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Clinical Uses: Immunosuppressive Drugs

Organ Transplantation:

Autoimmune disorders

  • Effectiveness Varies

    • Remissions may be obtained in:

      • autoimmune hemolytic anemia

      • idiopathic thrombocytopenic purpura

        •  plasma immunoabsorption: FDA-approved for AIDS-related ITP

      • type I diabetes mellitus

      • Hashimoto's thyroiditis

      • Temporal arteritis

    • Improvement:

      • systemic lupus erythematosus

      • acute glomerulonephritis

      • acquired factor VIII inhibitors (antibodies)

      • inflammatory myopathy

      • scleroderma

      • rheumatoid arthritis

  • Idiopathic aplastic anemia: possible autoimmune disease

    • may occur as a result of increased CD8+ T suppressor cell activity

      •  Hematopoietic suppression may be mediated by IFNg.

      •  ATG treatment may be a benefit to aplastic anemia patients

      •  plasma immunoabsorption may also be a promising new approach

  • Mechanism of drug action:

    • probably immunosuppressive properties

    • anti-inflammatory effects contribute

    • Effective drugs include:

      •  prednisone

      •  cyclosporine

      •  cyclophosphamide

      •  mercaptopurine

      •  antilymphocyte globulin

 

Summary of Clinical Immunosuppressive Agent Use (adapted from: Table 56-1, Barbuto, J.A.M, Akporiaye, E.T. and Hersh, E.M. Immunopharmacology, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 931)

Autoimmune disease

Immunosuppressive Agents

Idiopathic thrombocytopenic purpura

prednisone*, vincristine, mercaptopurine, azathioprine, high-dose gamma globulin, plasma immune absorption

Autoimmune hemolytic anemia

prednisone*, cyclophosphamide, chlorambucil, mercaptopurine, azathioprine, high-dose gamma globulin

Acute glomerulonephritis

prednisone*,mercaptopurine, cyclophosphamide

Acquired factor XIII antibodies

cyclophosphamide plus factor XIII

Miscellaneous "autoreactive" disorders {systemic lupus erythematosus, rheumatoid arthritis, Wegener's gramulomatosis, chronic active hepatitis, lipoid nephrosis, inflammatory bowel disease}

prednisone, cyclophosphamide, azathioprine, cyclosporine

Isoimmune Disease

 

Hemolytic anemia of the newborn

RHo(D) immune globulin*

Organ transplantation

 

Renal/Heart

cyclosporine, azathioprine, prednisone, antilymphocyte globulin (ALG), OKT3 monoclonal antibody, tacrolimus

Liver

cyclosporine, prednisone, azathioprine, tacrolimus

Bone marrow (HLA-matched)

cyclosporine, cyclophosphamide, prednisone, methotrexate, antilymphocyte globulin (ALG), total body irradiation, donor marrow purging with monoclonal anti-T cell antibodies, immunotoxins

*-Drug/treatment of choice

Immunomodulating Drugs

  • Overview:immunomodulating agents

  • Thymosin & Other Thymic Derivatives

    • Protein hormones: Synthesized by thymus epithelioid

    • Thymosin: provides T cell specificity to uncommitted lymphoid stem cells

    • Thymosin serum levels:

    • Mechanism: Thymosin:

      • enhance maturation of pre-T cells

    • Thymosin Derivatives:

      • thymosin-derived recombinant peptide:

        • thymosin a-1:

          • enhances IL-2 production

          • increases IL-2 receptor expression on T- lymphocytes

          • Clinical Trials: thymosin a-1:

            • cancer

            • chronic active hepatitis

    • Thymus-related peptides: T cell-stimulation

      • Thymopentin

      • Thymic humoral factor

  • Cytokines:

    • Potential Clinical Uses: treatment --

      • infections

      • autoimmune disorders

      • inflammatory disorders

      • cancer

    • Interferon (IFN)-a:

      • FDA approved: various neoplasms

        • Hairy cell leukemia

        • malignant melanoma

        • Kaposi sarcoma

      • FDA approved: Hepatitis B & C

      • Other uses:

        • activity in renal cell carcinoma

        • carcinoid syndrome

        • T cell leukemia

    • Interferon (IFN)-b:

      • FDA approval: relapsing-type multiple sclerosis

    • Interferon (IFN)- g :

      • FDA approval: chronic granulomatous disease

    • IL-2:

      • FDA approval: metastatic renal cell carcinoma

    • widespread investigational assessment of cytokine clinical usefulness

  • Levamisole:

    • enhances immune response:

      • increases size of delayed hypersensitivity reactions /T-cell-mediated immunity

      • FDA approval: in combination with flurouracil in treating postsurgical Dukes class C colorectal cancer

        • reduces recurrences-probable mechanism:

          • macrophage activation

  • Roquinimex -- investigational

    • increases NK cell number/reactivity

    • stimulates T and B cells

    • may stimulate immune function (post-bone marrow transplants)

  • BCG (Bacille Calmette-Guerin)

    • Mycobacterium bovis-viable strain; immunization against tuberculosis

    • has been used:

      • nonspecific adjuvant

      • immunostiumulant in cancer

    • Proposed Mechanism: macrophage activation

 

  • Other Immune modulators-investigational

    • Inosiplex, cyanoaziridine agents (azimexon, ciamexon, imexon)

    • diethyl dithiocarbamate -- may slow HIV progression

    • low-dose cyclophosphamide administered before immunization with tumor vaccine may increase immune response

    • indomethacin: reduced suppressor macrophage effects

    • cimetadine (and other H2 blockers) reduce suppressor lymphocyte activity

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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