Prolongation of cardiac allograft survival by a novel population of autologous CD117+ bone marrow-derived progenitor cells.

Autologous CD117(+) progenitor cells (PC) have been successfully utilized in myocardial infarction and ischemic injury, potentially through the replacement/repair of damaged vascular endothelium. To date, such cells have not been used to enhance solid organ transplant outcome. In this study, we determined whether autologous bone marrow-derived CD117(+) PC could benefit cardiac allograft survival, possibly by replacing donor vascular cells. Autologous, positively selected CD117(+) PC were administered posttransplantation and allografts were assessed for acute rejection. Although significant generation of recipient vascular cell chimerism was not observed, transferred PC disseminated both to the allograft and to peripheral lymphoid tissues and facilitated a significant, dose-dependent prolongation of allograft survival. While CD117(+) PC dramatically inhibited alloreactive T cell proliferation in vitro, this property did not differ from nonprotective CD117(-) bone marrow populations. In vivo, CD117(+) PC did not significantly inhibit T cell alloreactivity or increase peripheral regulatory T cell numbers. Thus, rather than inhibiting adaptive immunity to the allograft, CD117(+) PC may play a cytoprotective role in prolonging graft survival. Importantly, autologous CD117(+) PC appear to be distinct from bone marrow-derived mesenchymal stem cells (MSC) previously used to prolong allograft survival. As such, autologous CD117(+) PC represent a novel cellular therapy for promoting allograft survival.

Both innate and adaptive major histocompatibility complex class I-dependent immunity impair long-term islet xenograft survival.

Natural killer (NK) cells have long been appreciated for their rapid, proinflammatory contribution to host defense. However, more recent studies show an unexpected regulatory role for host major histocompatibility complex (MHC) class I-dependent immunity and NK cells in promoting tolerance induction to islet allografts. It is unclear whether the potential tolerance induction to islet xenografts follows similar requirements to those found in allograft tolerance. In this study, we determined whether induced islet xenograft prolongation also showed a reliance on MHC class I-dependent immune pathways. In particular, we tested whether NK1.1+ cells and/or CD8 T cells were required for the long-term islet xenograft survival in a rat-to-mouse transplant model. Short-term host treatment with combined anti-CD154 plus anti-LFA-1 (CD11a) resulted in prolonged, but not indefinite, survival of WF rat islet xenografts in C57BI/6 mouse recipients. In stark contrast with similar islet allograft studies, adjunct treatment with anti-NK1.1 therapy combined wither anti-CD154/anti-LFA-1 treatment led to long-term (>100 days) survival of the majority of islet xenografts. In parallel studies, we determined whether CD8 T cells also contributed a barrier to xenograft survival. Similar to results found in anti-NK1.1-treated animals, CD8-deficient (knockout) recipients also demonstrated augmented xenograft prolongation after combined anti-CD154/anti-LFA-1 therapy. Taken together, NK1.1+ cells (NK/NKT cells) and CD8 T cells constitute differing MHC class I-dependent immune pathways forming a significant barrier to xenograft prolongation.