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Absence of Recipient CCR5 Promotes Early and Increased Allospecific Antibody Responses to Cardiac Allografts ¹

Hiroyuki Amano^*,, Alice Bickerstaff^¶, Charles G. Orosz^¶, Andrew C. Novick^*, Hiroshi Toma and Robert L. Fairchild^2,*,,

^* 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, Ohio State University College of Medicine, Columbus, OH 43210

Acute rejection is mediated by T cell infiltration of allografts, but mechanisms mediating the delayed rejection of allografts in chemokine receptor-deficient recipients remain unclear. The rejection of vascularized, MHC-mismatched cardiac allografts by CCR5^–/– recipients was investigated. Heart grafts from A/J (H-2^a) donors were rejected by wild-type C57BL/6 (H-2^b) recipients on day 8–10 posttransplant vs day 8–11 by CCR5^–/– recipients. When compared with grafts from wild-type recipients, however, significant decreases in CD4⁺ and CD8⁺ T cells and macrophages were observed in rejecting allografts from CCR5-deficient recipients. These decreases were accompanied by significantly lower numbers of alloreactive T cells developing to IFN--, but not IL-4-producing cells in the CCR5^–/– recipients, suggesting suboptimal priming of T cells in the knockout recipients. CCR5 was more prominently expressed on activated CD4⁺ than CD8⁺ T cells in the spleens of allograft wild-type recipients and on CD4⁺ T cells infiltrating the cardiac allografts. Rejecting cardiac allografts from wild-type recipients had low level deposition of C3d that was restricted to the graft vessels. Rejecting allografts from CCR5^–/– recipients had intense C3d deposition in the vessels as well as on capillaries throughout the graft parenchyma similar to that observed during rejection in donor-sensitized recipients. Titers of donor-reactive Abs in the serum of CCR5^–/– recipients were almost 20-fold higher than those induced in wild-type recipients, and the high titers appeared as early as day 6 posttransplant. These results suggest dysregulation of alloreactive Ab responses and Ab-mediated cardiac allograft rejection in the absence of recipient CCR5.

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