Correlation between circulating endothelial progenitor cell function and allograft rejection in heart transplant patients

Abstract

Endothelial progenitor cells (EPCs) may contribute to rejection and cardiac allograft vasculopathy (CAV) by being intrinsically involved in the rejection process and causing neointimal hyperplasia. The mammalian target of rapamycin inhibitors (mTORi), sirolimus and everolimus, have been demonstrated to attenuate the progression of CAV and are cytotoxic to EPC. Thus, one mechanism by which mTORi may protect against CAV is by altering EPC function. Our study measured circulating EPC function and correlated this assessment with rejection episodes in heart transplant (HT) recipients. In addition, we examined the effect of mTORi on EPCs. Patients who received HT at our institution between 1995 and 2007 were included and stratified by International Society for Heart and Lung Transplantation (ISHLT) rejection grade. Group A (n = 13) consisted of patients with at least one moderate/severe rejection episode (grade > or = 2). Group B (n = 28) patients had no moderate/severe episodes (grade < 2). Patients were also independently stratified based on exposure as mTORi (n = 21) vs. non mTORi (n = 20). To assess EPC functional capacity, we counted the number of colony-forming units (CFU) of EPCs in peripheral blood samples from HT recipients. There were no significant differences in baseline characteristics between groups. The mean EPC-CFU counts/plate for group A (rejecting) were 30 +/- 6 vs.16 +/- 3 for group B (nonrejecting) (P = 0.03). The EPC-CFU counts/plate in the mTORi group (15 +/- 3) were lower compared to the non mTORi (27 +/- 5) group (P = 0.04). We found that EPC colony-forming capacity was higher in HT patients who experienced moderate/severe rejection episodes. Patients on mTORi showed a reduced EPC colony count consistent with our previous findings of EPC cytotoxicity. Detection of circulating EPC function post-transplant may reliably identify patient risk level for subsequent allograft rejection and allow for appropriate adjustments to immunosuppression. Converting to mTORi therapy may reduce EPC function and provide a novel mechanism to prevent rejection and possibly attenuate the development of CAV.

Circulating Apoptotic Endothelial Cells and Apoptotic Endothelial Microparticles Independently Predict the Presence of Cardiac Allograft Vasculopathy

“…Table 4 Discrimination The EPC number based on ex vivo culture assay was lower and EPC function was impaired in transplant recipients compared with healthy controls. Different classes of immunosuppressive drugs may affect EPC biology (31,32). Therefore, the lack of discriminative ability of EPC number and EPC function to detect the presence of CAV may be related to a generalized impairment of these parameters in heart transplant recipients receiving different classes of immunosuppressive drugs.…”

Sirolimus as Primary Immunosuppression Attenuates Allograft Vasculopathy With Improved Late Survival and Decreased Cardiac Events After Cardiac Transplantation

“…It is possible that the attenuation of the CAV in the context of recurrent cellular rejection by sirolimus may be through their potent cytotoxic effect on endothelial progenitor cells. 27 Converting to sirolimus therapy may reduce endothelial progenitor cell function and provide a novel mechanism to prevent rejection and possibly attenuate the development of CAV. Sirolimus also preferentially preserves the number and function of CD4 ϩ CD25 ϩ Foxp3 T lymphocytes (Tregs) compared with other T-cell subsets, unlike cyclosporine.…”

CD34+ Progenitor to Endothelial Cell Transition in Post-Pneumonectomy Angiogenesis

“…Despite the varied phenotypes of these cells (15), EPCs are typically associated with remodeling after vascular injury or ischemia. In the lung, the localization of EPCs was demonstrated in acute injury related to transplantation (16,17) and bacterial pneumonia (18), as well as monocrotaline-induced (19,20) and hypoxia-induced (21) pulmonary hypertension. In contrast, a post-pneumonectomy model after bone marrow transplantation failed to demonstrate the integration of blood-borne EPCs in the remaining lung 28 days after pneumonectomy (22).…”