymphopenia, monocytopenia,eosinopenia, but neutrophilia

    Interference with antigenpresentation, T-cell andmacrophage functions

    GLUCOCORTICOID EFFECTS AND TOXICITY

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    Major side effects arecommon due to high dosesnecessary for suppression

    Cushings syndrome glucose intolerance

    infections

    bone dissolution

    muscle wasting

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    Growth inhibition in pediatric transplants Cataracts (10% incidence)

    Bone disease (inhibition of osteoblastic activity,decreased calcium absorption, increased urinarycalcium excretion)

    Diabetes (insulin-resistance, gluconeogenesis)

    Hyperlipidemia (40-60% posttransplant accelerated

    atherogenesis, increased incidence if combined withcalcineurin inhibitors and sirolimus)

    Hypertension (60-80% in transplant patients)

    Increased cardiovascular risk factors

    Predisposition to infection (decr. PMN, T cell activity)

    CLINICAL CONCERNS WITH CORTICOSTEROIDS

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    Usually co-administered with other suppressive agents to treat auto-immunedisorders or treatment of transplant rejection

    Exact mechanism not elucidated

    Very broad anti-inflammatory effects

    Downregulate IL-1 and IL-6

    Cause apoptosis in activated cells

    IMMUNOSUPPRESSION

    GLUCOCORTICOIDS

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    CYTOTOXIC DRUGS

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    MECHANISM OF ACTION OF

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    MECHANISM OF ACTION OFMYCOPHENOLATE MOFETIL

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    Because the salvagepathway of purine synthesis

    is less active than the de

    novo pathway, lymphocytes

    depend on PRPP conversionto IMP and in turn GMP for

    DNA synthesis

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    Azathioprine; with cyclosporine and/or prednisonefor organ transplant rejection and severe RA

    Mycophenolate mofetil; with cyclosporine andprednisone for renal transplants

    Cyclophosphamide; for BMT

    Methotrexate; GVHD prophylaxis

    USES OF CYTOTOXIC AGENTS

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    ANTIBODY REAGENTS

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    Anti-CD3 Antibodies

    Binds to chain of CD3, which is involved in T-cell antigen recognition, signaling,and proliferation

    Administration of mAb followed by depletion of T cells from bloodstream andlymphoid organs

    Lack of IL-2 production

    Reduction of multiple cytokines

    Not IL-4 and IL-10

    Used to treat organ transplant rejection

    Muromonab-CD3 (Orthoclone OKT3)

    IMMUNOSUPPRESSION

    MONOCLONAL ANTIBODIES

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    Anti-IL-2 Receptor [Anti-CD25] Antibodies

    Exact mechanism not understood

    Binds to IL-2 receptor on surface of activated T cells

    No effect on resting T cells

    Stops current response

    Daclizumab and Basiliximab

    IMMUNOSUPPRESSION

    MONOCLONAL ANTIBODIES

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    Others include

    Alemtuzumab (mAb)targets CD52, causes lympholysis by inducing apoptosis oftargeted cells

    IL-1 Inhibition

    Alefaceptprotein, interferes with T-cell activation

    IMMUNOSUPPRESSION

    OTHER AGENTS

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    IMMUNOSTIMULANTS

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    Immunostimulants are applicable during infections, immunodeficiency, andcancer

    Levamisole

    Restores depressed immune function of B and T Cells, monocytes, and macrophages

    Causes agranulocytosis

    Removed from market in 2005

    IMMUNOSTIMULANTS

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    Levamisole

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    Thalidomide

    Teratogenetic

    BUT is useful to treat erythema nodosum leprosum and multiple myeloma

    IMMUNOSTIMULANTS

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    Thalidomide

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    Interferons

    Bind to spefici cell-surface receptors that initiate series of intracellular events

    Induction of enzymes

    Inhibition of cell proliferation

    Enhancement of immune activity

    Intron A - peptide used for tumor treatment and infectious diseases;

    Actimmune - peptide that activates phagocytes and induces generation ofoxygen metabolites that are toxic to a number of microorganisms

    IMMUNOSTIMULANTS

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    ActiveStimulation with an Antigen

    PassivePreformed antibody

    IMMUNIZATION

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    Vaccines

    Administration of antigen as a whole, killed organism, or a specific protein orpeptide constituent of an organism

    Booster dosesAnticancer vaccinesimmunizing patients with APCs expressing tumor

    antigen.

    ACTIVE IMMUNIZATION

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    Indications

    Individual is deficient in antibodiesimmunodeficiency

    Individual is exposed to an agent, inadequate time for active immunization

    Rabies

    Hepatitis B

    IMMUNE GLOBULIN

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    Nonspecific immunoglobulins

    Antibody-deficiency disorders

    Specific immune globulins

    High titers of desired antibody

    Hepatitis B, Rabies, Tetanus

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    RHO (D) IMMUNE GLOBULIN

    Antibodies against Rh(D) antigen onthe surface of RBC

    Rh-negative women may be sensitizedto Foreign Rh antigen on fetal RBC

    Anti-RH Antibodies produced inmother can damage subsequent

    fetuses by lysing RBCs

    Hemolytic disease of newborn

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    Induction and maintenance of immunologic tolerance - active state ofantigenic specific nonresponsiveness

    Still experimental

    IMMUNE TOLERANCE

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    Immunosuppresion

    Calcineurin inhibitors

    Glucocorticoids

    Antimetabolites

    Newer immunosuppresive agents

    Effective control of rejection

    Glucocorticoid withdrawal

    SUMMARY

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    Active or passive

    Activestimulation with antigen to develop antigens for future prevention

    Passiveadministration of antibodies to individual already exposed or about to be

    exposed to antigens

    Vaccinesactive; administration whole, killed organism, live organism, orspecific peptide from organism

    Immune Globulinused in passive immunization; used in individualsdeficient in antibodies

    IMMUNIZATION

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