{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T21:47:22Z","timestamp":1715982442382},"reference-count":27,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2007,1,8]],"date-time":"2007-01-08T00:00:00Z","timestamp":1168214400000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Xenotransplantation"],"published-print":{"date-parts":[[2007,1]]},"abstract":"<jats:p><jats:bold>Abstract:\u2002<\/jats:bold><jats:bold> Background:\u2002<\/jats:bold> In heart allograft in the rat, a sustained costimulation blockade with CTLA4Ig prevents alloreactive T\u2010cell activation and promotes a long\u2010term graft survival through the action of tolerogeneic dendritic cells. It is unclear whether similar mechanisms might occur after xenotransplantation. To test that hypothesis, we have analyzed the action of CTLA4Ig in a model of CD4<jats:sup>+<\/jats:sup>T cell\u2010mediated xenograft rejection.<\/jats:p><jats:p><jats:bold>Methods:\u2002<\/jats:bold> Hamster hearts were transplanted into LEW.1A rats receiving an accommodation\u2010inducing treatment consisting of a short course administration of LF15\u20100195 and a daily administration of cyclosporine A (CSA). To achieve long\u2010term delivery of CTLA4Ig, an intravenous administration of an adenovirus vector coding for mouse CTLA4Ig (Ad\u2010CTLA4Ig) was added to the accommodation induction protocol. On day 40 post\u2010transplantation, rejection was induced by CSA withdrawal. In other xenograft recipients, CD28\/B7 costimulation was inhibited at that time only by injections of CTLA4Ig or anti\u2010CD28 antibodies. Graft survival, immunohistology, as well as development of antibodies and regulatory cells were examined.<\/jats:p><jats:p><jats:bold>Results:\u2002<\/jats:bold> Xenografts survived 6\u2003days after CSA withdrawal in controls and were rejected, as previously described, through the action of CD4<jats:sup>+<\/jats:sup> xenoreactive T cells. Interfering with CD28\/B7 costimulation inhibited this xenoreactive T cell response and delayed rejection to day 10. In recipients that had received Ad\u2010CTLA4Ig, survival was prolonged to day 19 and this was accompanied by the appearance of regulatory cells exhibiting non\u2010donor\u2010specific suppressive activity dependent on IL\u20102, NO, and IDO. These regulatory cells were different from those previously identified after Ad\u2010CTLA4Ig administration in heart allograft in the rat. In these recipients, rejection occurred as a consequence of an evoked anti\u2010donor IgM response and complement activation and not of a cellular rejection as complement inhibition with cobra venom factor further prolonged xenograft survival.<\/jats:p><jats:p><jats:bold>Conclusion:\u2002<\/jats:bold> CD28\/B7 blockade delays CD4<jats:sup>+<\/jats:sup> T cell\u2010mediated rejection after CSA withdrawal in accommodated recipients of hamster heart xenografts. In addition, a sustained expression of CTLA4Ig has the potential of inducing cellular regulatory mechanisms. However, such treatment does not prevent the development of xenoreactive IgM antibodies that participate in vascular rejection processes in a complement\u2010dependent manner.<\/jats:p>","DOI":"10.1111\/j.1399-3089.2006.00361.x","type":"journal-article","created":{"date-parts":[[2007,1,8]],"date-time":"2007-01-08T16:32:04Z","timestamp":1168273924000},"page":"25-33","source":"Crossref","is-referenced-by-count":12,"title":["Induction of regulatory cells and control of cellular but not vascular rejection by costimulation blockade in hamster\u2010to\u2010rat heart 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