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Background Donor lymphocyte infusions can induce remissions in patients with relapse after allogeneic hematopoietic stem cell transplantation. Nevertheless, some grafted patients never display any signs of alloreactivity, either following allogeneic hematopoietic stem cell transplantation or after donor lymphocyte infusions. Consequently, they do not develop graft-versus-host disease and frequently do not respond to donor lymphocyte infusions. In a recently published clinical trial, we observed that elimination of CD4+CD25+Foxp3+ natural regulatory T cells from the donor lymphocyte product could improve alloreactivity and the associated anti-tumor effect in a small proportion of patients with relapsed hematologic malignancies. Here, we aimed to improve the effect of donor lymphocyte infusion by modifying the procedure for depletion of T regulatory cells.Design and Methods We directly compared depletion of regulatory T cells from human peripheral blood mononuclear cells achieved by selection of CD127-positive cells or by selection of CD25-negative cells. We tested the manipulated products (i) in vitro in mixed lymphocyte reactions and against pathogen-derived recall antigens and (ii) in vivo in experimental graft-versus-host disease.Results In vitro, we found that depletion of regulatory T cells through CD127 positive selection improved both alloreactive and pathogen-specific immune responses. In vivo, we observed accelerated donor T-cell division and enhanced graft-versus-host disease due to efficient regulatory T-cell depletion accompanied by enrichment in memory T cells.Conclusions Our results show that the strategy of CD127 positive selection is an efficient way of eliminating regulatory T cells from donor lymphocyte infusions and improves alloreactivity. This supports the investigation of CD127 positive selection in place of elimination of CD25-positive cells for clinical applications.

Background and Objectives: The aim of this study was to assess the feasibility of high-dose chemotherapy plus autologous hematopoietic stem cell transplantation (HDC/AHSCT) in AIDS-related lymphoma (ARL), and its long-term impact in patients with human immunodeficiency virus (HIV) treated with highly active antiretroviral therapy (HAART)., Design and Methods: Fourteen patients with relapsed or resistant ARL (8 with nonHodgkin's lymphoma and 6 with Hodgkin's disease) were treated with HDC/AHSCT while on HAART. HIV-1 proviral DNA load was quantified in 11 grafts., Results: Hematologic reconstitution was good. No toxic deaths occurred. Despite the large number of cells harboring HIV-1 proviral DNA (105 to 109) re-infused with the graft, HAART controlled HIV replication and led to CD4 cell reconstitution in 7 of the 8 patients who were still alive six months after AHSCT. Only two patients had opportunistic infections after AHSCT. There were no significant changes in viral load (VL) or CD4+ cell counts in most patients. One month after AHSCT, 10 patients were in complete remission (CR). Seven patients died from lymphoma between 1 and 10 months after AHSCT, and a further two patients died in CR (one from AIDS at 16 months, one from another tumor at 28 months). Five patients are alive: four are in CR, 14, 19, 32 and 49 months after AHSCT (median CD4+ cell count= 445/mL; undetectable VL in 3 patients), and one is being treated for relapsed lymphoma 36 months after AHSCT., Interpretation and Conclusions: HDC/AHSCT is feasible in AIDS-related lymphoma, in terms of harvesting, engraftment, adverse events and HIV control. It should be proposed to patients with poor-prognosis chemosensitive lymphoma.