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,
* Glickman Urological Institute and
Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195;
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
Department of Urology, Tokyo Women’s Medical School, Tokyo, Japan; and
¶ Department of Surgery, Transplantation Division, The Ohio State University College of Medicine, Columbus, OH 43210
Rejected MHC-mismatched cardiac allografts in CCR5–/– recipients have low T cell infiltration, but intense deposition of C3d in the large vessels and capillaries of the graft, characteristics of Ab-mediated rejection. The roles of donor-specific Ab and CD4 and CD8 T cell responses in the rejection of complete MHC-mismatched heart grafts by CCR5–/– recipients were directly investigated. Wild-type C57BL/6 and B6.CCR5–/– (H-2b) recipients of A/J (H-2a) cardiac allografts had equivalent numbers of donor-reactive CD4 T cells producing IFN-
, whereas CD4 T cells producing IL-4 were increased in CCR5–/– recipients. Numbers of donor-reactive CD8 T cells producing IFN- were reduced 60% in CCR5–/– recipients. Day 8 posttransplant serum titers of donor-specific Ab were 15- to 25-fold higher in CCR5–/– allograft recipients, and transfer of this serum provoked cardiac allograft rejection in RAG-1–/– recipients within 14 days, whereas transfer of either serum from wild-type recipients or immune serum from CCR5-deficient recipients diluted to titers observed in wild-type recipients did not mediate this rejection. Wild-type C57BL/6 and B6.CCR5–/– recipients rejected A/J cardiac grafts by day 11, whereas rejection was delayed (day 12–60, mean 21 days) in µMT–/–/CCR5–/– recipients. These results indicate that the donor-specific Ab produced in CCR5–/– heart allograft recipients is sufficient to directly mediate graft rejection, and the absence of recipient CCR5 expression has differential effects on the priming of alloreactive CD4 and CD8 T cells.
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1 This work was supported by National Institutes of Health Grants AI40459 and AI51620, and by the Roche Organ Transplant Research Foundation (60495086).
2 T.N. and H.A. contributed equally to this work and share principal authorship.
3 Address correspondence and reprint requests to Dr. Robert L. Fairchild, PhD, NB3-59, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195-0001. E-mail address: fairchr{at}ccf.org
4 Abbreviations used in this paper: AHR, acute humoral rejection; Treg, T regulatory.
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