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Although tremendous progress has been made since the introduction of allogeneic hematopoietic stem cell transplantation (HSCT) decades ago, there are still many obstacles to overcome. A major obstacle is the presence of T-lymphocytes in the recipient and in the donor. Recipient-derived T-lymphocytes not eliminated by the conditioning regimen are a major barrier and can lead to mixed chimerism or to complete rejection of the graft. Donor-derived T-lymphocytes can induce severe acute and chronic Graft-versus-Host Disease (GvHD). Currently published strategies for in vivo depletion of recipient-derived T-lymphocytes are discussed including the increase of the intensity of the conditioning regimen, the addition of anti-thymocyte globulin (ATG) or the anti-CD52 monoclonal antibody Campath. For the depletion or tolerization of the donor-derived T-lymphocytes, ex vivo-T-cell depletion methods, such as positive selection of CD34+ stem cells, negative depletion of CD3+ or TcRαβ+ T-lymphocytes or the use of post-transplant cyclophosphamide (PTCy) have been developed. All these currently used approaches have their disadvantages and new approaches should be investigated. In this review, we discuss current and propose new possible strategies to overcome the HLA barrier by using more specific T-cell directed therapies and/or by the combinations of current methods.

Ex vivo and in vivo T-cell depletion in allogeneic transplantation: towards less or non-cytotoxic conditioning regimens