Stem cell transplantation with S-59 photochemically treated T-cell add-backs to establish allochimerism in murine thalassemia.

Hematopoietic cell transplantation (HCT) from HLA-identical sibling donors has curative potential for beta-thalassemia. The probability of surviving free of thalassemia under these conditions is approximately 85%. The application of this therapy is limited because many patients lack an HLA-identical sibling donor. HLA-mismatched stem cell transplantation for thalassemia is severely restricted by graft rejection and the risks for graft-versus-host disease (GVHD). Thus, the development of a novel method that facilitates immunological tolerance and improves the safety of HLA-mismatched HCT would greatly expand the opportunity of HCT for thalassemia patients. We hypothesized that removal of T cells from the donor hematopoietic stem cell preparation and subsequent add-back after photochemical treatment with S-59, a psoralen, would promote and stabilize the engraftment and significantly reduce the risk of GVHD. This was tested in a MHC-mismatched HCT model of murine thalassemia. S-59-treated T cells were infused simultaneously with bone marrow-derived stem cells into mice with a heterozygous deletion of one beta-globin alleles that had been conditioned with a sublethal dose of total body irradiation. Mice that received treated T cells showed increased engraftment compared to those that did not receive T cells. T-cell treatment improved survival without GVHD compared to recipients that received untreated T cells. We conclude that photochemical treatment of T cells facilitates engraftment and minimizes GVHD in allo-HCT for murine thalassemia, and sets the stage for further development of such protocols for the treatment of patients with thalassemia.