The Graft Content of Donor T Cells Expressing γδTCR+ and CD4+foxp3+ Predicts the Risk of Acute Graft versus Host Disease after Transplantation of Allogeneic Peripheral Blood Stem Cells from Unrelated Donors

Abstract

Purpose: Recently, high numbers of regulatory T cells within the stem cell graft were described to be associated with less graft-versus-host disease (GVHD) after related peripheral blood stem cell transplantation (PBSCT). Studies in mice also suggest a distinct role of gyTCR + T cells in mediating GVHD. Therefore, the aim of this study was to define the yet-unknown role of regulatory and gyTCR + Tcells in human PBSCT from unrelated donors. Experimental Design: The frequency of bothT-cell subsets within the graft was analyzed in 63 patients receiving unrelated allogeneic PBSCT. The respective amounts were quantified by flow cytometry and PCR and further correlated with clinical outcome. + cells had a lower cumulative incidence of acute GVHD II-IV (44% versus 65%, P = 0.03). Interestingly, in patients who received higher concentrations of donor gyTCR + Tcells, acute GVHD II-IV was more frequent (66% versus 40%, P = 0.02). In multivariate analysis, only the graft concentration of gyTCR + Tcells (P = 0.002) and a positive cytomegalovirus status of the recipient (P = 0.03) were significantly associated with the occurrence of acute GVHD II-IV. Conclusion: Graft composition of T-cell subsets seems to affect the outcome of patients receiving allogeneic PBSCT from unrelated donors. Therefore, selective manipulation or add-back of particular subsets might be a promising strategy to reduce the incidence of GVHD.

Graft invariant natural killer T-cell dose predicts risk of acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation

“…30 Whether and how graft FoxP3 ϩ Tregs might protect from aGVHD has also been investigated extensively. Although a protective effect of high graft Treg content was suggested in some 10,11 but not all 31 reports, we found no evidence that the Treg dose affects the risk of aGVHD. Nevertheless, 2 phase 1 clinical trials designed to test the safety of Treg infusion for prevention of aGVHD have already been reported.…”

“…7 Because T-cell depletion of the graft is also associated with an increased risk of leukemia relapse and infections, research has also focused on identifying other cellular components of the graft that affect the incidence and severity of aGVHD. Indeed, the effect of the graft content of several immune effectors such as T, NK 8 and more recently B cells 9 as well as of the CD4 ϩ CD25 hi FoxP3 ϩ T regulatory cells (Tregs) 10,11 on the risk of aGVHD has been studied extensively.…”

Hematopoietic Stem Cell Transplantation: Evolution and Future Perspectives

“…Although pioneering studies trying to correlate Treg cells numbers and the risk of GvHD brought controversial results, several authors have now reported a lower cumulative incidence of GvHD in patients receiving a graft containing higher Treg cells [6][7][8].…”

Induction of Toll-like receptor 2 and 4 expression on CD4+ and CD8+ T cells in G-CSF-mobilized unrelated peripheral blood stem cell grafts during leukapheresis: impact on patient outcome

“…[1][2][3][4][5] Recently, Yakoub-Agha et al 6 presented a study in Leukemia, demonstrating that a high percentage of CD4 þ CCR7 þ T cells in marrow or peripheral blood stem cell (PBSC) grafts significantly correlated with the incidence of acute graft-versus-host disease (GVHD). A current hypothesis concerning its pathogenesis is that epithelial damage in the gut due to components of conditioning facilitates the translocation of lipopolysaccharide, a cell wall component of Gram-negative bacteria into the blood.…”

“…All patients received a myeloablative conditioning regimen prior to PBSCT and cyclosporine/methotrexate as GVHD prophylaxis as described recently. 5 No anti-thymocyte globulin was used during conditioning. All patients received unmanipulated PBSCs on day 0.…”