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

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.

Late-onset cytomegalovirus (CMV) in lung transplant recipients: can CMV serostatus guide the duration of prophylaxis?

Evidence supports the use of 12 months of cytomegalovirus prophylaxis in all at-risk lung transplants; whether cytomegalovirus serostatus can be used to further optimize this duration remains to be determined. The purpose of this retrospective study was to determine if cytomegalovirus serostatus of both donor and recipient were associated with late-onset cytomegalovirus. The primary outcome was the proportion of lung transplants that developed cytomegalovirus infection or disease during the 180-day period following 6 months of prophylaxis in each at-risk serotype. Two hundred forty-four consecutive lung transplants were evaluated, 131 were included. The proportion of recipients with cytomegalovirus differed significantly between serotypes (20 of 41 [48.8%] D+/R- vs. 19 of 56 [33.9%] D+/R+ vs. 2 of 34 [5.9%] D-/R+; p < 0.001). In a multivariate model, older age (odds ratio [OR], 1.05, 95% confidence interval [CI] 1.004-1.099; p = 0.03) and D+/R- serostatus (OR, 3.83; 95% CI 1.674-8.770; p = 0.002) were associated with cytomegalovirus. Among R+ lung transplants, D- serostatus was associated with the absence of cytomegalovirus (OR, 0.12; 95% CI 0.0263-0.563; p = 0.007). These findings suggest that in the valganciclovir era, cytomegalovirus serostatus of both donor and recipient may identify lung transplants at heightened risk for late-onset cytomegalovirus.

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.