Evaluation of regulatory immune cells that favor engraftment following haploidentical peripheral blood stem cell transplantation for sickle cell disease

Abstract

Abstract Haploidentical hematopoietic stem cell transplantation is one of the most widely available curative options for patients with sickle cell disease (SCD). Our previous non-myeloablative haploidentical peripheral blood stem cell transplantation (PBSCT) trial showed improved engraftment with post-transplant cyclophosphamide, but with a high incidence of allograft rejection. Here, our aim was to evaluate mechanisms of engraftment in SCD patients who underwent PBSCT. We analyzed and compared the following cells (Treg, Tr1, Th1, Th17, NK, Breg, pmnMDSCs, mMDSCs, eMDSCs, mDCs, and pDCs) in peripheral blood samples obtained from 20 transplanted patients at baseline (BSL), post-transplant day (PT-D) 30, 60, 100, and 180 using flow cytometry. Because we previously showed that 20% donor myeloid chimerism (DMC) is sufficient to reverse SCD, we classified patients at each time point as engrafted (DMC ≥20%) and rejected (DMC< 20%). Early MDSC frequencies were significantly elevated in engrafted patients (PT-D30). Patients were also evaluated based on engrafted/rejected at the end of study and mMDSC and Th17 cell frequencies were significantly elevated at PT-D30 and PT-D60 respectively in engrafted patients. All other cell populations were not statistically different. Tregs showed an elevated trend in engrafted patients and exhibited direct proportionality in patients with varying DMC levels. Our results reveal that eMDSC and mMDSC frequencies were elevated in engrafted patients and decreasing Tregs were associated with decreasing DMC. Taken together, eMDSCs, mMDSCs and Tregs may have a synergistic association in favoring the development of a tolerogenic immune milieu that promotes stable mixed chimerism after PBSCT in SCD patients.