In Vivo Costimulation Blockade-Induced Regulatory T Cells Demonstrate Dominant and Specific Tolerance to Porcine Islet Xenografts. Issue 7 (July 2017)

• Record Type: Journal Article
• Authors: Wu, Jingjing; Hu, Min; Qian, Yi Wen; Hawthorne, Wayne J.; Burns, Heather; Liuwantara, David; Alexander, Stephen I.; Yi, Shounan; O'Connell, Philip J.
• Is Part Of: Transplantation. Volume 101:Issue 7(2017)
• Publication Date: 2017-07
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation immunology -- Periodicals; 617.95
• DOI: 10.1097/TP.0000000000001482
• Languages: English
• ISSNs: 0041-1337

Abstract

Abstract : Background: Although islet xenotransplantation is a promising therapy for type 1 diabetes, its clinical application has been hampered by cellular rejection and the requirement for high levels of immunosuppression. The aim of this study was to determine the role of Foxp3 + regulatory T (Treg) cells in costimulation blockade–induced dominant tolerance to porcine neonatal islet cell cluster (NICC) xenografts in mice. Methods: Porcine-NICC were transplanted under the renal capsule of BALB/c or C57BL/6 recipients and given a single dose of CTLA4-Fc at the time of transplant and 4doses of anti-CD154 mAb to day 6. Depletion of Foxp3 + Treg cell was performed in DEpletion of REGulatory T cells mice at day 80 posttransplantation. Foxp3 + Treg cell from spleens of treated BALB/c mice (tolerant Treg cell), and splenocytes were cotransferred into islet transplanted nonobese diabetic background with severe combined immunodeficiency mice to assess suppressive function. Results: In treated mice, increased numbers of Foxp3 + Treg cell were identified in the porcine-NICC xenografts, draining lymph node, and spleen. Porcine-NICC xenografts from treated mice expressed elevated levels of TGF-β, IL-10 and IFN-γ. Porcine-NICC xenograft tolerance was abrogated after depletion of Foxp3 + Treg cell. Tolerant Treg cell produced high levels of IL-10 and had diverse T cell receptor Vβ repertoires with an oligoclonal expansion in CDR3 of T cell receptor Vβ14. These tolerant Treg cells had the capacity to transfer dominant tolerance and specifically exhibited more potent regulatory function to porcine-NICC xenografts that naive Treg cell. Conclusions: This study demonstrated that short-term costimulation blockade–induced dominant tolerance and that Foxp3 + Treg cell played an essential role in its maintenance. Foxp3 + Treg cells were activated and had more potent regulatory function in vivo than naive Treg cells. Abstract : The authors demonstrate that costimulation blockade by a CTLA4-Fc antibody induces tolerance in an xenograft islet transplant model in which FoxP3+ Treg play a key role in its maintenance. Supplemental digital content is available in the text.