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Immunosuppressive Agents

 

Sites of Drug Action

  • Rho(D) immune globulin-- Site 1.

  • Antilymphocyte globulin and monoclonal anti-T cell antiboides: Sites 1,2, 3.

  • Cyclophosphamide: Site 2.

  • Dactinomycin: Sites 2,3.

  • Methotrexate: Site 2.

  • Azathioprine: Site 2.

  • Cyclosporine, tacrolimus: Sites 2,3.

  • Prednisone: Sites 2,6

Corticosteroids

  • Lympholytic activity

  • reduces lymphoid content/size of:

    • spleen

    • lymph nodes

  • No toxic effect on myeloid/erythroid stem cells in bone marrow

  • May interfere with cell cycle of activated lymphoid cells

  • Cytotoxic to certain T cell subsets

    • immunologic effects: cell function modification

  • Inhibit production of inflammatory mediators:

    • platelet-activating factor

    • leukotrienes

    • prostaglandins

    • histamine

    • bradykinin

  • Effects on neutrophils/monocytes:

    •  reduced chemotaxis

    •  impaired bacteriocidal/fungicidal action

    •  no effect on monocyte/neutrophil phagocytic capability

  • Changes in leukocyte distribution:

    •  leukopenia (maybe due to lymphoid tissue sequestration)

    •  neutropenia (demargination/impaired neutrophil extravasation)

  •  Cytokine Effects:

    • Inhibition of monocyte IL-1 production decrease in IL-2 and IFNg production

  • Cellular immunity: more affected that humoral immunity (yet, primary antibody response diminished)

  •  Clinical Use: Glucocorticoids

    • Immunosuppression; anti-inflammatory effects

    • Clinical Indications:

      • Autoimmune disorders:

        •  hemolytic anemia

        •  idiopathic thrombocytopenic purpura

        •  inflammatory bowel disease

        •  lupus erythematosus

        •  Hashimoto's thyroiditis

        •  bronchial asthma

        •  modulation: allergic reactions

      • Organ transplantation -- especially during rejection crises:

  •  Adverse Effects:

    •  Adrenal suppression

    •  Viral/bacterial/fungal infections may occur when corticosteroids are used chronically for immunosuppression

 

Cyclosporine

  • Pharmacokinetics/Pharmacodynamics:

    • Slow, incomplete absorption (20-50% after oral administration);

    • Elimination half-life: 24 hours

    • Cyclosporine -- completely metabolized; biliary excretion

    • Fat-soluble peptide antibiotic

  • Site of action: early stage in antigen receptor-induced T cell differentiation -- blocks T cell activation

  • Inhibits gene transcription of:

    • IL-2

    • IL-3

    • IFNg

    • other factors produced by antigen-stimulate T cells

    • Does not block effects of these factors on primed T cells or interaction with antigen

  • Immunosuppressive agent: highly efficacious in human organ transplantation treating graft-versus-host syndrome

  • Effective in treatment of some autoimmune disorders

  • Cyclosporine +/- prednisone-- lower rejection and infection complication incidence compared to combination treatment with azathioprine, prednisone, antilymphocyte antibodies.

  •  Adverse Effects -- toxicities

    • nephrotoxicity

    • hyperglycemia

    • hyperlipidemia

    • osteoporosis

    • transient liver dysfunction

    • in children after heart transplantation: increased cholelithiasis incidence

  •  Clinical Use:

    • sole immunosuppressive (monotherapy): cadaveric kidney, pancreas, and liver transplants

    • Useful in heart transplants

    • Useful in autoimmune disorders including:

      •  rheumatoid arthritis

      •  uveitis

      •  early treatment of type one diabetes

        • two-thirds of children (early diabetic presentations) are able to stop or reduced insulin treatment within six weeks after cyclosporine treatment

          • Mechanism (proposed): cyclosporine interferes with anti-islet cell autoimmune process, causative for Type I diabetes.

 

Tacrolimus (FK 506)

  • Immunosuppressive macrolide antibiotic

  • Pharmacokinetics/pharmacodynamics:

    • oral or intravenous administration

    • oral administration -- peak concentration: 1-4 hours

    • IV administration: half-life -- 9-12 hours

    • Drug Metabolism: hepatic P450 system

  • Mechanism action: similar to cyclosporine

    • Cyclosporine and Tacrolimus: bind to cytoplasmic peptidyl-prolyl-isomerases:

      •  cyclosporine binds to cyclophilin

      •  tacrolimus binds to FK binding protein

      •  resultant complexes inhibit calcineurin (cytoplasmic phosphatase)

        • calcineurin activity: responsible for activation of a T cell-specific transcription factors, NF-AT.

  • Tacrolimus: inhibits immune responses (10-100 times more potent of cyclosporine) approved for use in liver transplantation

    • Adverse/Toxic Effects:

      • nephrotoxicity

      • neural toxicity

      • hyperglycemia (requires insulin supplementation)

      • gastrointestinal disturbance

      • higher incidence of serious toxicity in liver transplant patients trade with tacrolimus compared to the cyclosporine-treated patients

Interferons

  • Three families:

    • IFN-a--type I IFNs; acid-stable proteins; act on same target cell receptor

    • IFN-b--type I IFNs; acid-stable proteins; act on same target cell receptor

    • IFN-g--type II IFN: acid-labile; acts on separate target cell receptors

  • Type I IFNs -- typically induced by viral infections;

    •  leukocyte production- IFN-a

    •  Fibroblasts; endothelial cells-IFN-b

    •  Activated T lymphocytes-IFN-g

  • Interferon Effects:

    • IFN-g: Immune Enhancing

      • increased antigen presentations with macrophage, natural killer cell, cytotoxic T lymphocyte activation

    • IFN-a & IFN-b:effective in inhibiting cellular proliferation (more effective than IFN-g in this regard)

  • Some Clinical Uses:

    • immunotherapy in cancer

    • multiple sclerosis (IFN-b): reduced rate of exacerbation/less disease severity; minimal side effects; FT approved for this indication.

Newer Immunosuppressive Agents

  • Mycophenolate mofetil-- derivative of mycophenolic acid (isolated from Penicillium glaucum)

    • inhibits T and B lymphocytes responses

      • including mitogen/mixed lymphocyte responses

      • inhibits de novo purine synthesis pathway

    • Possible Clinical Use:

      •  refractory kidney/liver transplant rejection

      •  in combination with prednisone: alternative to cyclosporine or tacrolimus (if patients intolerant of those drugs)

      •  may reduce acute rejection in cadaveric kidney allografts

      • may replace azathioprine in heart transplantation (reduced rejection frequency -- without major side effects reprint

      •  Gastrointestinal Side Effects

      •  Related drugs of interest:

        • mizoribine

        • brequinar sodium

  • 15-desoxyspergualin

    • Potent Antimonocytic Effects:

      • decreased MAC antigen expression

      • decreased antigen processing/presentation

      • inhibition free radical generation

      • antilymphocytic effects:

        • reduced antibody production after immunization

        • suppression: cytotoxic cell generation during mixed lymphocyte reaction

      • Acts late in T cell and B-cell responses to activation (suppressing secondary antibody responses)

    • Clinical Uses:15-desoxyspergualin

      • management of acute rejection: renal transplantation

      • maybe effective in management of rejection in pancreas/heart transplantation

  • Sirolimus (rapamycin)

    •  macrolide antibiotic

    •  structural similarity: tacrolimus

    •  binds to FK-binding protein (FKBP)

    • Mechanism of Action: Sirolimus

      • Blocks T cell response to cytokines

      • Inhibits B-cell proliferation

      • Inhibits immunoglobulin production

      • Inhibits cell profilerative responds to CSF (colony stimulating factors)

    • Possible Clinical Uses: Sirolimus

      • management of kidney/heart allografts

      • + cyclosporine: psoriasis, uvoretinitis

  • Thalidomide:

    • Significant teratogenic effects when used during pregnancy

    • Significant immunomodulatory effects:

    • Clinical Uses:Thalidomide

      • Management of some leprosy reactions

      • treatment of skin manifestations: lupus erythematosus

Primary Source: Barbuto, J.A.M, Akporiaye, E.T. and Hersh, E.M. Immunopharmacology, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 916-940
Haynes, B. F., Fauci, A.S. Disorders of the Immune System, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1753-1776.
Carpenter, C. B. The Major Histocompatibility Gene Complex, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1777-1782.
Cooper,M.D, and Lawton III, A. R. Primary Immune Deficiency Diseases, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1783-1791.
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