mpt immunomodulator
TRANSCRIPT
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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
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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
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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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