Medical Pharmacology Chapter 40: Clinical Uses: Immunosuppressive Drugs

• Overview

  • Three primary clinical uses of immunosuppressive drugs:

    • Organ Transplantation

    • Autoimmune Diseases

    • Isoimmune Disorders (e.g. hemolytic disease and the newborn)

• Organ Transplantation

  •  Tissue Typing:  donor/recipient histocompatibility match:

    • human leukocyte antigen (HLA) haplotype system

    • In vitro mixed lymphocyte culture (MLC)

    • Good histocompatibility:

      • Decreases chance of graft rejection

      • Decreases immunosuppressive therapy requirement

  •  Primary Renal Disease

    • Two primary types of glomerular injury  immune-mediated:

      •  Systemic lupus erythematosus (renal aspect)

      •  Acute glomerulonephritis

      •  Immunosuppressive treatment may be beneficial -- not definitively resolved

      •  Underlying disease may easily damage the new, transplanted kidney

        • e.g. patients with anti-basement membrane antibody® acute graft rejection (such patients may require immunosuppressive treatment for 6-8 weeks after bilateral nephrectomy, before donor transplantation)

        • Patients with systemic lupus erythematosus: poor candidates for transplant until systemic disease is controlled

    • Factors which have improved success rate in renal transplantation:

      •  Prior blood transfusions

      •  Cyclosporine (improved graft survival, patients survival, decreased patient morbidity)

        • 80% of carefully selected (not related) transplanted kidneys survive over two years

        • OKT3 (monoclonal anti-T cell antibody): significant reduction in acute graft rejection

  • Bone marrow transplantation in patients with

    • Aplastic anemia, refractory acute leukemia

      • Intensive immunosuppression before transplantation required

      • Monoclonal antibody to leukemia-, lymphoma-, neuroblastoma-associate antigens are employed to (cleanup) patient's own bone marrow: autologous transplantation

      • Monoclonal antibody-immunotoxin conjugates: may allow broader useof autologous bone marrow treatment

      • Patients who cannot receive either autologous bone marrow or a grant from an identical twin require immunosuppression postengraftment to reduce graft-versus-host syndrome {caused by donor immunocytes in marrow graft}

        •  Cyclosporine or anti-T cell antisera may be helpful in altering or preventing graft-versus-host syndrome

      • Severe combined immunodeficiency disease (congenital SCID)-- HLA- & MLC-matched donor

      • Cyclosporine -- effective immunosuppressive drugs for:

        • Renal

        • Cardiac

        • Hepatic

        • Bone marrow 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

*-Drug/treatment of choice

• Immunomodulating Drugs

  • Overview:  immunomodulating agents

    • Rationale is that immunomodulating agents may enhance immune responsiveness in patients with:

      •  Selected immunodeficiency

      •  Generalized immunodeficiency

    • Potential Clinical Uses:

      • Immunodeficiency diseases

      • Chronic infections

      • Cancer

    • Current Drugs:  most immunomodulating/immunostimulating drugs: investigational except:

      • BCG

      • Levamisole

  • Thymosin and Other Thymic Derivatives

    • Protein hormones: Synthesized by thymus epithelioid

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

    • Thymosin serum levels:

      • High -- normal childhood, early adulthood

      • Falling -- age group '30s-40s

      • Low -- elderly

      • Low -- DiGeorge's syndrome (T cell deficiency)

        • Treatment option: fetal thymus transplantation

    • 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

    • 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

• Other Immune modulators:  investigational

  • Inosiplex, cyanoaziridine agents (azimexon, ciamexon, imexon

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

  • Lndomethacin: reduced suppressor macrophage effects

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

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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