Corticosteroids

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• 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

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• Effects on neutrophils/monocytes:
  •  reduced chemotaxis
  •  impaired bacteriocidal/fungicidal action
  •  no effect on monocyte/neutrophil phagocytic capability

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• Changes in leukocyte distribution:
  •  leukopenia (maybe due to lymphoid tissue sequestration)
  •  neutropenia (demargination/impaired neutrophil extravasation)

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•  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)

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•  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:

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•  Adverse Effects:
  •  Adrenal suppression
  •  Viral/bacterial/fungal infections may occur when corticosteroids are used chronically for immunosuppression

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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

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•  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.

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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

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• 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.

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• 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

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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

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• 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)

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• 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.

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New 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

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• 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

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• 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

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• 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

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