New immunosuppressive therapies are required to overcome present limitations to transplantation success.
There have been four stages in the development of therapeutic immunosuppression: anti-proliferative strategies, anti-inflammatory steroids, lymphocyte depletion and disruption of cytokines.
The molecular targets of most immunosuppressive agents available at present are widely distributed among human tissues, producing a range of adverse side effects.
Immunosuppressive therapy at present involves a three phase strategy: immunosuppression is established in the first week post-transplantation (the induction phase); for the next 90 days, the risks of acute rejection episodes are minimized while reducing unacceptable toxicity (the equilibration phase). In the maintenance phase that follows, immunosuppression is progressively reduced.
Potential fifth-generation approaches include refinements of the depletion model, manipulation of cell trafficking, interruption of the maturation of antigen-presenting cells, donor-antigen modification, identification of lymphoid-selective targets in the cytokine model and immune deviation.
Immunosuppressive therapy aims to protect transplanted organs from host responses. Individuals have unique repertoires of responses to foreign antigens and toxic reactions to immunosuppressants; the former determining the type or intensity of rejection reactions and the latter influencing the severity of iatrogenic effects. Because existing agents target molecules that are widely distributed in tissues, new strategies must selectively block lymphoid cells only, disrupt alloresponses but not innate immune responses, interact synergistically with other agents, facilitate the homeostatic process that naturally leads to graft acceptance and ideally only interrupt donor-specific responses. Approaches presently under investigation aim to alter cell trafficking, or selectively deviate the maturation of antigen-presenting cells or inhibit lymphocyte-activation cascades — events that are crucial to rejection responses.
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I would like to acknowledge the expert editorial assistance of J. A. Kochis and the skilled preparation of the elegant figures by S. Holmes. This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases.
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Kahan, B. Individuality: the barrier to optimal immunosuppression. Nat Rev Immunol 3, 831–838 (2003). https://doi.org/10.1038/nri1204
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