mpt immunomodulator

7/28/2019 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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