Murine insulin-producing islet cells made to express stromal-derived factor-1 (SDF-1) and transplanted into allogeneic mice resisted T cell responses to the graft, ensuring its prolonged survival. This observation was made by Natalia Papeta and Tao Chen, research fellows in the laboratory of Mark Poznansky, HMS assistant professor of medicine, and colleagues at Massachusetts General Hospital. The research appears in the Jan. 27 issue of Transplantation.
In a previous study, Poznansky had found that T cells are repelled by high concentrations of the chemokine SDF-1 via a mechanism termed fugetaxis. This property mirrors the protein’s physiological role in the thymus, where a high concentration of SDF-1 facilitates the exit of mature T cells into the peripheral circulation. In the present study, the investigators aimed to exploit the repellent properties of SDF-1 to prevent T cell infiltration of the transplanted tissue and thereby prolong graft survival.
The team first induced diabetes in recipient mice. Following the introduction of allogeneic insulin-producing islet cells transduced with SDF-1 into the mice, their levels of blood glucose were scored to determine the function of the transplanted tissue. The ability of the tissue to normalize blood glucose levels was used as an indicator of its survival and overall health in the recipient animals. In 80 percent of the mice expressing a high amount of SDF-1, blood glucose levels returned to normal. But mice that were SDF-1 negative were unable to demonstrate this effect due to destruction of the allograft. At the cellular level, success of the graft was manifested as a clearly evident reduction of alloreactive–T cell infiltration into the transplanted tissue that expressed a high level of SDF-1. In vitro model systems demonstrated that high concentrations of SDF-1 primarily blocked the migration of alloreactive cytotoxic T cells into the donor tissue.
The primary aim of this work was to utilize high concentrations of SDF-1 to achieve “immune isolation” for the transplanted tissue, said Poznansky. The method differs conceptually from existing methods of immunosupression that are widely used to alleviate immune responses to allografts. By using the chemorepellent properties of SDF-1 for T cells, the researchers created a local niche where the transplanted tissue could avoid alloreactive cell-mediated responses and remain healthy. This novel approach could potentially obviate the need for immunosuppressive drugs and the inevitable systemic effects associated with their use. As a next step, Poznansky hopes to extend these results to non-obese diabetic mice, which offer a close parallel with human type 1 diabetes.
This research was funded by the Juvenile Diabetes Research Foundation and the National Institutes of Health.