Costimulation Blockade Induces Tolerance to HESC Transplanted to the Testis and Induces Regulatory T-cells to HESC Transplanted into the heart

¹ Department of Molecular Medicine and Surgery, Division of Cardiothoracic Surgery and Anaesthesiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
² Department of Medicine, Division of Cardiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
³ Department of Clinical Immunology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
⁴ Department of Gynaecology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
⁵ Department of Nephrology and Transplantation, Lund University, Lund, Sweden
⁶ Department of Heart Diseases, Cardiothoracic Surgery, Haukelands University Hospital, Bergen, Norway

^* To whom correspondence should be addressed. E-mail: karl-henrik.grinnemo{at}karolinska.se.

	Abstract

In order to study the ability of costimulation blockade to induce tolerance to human embryonic stem cells (HESC), SCID and immunocompetent C57BL/6 mice treated with costimulation blockade received intra-testicular and intra-myocardial HESC transplants. All SCID mice with intra-testicular HESC transplants developed teratoma. When SCID mice were transplanted intra-myocardially, only two of five mice developed teratoma-like tumors. C57BL/6 mice transplanted intra-testicularly and treated with costimulation blockade all developed teratoma and were surrounded by CD4⁺CD25⁺Foxp3⁺ T cells, while isotype control treated recipients rejected their grafts. Most C57BL/6 mice transplanted intra-myocardially and treated with costimulation blockade demonstrated lymphocytic infiltrates one month after transplantation where as one maintained its graft. Isolation of regulatory T- cells from intra-myocardial transplanted recipients treated with costimulation blockade demonstrated specificity towards undifferentiated HESC and down-regulated naive T-cell activation towards HESC. These results demonstrate that costimulation blockade is sufficiently robust to induce tolerance to HESC in the immune-privileged environment of the testis. HESC specific regulatory T-cells developed to HESC transplanted to the heart and the success of transplantation was similar to that seen in SCID mice.