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*INSERM Unité 542, Villejuif, France;
Département de Néphrologie, Hôpital Bicêtre, Le Kremlin-Bicêtre Université, Paris-Sud Le Kremlin-Bicêtre, France;
Commissariat à l’Energie Atomique, I2BM, Service de Recherches en Hemato-Immunologie, Paris, France;
Université Paris 7, Service de Recherche en Hemato-Immunologie, Hopital Saint-Louis, Paris, France; and
¶IFRNT, Institut Francilien de Recherche en Néphrologie et Transplantation
CTLA4-Ig (Belatacept) is a new recombinant molecule that interferes with the signal of T lymphocyte activation and prevents acute rejection after renal transplantation. HLA-G acts as a naturally tolerogenic molecule in humans. In this study, we analyzed whether HLA-G contributes to CTLA4-Ig-mediated graft acceptance. Our results demonstrate that patients treated with CTLA4-Ig displayed significantly higher soluble HLA-G (sHLA-G) plasma concentrations (72 ± 14 ng/ml) than patients treated with calcineurin inhibitors (5 ± 1 ng/ml) or healthy donors (5 ± 5 ng/ml). Notably, sHLA-G purified from plasma of CTLA4-Ig-treated patients was biologically active as it inhibited allogeneic T cell proliferation in vitro. Dendritic cells (DC) were identified as one of the cellular sources of sHLA-G in CTLA4-Ig-treated patients. Supporting this observation, we showed that DC generated in vitro in presence of CTLA4-Ig released sHLA-G in response to allostimulation. These CTLA4-Ig-treated DC acted as tolerogenic APC through sHLA-G secretion as they suppressed T cell alloproliferation, which could be restored by using a neutralizing anti-HLA-G Ab. These data define a novel pathway by which CTLA4-Ig immunomodulates allogenic response through posttranscriptional regulation of HLA-G expression in DC. CTLA4-Ig-mediated HLA-G release appears as a critical factor in T cell alloresponse inhibition, thereby contributing to the immunosuppressive effect and graft acceptance.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Association pour 1’Utilisation du rein Artificiel and the Société Francophone de Transplantation and by the Commissariat à l’Energie Atomique.
2 R.B. and A.N. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Antoine Durrbach, Département de Néphrologie, Hôpital du Kremlin-Bicêtre, 78 rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France. E-mail address: antoine.durrbach{at}vjf.inserm.fr
4 Abbreviations used in this paper: CNI, calcineurin inhibitor; DC, dendritic cell; HD, healthy volunteer blood donor; iDC, immature DC; mDC, mature DC; sHLA-G, soluble HLA-G.
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