Card Set Information
medications used for immunosuppresion
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
Vasoconstriction of renal vasculature
Interstitial fibrosis of renal parenchyma with arteriolar
Hirsutism & gingival hyperplasia
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
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
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 &
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?
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
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
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
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
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 &
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
Side-effects; fever, chills, arthralgia,
thrombocytopaenia, leucopaenia, and serum
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
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