2010 - TTS International Congress


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T Cell Diversity and Functional Biology

87.1 - Regulatory T cell therapy prolongs human skin allograft survival in a humanised mouse model

Presenter: Fadi, Issa, Oxford,
Authors: Issa F., Wieckiewicz J., Goto R., Goodacre T., Wood K.

REGULATORY T CELL THERAPY PROLONGS HUMAN SKIN ALLOGRAFT SURVIVAL IN A HUMANISED MOUSE MODEL

T CELL DIVERSITY AND FUNCTIONAL BIOLOGY

F. Issa1, J. Wieckiewicz2, R. Goto1, T. Goodacre3, K.J. Wood1
1Transplantation Research Immunology Group, Nuffield Department of Surgery, University of Oxford, Oxford/UNITED KINGDOM, 2Nuffield Department Of Surgery, Transplantation Research Immunology Group, Oxford/UNITED KINGDOM, 3Department Of Plastic And Reconstructive Surgery, Nuffield Department of Surgery, Oxford/UNITED KINGDOM

Body: Introduction: Transplantation is the most effective treatment for end-stage organ failure but chronic rejection and the side effects of long-term immunosuppression are major challenges. Tolerance isan ideal solution to these problems. Regulatory T cells (Treg) are emerging as a promising therapy for the induction of tolerance. In this study we investigated the potential of ex vivo expandedhuman Treg to extend survival of an allogeneic human skin transplant in a novel humanised mouse model. Methods: Balb/c Rag2-/-cgamma-/- mice, which lack T, B and natural killer cells received a 1x1cmhuman split-thickness skin graft on the left dorsal thorax which was allowed to heal and revascularise over 5 weeks. Mice were then reconstituted with allogeneic or syngeneic human peripheral bloodmononuclear cells (PBMC) by intraperitoneal injection to produce a functional human immune system in vivo. Treg were produced by culturing flow-sorted CD4+CD25+CD127lo cells from human buffy coatswith recombinant human IL-2 and CD3/CD28 beads over two 7-day rounds. Treg were tested for in vitro suppressive capabilities before in vivo use. Mice received PBMC with or without Treg. Animals weresacrificed after rejection and peripheral lymphoid tissues and grafts analysed for the presence of human leucocytes. Results: 5x10(6) or 10x10(6) PBMC injected intraperitoneally successfullyreconstituted animals and caused rejection of human skin allografts with similar kinetics (median survival times (MST) 32 (n=10) and 33 (n=10) days respectively). Mice receiving human skintransplants but no cellular adoptive transfer engrafted skin long-term (n=4, MST>100 days). At rejection, human T cells were present in the graft, draining lymph node, blood and spleen ofreconstituted animals. Of reconstituting cells, CD4+ T cells comprised approximately two thirds with the remaining population being CD8+ T cells. Using 5x10(6) PBMC, the addition of 5x10(6) Tregderived from the same buffy coat induced long-term, stable survival of skin grafts (p=0.0389). The addition of Treg did not affect PBMC engraftment, with no significant difference between human CD45+cell numbers in the spleens of animals receiving PBMC or PBMC with Treg (mean=7.7x10(6) cells, n=13 cf. mean=8.8x10(6) cells, n=7, respectively). Conclusion: In summary, we have shown that ex vivoexpanded CD4+CD25+CD127lo human Treg display powerful suppressive capabilities in vivo, with the ability to prevent allograft rejection in a humanised mouse model without affecting the reconstitutionof human leucocytes within the mouse.

Disclosure: All authors have declared no conflicts of interest.


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