The BH3‐mimetic ABT‐737 inhibits allogeneic immune responses |
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| Authors: | Pietro E Cippà Anna K Kraus Ilka Edenhofer Stephan Segerer Jin Chen Martin Hausmann Yang Liu Annick Guimezanes Philip D Bardwell Rudolf P Wüthrich Thomas Fehr |
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| Institution: | 1. Institute of Physiology, University of Zürich, Switzerland;2. Division of Nephrology, University Hospital Zürich, Switzerland;3. Institute of Anatomy, University of Zürich, Switzerland;4. Division of Nephrology, University Hospital Zürich, Switzerland;5. Division of Gastroenterology and Hepatology, University Hospital Zürich, Switzerland;6. Centre d’Immunologie de Marseille‐Luminy, Université de la Méditerranée, Marseille, France;7. Abbott Bioresearch Center, Worcester, MA, USA |
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| Abstract: | Apoptosis controls the adaptive immune system through regulation of central and peripheral lymphocyte deletion. Therefore, substances that selectively interact with the intrinsic apoptosis pathway in lymphocytes offer unexplored opportunities to pharmacologically modulate the immune response. Here, we present evidence that the BH3‐mimetic ABT‐737 suppresses allogeneic immune responses. In vitro, ABT‐737 prevented allogeneic T‐cell activation, proliferation, and cytotoxicity by apoptosis induction, but without impairing the physiological functions of remaining viable T cells. In vivo, ABT‐737 was highly selective for lymphoid cells and inhibited allogeneic T‐ and B‐cell responses after skin transplantation. The immunosuppressive effect of ABT‐737 was markedly increased in combination with low‐dose cyclosporine A, as shown by the induction of long‐term skin graft survival without significant inflammatory infiltrates in 50% of the recipients in an MHC class I single antigen mismatched model. Thus, pharmacological targeting of Bcl‐2 proteins represents a novel immunosuppressive approach to prevent rejection of solid organ allografts. |
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| Keywords: | ABT‐737 allograft apoptosis Bcl‐2 immunosuppression transplantation |
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