Immunosuppresion

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Author:
N.Hassan
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300493
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Immunosuppresion
Updated:
2015-04-11 19:43:44
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immunlogy
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Description:
medications used for immunosuppresion
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  1. What does cyclosporin work?
    neutral hydrophilic, initially show that non-toxic concentrations completely block T-cell activation.
  2. What is the mechanism of action of cyclosporin (immunophillin binder)?
    Binds with cyclophilin

    Cs-cyclophilin binds to the calcineurin -calmodulin complex.

    Inhibits the phosphorylation of NF-AT.

    • NF-AT is required for transcription of genes
    • involved in early T-cell activation (e.g. IL-2).
  3. What is are the side effects and problems of cyclosporin?
    • Metabolism via P450; thus several drug interactions
    •  Highly nephrotoxic
    •  Vasoconstriction of renal vasculature
    •  Interstitial fibrosis of renal parenchyma with arteriolar
    • lesions
    •  Haemolytic-uraemic syndrome
    •  Hirsutism & gingival hyperplasia
    •  Neurological complications
    •  Headaches, tremors & seizures
    •  Others:
    •  Hyperlipidaemia, hepatotoxicity, hyperuricaemia
  4. What are the specific benefits of cyclosporin?
    • Significantly improved renal transplants, but
    • greatest impact in non-renal transplants
    •  Liver transplantation; 1-year survival
    • increased from 30% to 70%
    •  Its use marked the advent of specific
    • immunosuppressive agents, and still plays a
    • central role in immunosuppressive cocktails
  5. What is Tacrolimus (immunophillin binder) (FK506)?
    • Metabolite of the soil fungus Streptomyces
    • tsukubaensis (Japan)
    •  A macrolide lactone
    •  Distinct structure to CsA, but functions in a
    • similar manner and is about 100x more potent
  6. Mechanisms of action of Tacrolimus?
    •  Binds the immunophilin – FKBP12
    •  Also binds calcineurin-calmodulin
    •  Inhibits transcription in a manner similar to CsA
    •  Net effect is drug inhibition of T-cell function by
    • prevention of synthesis of important cytokines
    • (e.g. IL-2)
  7. What is the drug profile of Tracolimus?
    • Similar action to CsA, but 100x more potent
    •  CsA & FK506 bind immunophilins (but cyclophilin
    • & FKBP12 resp.)
    •  Similar side-effects to CsA (nephrotoxicity &
    • neurotoxicity). Also:
    •  Hypertension (secondary to renal tubular acidosis)
    •  Neurotoxicity – may be severe – seizures & coma
    •  Hyperglycaemia – IDDM higher with FK506 c/f CsA
    •  GI tract – (~50%) – mild cramps to severe diarrhoea
    •  Capable of rescuing patients experiencing
    • rejection
    •  Largely used in liver transplantation (rescued
    • those failing on CsA)
  8. What are the three antimetabolites?
    • 1. Aziothroprine 
    • 2. Leflunomide
    • 3. Mycophenolate mofetil
  9. What is aziothroprine?
    • Introduced in 1962 in combination with steroids;
    • used less since CsA
    •  Antimetabolite – derivative of 6-mercaptopurine
    •  Acts late in immune process – interferes with DNA
    • synthesis
    •  Suppresses proliferation of B & T cells
    •  Arrests cell cycle of promyelocytes; reduces
    • monocyte number
    •  Valuable in preventing onset of rejection
    •  Not effective in treatment of rejection episodes
  10. What are aziothroprine side effects.
    •  Bone marrow suppression
    •  Leucopenia, thrombocytopenia, anaemia
    •  Suppression reversible & dose related
    •  Hepatotoxicity
    •  GI disturbances (nausea & vomiting)
    •  Pancreatitis
    •  Alopecia
    •  Interacts strongly with allopurinol
  11. What is Mycophenolate mofetil (MMF)?
    •  FDA approved in 1995 for acute rejection of renal
    • allografts
    •  Semisynthetic derivative of mycophenolate acid
    • (MPA) isolated from the mould Penicillin glaucum
    •  MPA is active compound of MMF
    •  MPA – reversible inhibitor of IMPDH (inosine monoP
    • dehydrogenase)
    •  IMPDH – crucial rate-limiting enzyme in de novo
    • synthesis of purines
    •  Activated lymphocytes only have de novo synthesis
    •  Net effect is anti-proliferative on T- and B-cells
  12. What is the mechanism of Mycophenolate mofetil (MMF).
    •  Does not affect cytokine production or events
    • following Ag recognition (c/f CsA, FK506,
    • sirolimus)
    •  Selective antimetabolite (c/f Aza)
    •  Down-regulates adhesion molecule expression
    • on lymphocytes
    •  Inhibits proliferation of human arterial
    • smooth muscle cells (potential role in chronic
    • rejection?)
  13. Use in transplantation of Mycophenolate mofetil (MMF)
    • Used mainly in renal grafting
    •  Primary therapy for AR prevention & rescue of
    • refractory AR
    •  Lower rejection with MMF c/f Aza
    •  Prevents chronic rejection in animal models
  14. Side effects of Mycophenolate mofetil (MMF).
    • Similar to those seen with Aza
    •  GI effects (diarrhoea, gastritis, vomiting) more
    • common with MMF
    •  Clinically important leucopenia (~30%) – dose
    • dependent & reversible
  15. What are the biological immunosupressives?
    •  Polyclonal Abs used vs lymphocytes since 1960s
    •  Monoclonals now used – targeted to specific
    • cellular subsets
    •  Many directed against functional secreted
    • molecules or receptors
    •  Disadvantage – potential for anti-mouse Abs to
    • develop
    •  Thus “humanised” forms of antibody generated
    •  “humanised” forms – very long half-life, reduced
    • immunogenicity, potential for indefinite &
    • repeated use
  16. What are polyclonal antibodies?
    • Polyclonals produced by immunising animals
    • with human lymphoid tissue; serum removed
    • after immune response; relevant antibodies
    • purified
    •  After Ab treatment, lymphocyte levels fall;
    • used to prevent rejection & treat AR
    •  Antithymocyte globulin (ATGAM)
    •  thymoglobulin
  17. Example of polyclonal antibodies?
    • ATGM-Prepared by immunising horses with human
    • thymocytes
    •  Infused via central vein – peripheral infusion
    • associated with thrombophlebitis
    •  Patients pre-medicated to avoid allergic
    • reaction (methylprednisolone)
    •  Side-effects; fever, chills, arthralgia,
    • thrombocytopaenia, leucopaenia, and serum
    • sickness-like illness
    •  CMV infections more common after ATGAM (&
    • other Ab preps)
  18. What are thymoglobulin?
    •  Prepared by immunising rabbits with human
    • thymocytes
    •  Used to prevent & treat rejection in solid
    • organ trasplants
    •  Statistically superior to ATGAM in preventing
    • AR (and reversing AR) in renal transplants
    •  Not quite as efficient as OKT3, but fewer
    • side-effects
  19. What are monoclonal antibodies?
    •  Produced by hybridisation of murine antibodysecreting
    • B lymphocytes with nonsecreting
    • myeloma cell line
    •  OKT3 – most commonly used
    •  New “humanised” Abs are being developed with
    • significantly lower potential for toxicity

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