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Distinct Subsets of Dendritic Cells Regulate the Pattern of Acute Xenograft Rejection and Susceptibility to Cyclosporine Therapy¹

Hao Wang^*,,¶, Jacqueline Arp, Xuyan Huang, Weihua Liu, Siobhan Ramcharran^¶, Jifu Jiang, Bertha Garcia, Nobuyuki Kanai, Weiping Min, Peta J. O’Connell^,,¶ and Robert Zhong^2,*,,,,¶

^* Multi-Organ Transplant Program, London Health Sciences Centre-University Hospital, London, Ontario, Canada; Department of Surgery, University of Western Ontario, London, Ontario, Canada; Transplantation Group, Robarts Research Institute, London, Ontario, Canada; and Department of Pathology and ^¶ Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada

We determined whether distinct subclasses of dendritic cells (DC) could polarize cytokine production and regulate the pattern of xenograft rejection. C57BL/6 recipients, transplanted with Lewis rat hearts, exhibited a predominantly CD11c⁺CD8⁺ splenic DC population and an intragraft cytokine profile characteristic of a Th1-dominant response. In contrast, BALB/c recipients of Lewis rat heart xenografts displayed a predominantly CD11c⁺CD8^– splenic DC population and IL-4 intragraft expression characteristic of a Th2 response. In addition, the CD11c⁺IL-12⁺ splenic DC population in C57BL/6 recipients was significantly higher than that in BALB/c recipients. Adoptive transfer of syngeneic CD8^– bone marrow-derived DC shifted a Th1-dominant, slow cell-mediated rejection to a Th2-dominant, aggressive acute vascular rejection (AVR) in C57BL/6 mice. This was associated with a cytokine shift from Th1 to Th2 in these mice. In contrast, transfer of CD8⁺ bone marrow-derived DC shifted AVR to cell-mediated rejection in BALB/c mice and significantly prolonged graft survival time from 6.0 ± 0.6 days to 14.2 ± 0.8 days. CD8⁺ DC transfer rendered BALB/c mice susceptible to cyclosporine therapy, thereby facilitating long-term graft survival. Furthermore, CD8⁺ DC transfer in IL-12-deficient mice reconstituted IL-12 expression, induced Th1 response, and attenuated AVR. Our data suggest that the pattern of acute xenogeneic rejection can be regulated by distinct DC subsets.