Overview

Act predominantly on T cells
- Different classes of agent act at different sites during T-cell activation
- Can be classified according to their principal mode of action in preventing the T cell-dependent rejection response
Immunosuppression Regimens
- Most use a combination of agents

Calcineurin inhibitor

Ciclosporin and Tacrolimus
- Mainstay of most modern immunosuppressive protocols
Structurally distinct but work through same pathway
- Block activity of calcineurin within the cytoplasm of the T cell
- Calcineurin plays a critical role in transcription of IL-2, (the main T-cell growth factor) and other cytokines after T-cell activation
- Blocks cytokine synthesis
Similar efficacy, choice between two is unit preference
Share a number of side effects
- Most notable is nephrotoxicity
- May reduce dose if renal transplant has ATN
Action depends on blood concentration – needs monitoring!

Immunomodulators in the context of IBD
- Stops lymphocyte proliferation and clonal expansion
Azathioprine
- Converted in liver to active metabolite: 6-mercaptopurine
- Blocks purine metabolism - thereby inhibits cellular proliferation
Mycophenolate Mofetil (MMF)
- Newer and has now replaced azathioprine as the agent of choice in many centres
- Converted to its active metabolite, mycophenolic acid
- Inhibits enzyme which is the rate-limiting enzyme in purine nucleotide synthesis
- Lymphocytes do not have a salvage pathway for purine synthesis ⇒ Ability to proliferate selectively impaired
Main side effects:
- Bone marrow suppression
- Gastrointestinal symptoms

Monoclonal Antibodies
- E.g. OKT3
- Directed against the IL-2 receptor on T lymphocytes (CD25)
- Commonly given at the time of transplantation to temporarily augment the effects of calcineurin blockade during the early post-transplant period
- Effect lasts for a few weeks only and they lack any significant agent- specific side-effects
Polyclonal Antibodies
- Anti-Lymphocyte Globulin (ALG) or Anti-Lymphocyte Serum (ALS)
- Aso widely used as a more potent and alternative induction agent
- Cause a temporary depletion of circulating lymphocytes
- Reduces rejection
- But may lead to increase in infection and malignancy

Sirolimus and Everolimus
Inhibit mTOR
- Interfere with intracellular signaling from the IL-2 receptor
- Arrest T-cell division in the G1 phase
Not nephrotoxic (cf Calcineurin inhibitors)
Adverse Effects:
- Lymphocele formation
- Impaired wound healing
- Adverse effect on blood lipid profile
- Thrombocytopenia
- Potentially serious pneumonitis

Principles of Immunosuppression

Side Effects of Immunosuppression