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What does cyclosporin work?
neutral hydrophilic, initially show that non-toxic concentrations completely block T-cell activation.
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).
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
- Haemolytic-uraemic syndrome
- Hirsutism & gingival hyperplasia
- Neurological complications
- Headaches, tremors & seizures
- Hyperlipidaemia, hepatotoxicity, hyperuricaemia
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
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
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)
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
- Largely used in liver transplantation (rescued
- those failing on CsA)
What are the three antimetabolites?
- 1. Aziothroprine
- 2. Leflunomide
- 3. Mycophenolate mofetil
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
- 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
What are aziothroprine side effects.
- Bone marrow suppression
- Leucopenia, thrombocytopenia, anaemia
- Suppression reversible & dose related
- GI disturbances (nausea & vomiting)
- Interacts strongly with allopurinol
What is Mycophenolate mofetil (MMF)?
- FDA approved in 1995 for acute rejection of renal
- 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
- 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
What is the mechanism of Mycophenolate mofetil (MMF).
- Does not affect cytokine production or events
- following Ag recognition (c/f CsA, FK506,
- Selective antimetabolite (c/f Aza)
- Down-regulates adhesion molecule expression
- on lymphocytes
- Inhibits proliferation of human arterial
- smooth muscle cells (potential role in chronic
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
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
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
- Thus “humanised” forms of antibody generated
- “humanised” forms – very long half-life, reduced
- immunogenicity, potential for indefinite &
- repeated use
What are polyclonal antibodies?
- Polyclonals produced by immunising animals
- with human lymphoid tissue; serum removed
- after immune response; relevant antibodies
- After Ab treatment, lymphocyte levels fall;
- used to prevent rejection & treat AR
- Antithymocyte globulin (ATGAM)
Example of polyclonal antibodies?
- ATGM-Prepared by immunising horses with human
- 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)
What are thymoglobulin?
- Prepared by immunising rabbits with human
- 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
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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