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The Immune Response - why and how ?:

The Immune Response - why and how ? Discriminate: Self / Non self Destroy: Infectious invaders Dysregulated self (cancers) Immunity: Innate, Natural Adaptive, Learned

Who are involved ?:

Who are involved ? Innate Complement Granulocytes Monocytes/macrophages NK cells Mast cells Basophils Adaptive: B and T lymphocytes B: antibodies T : helper, cytolytic, suppressor.


IMMUNE MODIFIERS Immunosuppressants Immunostimulants ? Immune tolerance


Immunosuppressants Glucocorticoids Calcineurin inhibitors Cyclosporine Tacrolimus Antiproliferative / antimetabolic agents Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Others – methotrexate, cyclophosphamide, thalidomide and chlorambucil

PowerPoint Presentation:

Antibodies Antithymocyte globulin Anti CD3 monoclonal antibody Muromonab Anti IL-2 receptor antibody – Daclizumab, basiliximab Anti TNF alpha – infliximab, etanercept


Immunostimulants Levamisole Thalidomide BCG Recombinant Cytokines Interferons Interleukin-2


Immunosuppressants Organ transplantation Autoimmune diseases Life long use Infection, cancers Nephrotoxicity Diabetogenic Problem


Glucocorticoids Induce redistribution of lymphocytes – decrease in peripheral blood lymphocyte counts Intracellular receptors – regulate gene transcription Down regulation of IL-1, IL-6 Inhibition of T cell proliferation Neutrophils, Monocytes display poor chemotaxis Broad anti-inflammatory effects on multiple components of cellular immunity

USES - Glucocorticoids:

USES - Glucocorticoids Transplant rejection GVH – BM transplantation Autoimmune diseases – RA, SLE, Hematological conditions Psoriasis Inflammatory Bowel Disease, Eye conditions


Toxicity Growth retardation Avascular Necrosis of Bone Risk of Infection Poor wound healing Cataract Hyperglycemia Hypertension

Calcineurin inhibitors:

Calcineurin inhibitors Cyclosporine Tacrolimus Most effective immunosuppressive drugs Target intracellular signaling pathways Blocks Induction of cytokine genes


Cyclosporine More effective against T-cell dependent immune mechanisms – transplant rejection, autoimmunity IV, Oral Uses Organ transplantation: Kidney, Liver, Heart Rheumatoid arthritis, IBD, uveitis Psoriasis Aplastic anemia Skin Conditions- Atopic dermatitis, Alopecia Areata, Pemphigus vulgaris, Lichen planus, Pyoderma gangrenosum

Toxicity : Cyclosporine:

Toxicity : Cyclosporine Renal dysfunction Tremor Hirsuitism Hypertension Hyperlipidemia Gum hyperplasia Hyperuricemia – worsens gout Calcineurin inhibitors + Glucocorticoids = Diabetogenic

Drug Interaction : Cyclosporine:

Drug Interaction : Cyclosporine CYP 3A4 Inhibitors: CCB, Antifungals, Antibiotics, HIV PI, Grape juice Inducers: Rifampicin, Phenytoin Additive nephrotoxicity: NSAIDs


Tacrolimus Inhibits T-cell activation by inhibiting calcineurin Use Prophylaxis of solid-organ allograft rejection

Toxicity - Tacrolimus:

Toxicity - Tacrolimus Nephrotoxicity Neurotoxicity-Tremor, headache, motor disturbances, seizures GI Complaints Hypertension Hyperglycemia Risk of tumors, infections Drug interaction Synergistic nephrotoxicity with cyclosporine CYP3A4

Antiproliferative and Antimetabolic drugs:

Antiproliferative and Antimetabolic drugs Sirolimus Everolimus Azathioprine Mycophenolate Mofetil Others: Methotrexate Cyclophosphamide Thalidomide Chlorambucil


Sirolimus Inhibits T-cell activation and Proliferation Complexes with an immunophilin, Inhibits a key enzyme in cell cycle progression – mammalian target of rapamycin (mTOR)


Sirolimus Uses Prophylaxis of organ transplant rejection along with other drugs Toxicity Increase in serum cholesterol, Triglycerides Anemia Thrombocytopenia Hypokalemia Fever GI effects Risk of infection, tumors Drug Interactions : CYP 3A4


Everolimus Shorter half life compared to sirolimus Shorter time taken to reach steady state Similar toxicity, drug interactions


Azathioprine Purine antimetabolite Incorporation of false nucleotide 6 Thio-IMP 6Thio-GMP 6Thio-GTP Inhibition of cell proliferation Impairment of lymphocyte function Uses Prevention of organ transplant rejection Rheumatoid arthritis

Toxicity - Azathioprine :

Toxicity - Azathioprine Bone marrow suppression- leukopenia, thrombocytopenia, anemia Increased susceptibility to infection Hepatotoxicity Alopecia GI toxicity Drug interaction: Allopurinol

Mycophenolate Mofetil:

Mycophenolate Mofetil Prodrug  Mycophenolic acid Inhibits IMPDH – enzyme in guanine synthesis T, B cells are highly dependent on this pathway for cell proliferation Selectively inhibits lymphocyte proliferation, function – Antibody formation, cellular adhesion, migration

Uses - Mycophenolate Mofetil:

Uses - Mycophenolate Mofetil Prophylaxis of transplant rejection Combination: Glucocorticoids Calcineurin Inhibitors Toxicity GI, Hematological Diarrhea, Leucopenia Risk of Infection

Drug Interaction:

Drug Interaction Decreased absorption when co-administered with antacids Acyclovir, Gancyclovir compete with mycophenolate for tubular secretion


FTY720 S1P-R agonist – sphingosine 1 receptor Reduce recirculation of lymphocytes from lymphatic system to blood and peripheral tissues “Lymphocyte homing” – periphery into lymph node Protects graft from T-cell-mediated attack Uses Combination immunosuppression therapy in prevention of acute graft rejection


Toxicity Lymphopenia Negative chronotropic effect S1P-receptor on human atrial myocytes


Antibodies Against lymphocyte cell-surface antigens Polyclonal / Monoclonal


Antibodies Antithymocyte Globulin Monoclonal antibodies Anti-CD3 Monoclonal antibody (Muromonab-CD3) Anti-IL-2 Receptor antibody (Daclizumab, Basiliximab) Campath-1H (Alemtuzumab) Anti-TNF Agents Infliximab Etanercept Adalimumab LFA-1 Inhibitor ( lymphocyte function associated) Efalizumab

Anti-thymocyte Globulin:

Anti-thymocyte Globulin Purified gamma globulin from serum of rabbits immunized with human thymocytes Cytotoxic to lymphocytes & block lymphocyte function Uses Induction of immunosuppression – transplantation Treatment of acute transplant rejection Toxicity Hypersensitivity Risk of infection, Malignancy

Anti-CD3 Monoclonal Antibody:

Anti-CD3 Monoclonal Antibody Muromonab-CD3 Binds to CD3, a component of T-cell receptor complex involved in antigen recognition cell signaling & proliferation


Muromonab-CD3 Antibody treatment Rapid internalization of T-cell receptor Prevents subsequent antigen recognition


Uses Treatment of acute organ transplant rejection Toxicity “Cytokine release syndrome” High fever, Chills, Headache, Tremor, myalgia, arthralgia, weakness Prevention: Steroids

Anti-IL-2 Receptor Antibodies :

Anti-IL-2 Receptor Antibodies Daclizumab and Basiliximab Bind to IL-2 receptor on surface of activated T cells  Block IL-2 mediated T-cell activation Uses Prophylaxis of Acute organ rejection Toxicity Anaphylaxis, Opportunistic Infections

Campath-1H (Alemtuzumab):

Campath-1H (Alemtuzumab) Targets CD52 – expressed on lymphocytes, monocytes, Macrophages Extensive lympholysis – Prolonged T & B cell depletion Uses Renal transplantation

Anti-TNF Agents:

Anti-TNF Agents TNF – Cytokine at site of inflammation Infliximab Etanercept Adalimumab


Infliximab Uses Rheumatoid arthritis Chron’s disease – fistulae Psoriasis Psoriatic arthritis Ankylosing spondylosis Toxicity Infusion reaction – fever, urticaria, hypotension, dyspnoea Opportunistic infections – TB, RTI, UTI


Etanercept Fusion protein Ligand binding portion of Human TNF- α receptor fused to Fc portion of human IgG1 Uses Rheumatoid arthritis

moderate to severely active crohn’s disease:

moderate to severely active crohn’s disease Adalimumab Recombinant human anti-TNF mAb

LFA-1 Inhibitor - Efalizumab:

LFA-1 Inhibitor - Efalizumab Monoclonal Ab Targeting Lymphocyte Function Associated Antigen Blocks T-cell Adhesion, Activation, Trafficking Uses Organ transplantation Psoriasis

Sites of Action of Selected Immunosuppressive Agents on T-Cell Activation:

Sites of Action of Selected Immunosuppressive Agents on T-Cell Activation DRUG SITE OF ACTION Glucocorticoids Glucocorticoid response elements in DNA (regulate gene transcription) Muromonab- CD3T-cell receptor complex (blocks antigen recognition) Cyclosporine Calcineurin (inhibits phosphatase activity) Tacrolimus Calcineurin (inhibits phosphatase activity) Azathioprine Deoxyribonucleic acid (false nucleotide incorporation) Mycophenolate Mofetil Inosine monophosphate dehydrogenase (inhibits activity) Daclizumab, Basiliximab IL-2 receptor (block IL-2-mediated T-cell activation) Sirolimus Protein kinase involved in cell-cycle progression (mTOR) (inhibits activity )


Immunostimulants Levamisole Thalidomide BCG Recombinant Cytokines Interferons Interleukin-2


Immunization Vaccines Immune Globulin Rho (D) Immune Globulin


Levamisole Antihelminthic Restores depressed immune function of B, T cells, Monocytes, Macrophages Adjuvant therapy with 5FU in colon cancer Toxicity Agranulocytosis


Thalidomide Birth defect Contraindicated in women with childbearing potential Enhanced T-cell production of cytokines – IL-2, IFN- γ NK cell-mediated cytotoxicity against tumor cells USE: Multiple myeloma

Bacillus Calmette-Guerin:

Bacillus Calmette-Guerin Live, attenuated culture of BCG strain of Mycobacterium Bovis Carcinoma Bladder Adverse Effects Hypersensitivity Shock Chills


Interferons Antiviral Immunomodulatory activity Bind to cell surface receptors – initiate intracellular events Enzyme induction Inhibition of cell proliferation Enhancement of immune activities Increased Phagocytosis

Interferon alfa-2b:

Interferon alfa-2b Hairy cell leukemia Malignant melanoma Kaposi sarcoma Hepatitis B Adverse reactions Flu-like symptoms – fever, chills, headache CVS- hypotension, Arrhythmia CNS- depression, confusion

Interleukin-2 (aldesleukin):

Interleukin-2 (aldesleukin) Proliferation of cellular immunity – Lymphocytosis, eosinophilia, release of multiple cytokines – TNF, IL-1, IFN- γ Uses Metastatic renal cell carcinoma Melanoma Toxicity Cardiovascular: capillary leak syndrome, Hypotension


Immunization Active – Stimulation with an Antigen Passive – Preformed antibody

Active immunization:

Active immunization Vaccines Administration of antigen as a whole, killed organism, or a specific protein or peptide constituent of an organism Booster doses Anticancer vaccines – immunizing patients with APCs expressing tumor antigen.

Immune Globulin:

Immune Globulin Indications Individual is deficient in antibodies – immunodeficiency Individual is exposed to an agent, inadequate time for active immunization Rabies Hepatitis B

PowerPoint Presentation:

Nonspecific immunoglobulins Antibody-deficiency disorders Specific immune globulins High titers of desired antibody Hepatitis B, Rabies, Tetanus

Rho (D) Immune Globulin:

Rho (D) Immune Globulin Antibodies against Rh(D) antigen on the surface of RBC Rh-negative women may be sensitized to “Foreign” Rh antigen on fetal RBC Anti-RH Antibodies produced in mother can damage subsequent fetuses by lysing RBC’s Hemolytic disease of newborn

Immune tolerance:

Immune tolerance Induction and maintenance of immunologic tolerance - active state of antigenic specific nonresponsiveness Still experimental


Summary Immunosuppresion Calcineurin inhibitors Glucocorticoids Antimetabolites Newer immunosuppresive agents Effective control of rejection Glucocorticoid withdrawal

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