Immunosuppresion

neutral hydrophilic, initially show that non-toxic concentrations completely block T-cell activation.

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).

• 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

• 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

• 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

•  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)

• 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)

• 1. Aziothroprine 
• 2. Leflunomide
• 3. Mycophenolate mofetil

• 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

•  Bone marrow suppression
•  Leucopenia, thrombocytopenia, anaemia
•  Suppression reversible & dose related
•  Hepatotoxicity
•  GI disturbances (nausea & vomiting)
•  Pancreatitis
•  Alopecia
•  Interacts strongly with allopurinol

•  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

•  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?)

• 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

• Similar to those seen with Aza
•  GI effects (diarrhoea, gastritis, vomiting) more
• common with MMF
•  Clinically important leucopenia (~30%) – dose
• dependent & reversible

•  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

• 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

• 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)

•  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

•  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