C-kit-derived CD11b+ cells are critical for cardiac allograft prolongation by autologous C-kit+ progenitor cells

Abstract

Autologous C-kit⁺ cells robustly prolong cardiac allografts. As C-kit⁺ cells can transdifferentiate to hematopoietic cells as well as non-hematopoietic cells, we aimed to clarify the class(es) of C-kit-derived cell(s) required for cardiac allograft prolongation. Autologous C-kit⁺ cells were administered post-cardiac transplantation and allografts were evaluated for C-kit⁺ inoculum-derived cells. Results suggested that alloimmunity was a major signal for trafficking of C-kit-derived cells to the allograft and demonstrated that C-kit⁺ inoculum-derived cells expressed CD11b early after transfer. Allograft survival studies with CD11b-DTR C-kit⁺ cells demonstrated a requirement for C-kit⁺-derived CD11b⁺ cells. Co-therapy studies demonstrated near complete abrogation of acute rejection with concomitant CTLA4-Ig therapy and no loss of prolongation in combination with Cyclosporine A. These results strongly implicate a C-kit-derived myeloid population as critical for allograft preservation and demonstrate the potential therapeutic application of autologous C-kit⁺ progenitor cells as calcineurin inhibitor-sparing agents and possibly as co-therapeutics for durable graft survival.

Keywords: Allograft prolongation; CD11b; Cardiac transplantation; Cell therapy; Ckit; Progenitor cell.