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-α--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-α

  •  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-α and 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