iNKT cell activation plus T-cell transfer establishes complete chimerism in a murine sublethal bone marrow transplant model

Abstract

Transplant tolerance induction makes it possible to preserve functional grafts for a lifetime without immunosuppressants. One powerful method is to generate mixed hematopoietic chimeras in recipients by adoptive transfer of donor-derived bone marrow cells (BMCs). In our murine transplantation model, we established a novel method for mixed chimera generation using sublethal irradiation, CD40-CD40L blockade, and invariant natural killer T-cell activation. However, numerous BMCs that are required to achieve stable chimerism makes it difficult to apply this model for human transplantation. Here, we show that donor-derived splenic T cells could contribute to not only the reduction of BMC usage but also the establishment of complete chimerism in model mice. By cotransfer of T cells together even with one-fourth of the BMCs used in our original method, the recipient mice yielded complete chimerism and could acquire donor-specific skin-allograft tolerance. The complete chimeric mice did not show any remarks of graft versus host reaction in vivo and in vitro. Inhibition of the apoptotic signal resulted in increase in host-derived CD8 T cells and chimerism brake. These results suggest that donor-derived splenic T cells having veto activity play a role in the depletion of host-derived CD8 T cells and the facilitation of complete chimerism.

Chimerism through the activation of invariant natural killer T cells prolongs graft survival after transplantation of induced pluripotent stem cell–derived allogeneic cardiomyocytes

“…This indicates that donor bone marrow cells are required for further expansion of Tregs and are indispensable for the establishment of mixed-chimera mice. Although the co-transplantation of donor splenic T cells reduced the number of bone marrow cells down to one-fourth, the requirement of harvesting donor bone morrow cells makes it difficult to apply this model for human allogeneic iPSC-CMs transplantation [ 30 ]. The identification of the responsible cell type in bone marrow cells for the establishment of mixed-chimera mice and its differentiation from iPSCs could help induce mixed-chimera mice without transplantation of donor bone marrow cells, which would be clinically acceptable.…”

Myeloid-Derived Suppressor Cells as a Regulator of Immunity in Organ Transplantation

“…In fact, mixed chimerism is a clinically available method for induction of transplant tolerance [112]. These approaches have been extensively focused in clinic as a promising tolerance induction regimen [113,114,115]. It is worth investigating MDSCs and iNKT cells interaction.…”