• 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: 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

  • 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

  • was 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

  • Byndomethacin: reduced suppressor macrophage effects

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