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Characterization of Donor Dendritic Cells and Enhancement of Dendritic Cell Efflux With cc-Chemokine Ligand 21

A Novel Strategy to Prolong Islet Allograft Survival

¹ Transplantation Research Center, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
² Department of Medicine, San Raffaele Scientific Institute, Milan, Italy
³ CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, Massachusetts
⁴ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Reza Abdi, MD, Transplantation Research Center (TRC), Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave., Boston, MA 02115. E-mail: rabdi{at}rics.bwh.harvard.edu

Abbreviations: BrdU, bromodeoxyuridine; dDC, donor dendritic cell; DC, dendritic cell; DT, diphtheria toxin; FACS, fluorescence-activated cell sorting; GFP, green fluorescent protein; MCH, major histocompatibility complex; MLR, mixed lymphocyte reaction; rDC, recipient dendritic cell

Dendritic cells (DCs) are the most potent antigen-presenting cells, yet little data are available on the differential characteristics of donor and recipient DCs (dDCs and rDCs, respectively) during the process of islet allograft rejection. DTR-GFP-DC mice provide a novel tool to monitor DC trafficking and characteristics during allograft rejection. We show rapid migration of dDCs to recipient lymphoid tissues as early as 3 h post–islet allotransplantation. Compared with rDCs, dDCs express different patterns of chemokine receptors, display differential proliferative capacity, and exhibit a higher level of maturity; these findings could be attributed to the effects of injury that dDCs undergo during islet cell preparation and engraftment. Intriguingly, we detected dDCs in the spleen of recipients long after rejection of islet allografts. Given that dDCs express high levels of CCR7, islets were cultured before transplant with the ligand for CCR7 (CCL21). This novel method, which enabled us to enhance the efflux of dDCs from islet preparations, resulted in a prolongation of islet allograft survival in immunocompetent recipients. This study introduces dDCs and rDCs as two distinct types of DCs and provides novel data with clinical implications to use chemokine-based DC-depleting strategies to prolong islet allograft survival.

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