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Anti-CD28 Antibodies Modify Regulatory Mechanisms and Reinforce Tolerance in CD40Ig-Treated Heart Allograft Recipients¹

Carole Guillonneau^2,*, Céline Séveno^2,*, Anne-Sophie Dugast^*, Xian-Liang Li^*, Karine Renaudin, Fabienne Haspot^*, Claire Usal^*, Joëlle Veziers^*, Ignacio Anegon^3,4,* and Bernard Vanhove^3,4,*

^* Institut National de la Santé et de la Recherche Médicale, Unité 643, Centre Hospitalier de l’Université Nantes, Institut de Transplantation et de Recherche en Transplantation, Université de Nantes, Faculté de Médecine, Nantes, France; and Service d’Anatomie Pathologique du Centre Hospitalier de l’Université de Nantes, Nantes, France

Blockade of CD40-CD40 ligand (CD40L) costimulation has been shown to synergize with that of CTLA4/CD28-B7 to promote transplant tolerance. To date, however, CD28-B7 interactions have been prevented using B7-blocking reagents like CTLA4-Ig that inhibit CD28-B7 together with CTLA4-B7 interactions. In this study, we have tested anti-CD28 Abs to prevent selectively CD28-B7 interactions while preserving CTLA4-B7 in addition to CD40-CD40L blockade. In the LEW.1W to LEW.1A rat combination, interfering with CD40-CD40L interactions by CD40Ig administration through gene transfer resulted in indefinite heart allograft survival due to the appearance of clonotypic CD8⁺CD45RC^low regulatory T cells that were capable of transferring the tolerant state to naive animals. However, cardiac transplants in these recipients systematically developed chronic rejection lesions. Whereas anti-CD28 Ab monotherapy only delayed acute rejection and failed to induce tolerance, coadministration of anti-CD28 Abs and CD40Ig resulted in the long-term acceptation of allografts without chronic rejection lesions in 60% of the recipients, reduced the level of intragraft mRNA transcripts for cytokines and immune factors, and fully abrogated alloantibody production. In addition, the nature of regulatory cells was modified: the CD8⁺CD45RC^low clonotypic T cells described in the CD40Ig-treated animals could not be found in cotreated animals, and the other CD8⁺CD45RC^low cells had no regulatory activity and a different cytokine expression profile. Instead, in cotreated recipients we found IDO-dependent non-T cells with regulatory activity in vitro. Thus, the addition of a short-term anti-CD28 treatment with CD40Ig resulted in decreased heart allograft chronic rejection lesions, complete inhibition of Ab production, and modified regulatory mechanisms.

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 was supported in part by Roche Organ Transplant Research Foundation Grant 466230972 (to B.V.).

² C.G. and C.S. contributed equally to this report.

³ I.A. and B.V. are both senior and corresponding authors and are listed in alphabetical order.

⁴ Address correspondence and reprint requests to Dr. Bernard Vanhove or Dr. Ignacio Anegon, Institut de Transplantation et de Recherche en Transplantation, Institut National de la Santé et de la Recherche Médicale Unité 643, Centre Hospitalier de l’Université Hotel Dieu, 30 Boulevard Jean Monnet, 44093 Nantes Cedex 1, France. E-mail addresses: Bernard.Vanhove{at}univ-nantes.fr and Ignacio.Anegon{at}univ-nantes.fr

⁵ Abbreviations used in this paper: CD40L, CD40 ligand; AdCD40Ig, adenoviral vector coding extracellular portion of mouse CD40 fused to human IgG1 constant domain coding sequences; Addl324, adenovirus dl324 (noncoding adenovirus); AU, arbitrary unit; BN, Brown Norway; CR, CD40Ig plus anti-CD28 Ab-treated allograft recipient developing histological lesions of chronic rejection; C_t, threshold cycle; FoxP3, Forkhead box P3; HO-1, heme oxygenase-1; GITR, glucocorticoid-induced TNFR-related protein; HPRT, hypoxanthine phosphoribosyltransferase; IP, infectious particle; MCF, mean channel fluorescence; 1-MT, D-1-methyl-tryptophan; Tol, CD40Ig plus anti-CD28 Ab-treated allograft recipient displaying no histological lesions of chronic rejection; Treg, regulatory T cell.