Immunosuppressive Drugs


Immunosuppressive drugs are used for the prevention or treatment of rejection after transplantation of solid organs, tissues and cells, as well as therapy of autoimmune and a variety of other diseases. Primary goals of immunosuppression are: (1) to effectively control immune responses against foreign antigens and (2) to minimise any undesired drug side effects and toxicities. The development of numerous substances, together with the understanding of their molecular action has paved the way to meet these goals, and to individualise immunosuppression. The objective of this inventory is to give a systematic overview on immunosuppressive agents currently in use or under evaluation for transplantation, as a guide for scientific research and clinical practice.

Key Concepts:

  • Immunosuppressive drugs are required for prophylaxis and therapy of rejection in solid organ transplantation.

  • A broad spectrum of immunosuppressive drugs is available and new drugs are in the pipeline or under development.

  • Some immunosuppressive drugs are critical dose drugs with a narrow therapeutic index and require therapeutic drug monitoring.

  • Calcineurin inhibitors are commonly used as the basic immunosuppressives despite their nephrotoxic potential.

  • Immunosuppressive drug combinations with different mode of actions are helpful to lower single drug dosages and avoid drug‐related adverse effects as well as to use synergistic or additive immunosuppressive effects.

  • Many factors (e.g. age, gender, liver or renal dysfunction, genetic polymorphism, drug–drug interactions, etc.) can alter the pharmacokinetics of immunosuppressive drugs.

  • Withdrawal of immunosuppressive medication in solid organ transplantation can cause graft failure.

Keywords: corticosteroids; cyclosporine A; tacrolimus; rapamycin; mycophenolate mofetil; azathioprine; monoclonal antibodies; polyclonal antibodies; new immunosuppressive drugs

Figure 1.

Interaction of graft (red) and recipient (blue) cells and tissue, for example, in kidney transplantation. The recognition of foreign antigen (afferent phase) activates a T‐cell response, which results in a specific immune response against the foreign antigen (efferent phase). The specific immune reaction from the recipient directed against the graft is called host‐versus‐graft reaction, whereas the attack against the recipient driven by the graft is a graft‐versus‐host reaction.

Figure 2.

Interaction of antigen‐presenting cell (APC) and T cell. The APC presents antigen (Ag) by major histocompatibility complex (MHC) class I or II molecules to the T cells. Antigen presented by MHC class I molecules is recognised by CD8+ T cells, and MHC class II presented antigen by CD4+ T cells. Co‐stimulatory signals are required to activate the T cells (B7–CD28, CD40–CD40L). Adhesion molecules are necessary to reinforce the intercellular contact.

Figure 3.

Intracellular T‐cell signalling. Three signals are involved in T‐cell activation. The ‘first signal’ is the interaction of MHC/Ag–TCR/CD3. The conformational alteration of the TCR/CD3 complex activates a series of (PTKs). The PTKs activate the calcineurin pathway. The soluble mediator inositol 1,4,5‐triphosphate (IP3) includes calcium release from the endoplasmic reticulum and through cell membrane channels. Calcium binds calmodulin and calcineurin. The activated calcineurin dephosphorylates NFATp, enabling it to translocate into the nucleus and binds it to cytokine promoters (e.g. IL‐2). The ‘second signal’ is believed to be transmitted by phosphatidyl inositol 3 OH‐kinase (PI3K) after activation of the co‐stimulatory receptor CD28. Cytokine production is initiated when ‘first signal’ and ‘second signal’ are simultaneously present. Absence of the co‐stimulatory signal results in anergy. Cytokines such as IL‐2 engage their receptors (third signal) and activate PTKs and consecutively TOR. Finally, two cyclin/CDK enzyme complexes that are essential for progression from G1‐ to S‐phase of DNA synthesis are activated in the nucleus. (Reproduced from Halloran, .)

Figure 4.

Targets of immunosuppressive drugs during T‐cell activation (steps 1–5). The immunosuppressive drugs are depicted according to their targets in the T‐cell activation process (see Inventory for abbreviations of drug names). The cell cycle phase is outlined additionally.



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Further Reading

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Braun, Felix, Becker, Thomas, Renders, Lutz, and Ringe, Burckhardt(Jul 2012) Immunosuppressive Drugs. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001243.pub3]