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Prepublished online as a Blood First Edition Paper on July 31, 2003; DOI 10.1182/blood-2003-04-1075.
Submitted April 7, 2003
Accepted July 21, 2003
Cathepsin B-dependent apoptosis triggered by antithymocyte globulins (ATGs): a novel mechanism of T cell depletion
Marie-Cecile Michallet, Frederic Saltel, Xavier Preville, Monique Flacher, Jean-Pierre Revillard, and Laurent Genestier*
Laboratoire d'Immunopharmacologie, INSERM, Unite 503, Centre d'Etudes et de Recherche en Virologie et Immunologie, Lyon, France
Laboratoire de Biologie Moléculaire et Cellulaire, UMR 5665 CNRS/ENS, Lyon, France
BT PHARMA-BIOTOP, Institut Pasteur, Paris, France
Laboratoire d'Immunopharmacologie, INSERM, Unite 503, Centre d'Etudes et de Recherche en Virologie et Immunologie, Lyon, France; Centre d'Etudes et de Recherche en Virologie et Immunologie, INSERM, Unite 404, Lyon, France
* Corresponding author; email: genestier{at}cervi-lyon.inserm.fr.
Antithymocyte globulins (ATGs), the IgG fraction of sera from rabbits or horses immunized with human thymocytes or T cell lines, are used in conditioning regimens for bone marrow transplantation, treatment of acute graft-versus-host disease, prevention or treatment of acute rejection in organ transplantation and in severe bone marrow aplasia. In nonhuman primates, ATGs induce a rapid, dose-dependent, T cell depletion in peripheral lymphoid tissues, where apoptotic cells can be demonstrated in T cell zones. We show here that increasing ATG concentrations in vitro resulted in a reduction of lymphocyte proliferative responses, associated with a rapid increase in the percentage of apoptotic cells. Apoptosis did not require prior exposure to interleukin-2, nor was it the consequence of CD178/CD95 or TNF/TNF-R interactions, and was therefore clearly different from activation-induced cell death. Cytochrome c release, caspase-9 and caspase-3 activation were not implicated, excluding a direct involvement of the intrinsic mitochondrial pathway. The cystein protease inhibitor E64d, as well as cathepsin B specific inhibitors, conferred significant protection, while apoptosis was associated with the release of active cathepsin B into the cytosol. The data demonstrate a role for cathepsin B in T cell apoptosis induced by ATGs at concentrations achieved during clinical use.
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