title: Stem cell transplantation with S-59 photochemically treated T-cell add-backs to establish allochimerism in murine thalassemia.
abstract: 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.
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA. fkuypers@chori.org
authors.forename: Frans A
authors.initials: FA
authors.lastname: Kuypers
authors.forename: Gordon
authors.initials: G
authors.lastname: Watson
authors.forename: Ezra
authors.initials: E
authors.lastname: Sage
authors.forename: Mark C
authors.initials: MC
authors.lastname: Walters
authors.forename: James
authors.initials: J
authors.lastname: Hamrick
authors.forename: John E
authors.initials: JE
authors.lastname: Hearst
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002469:Cell Separation; D005260:Female; D011564:Furocoumarins / Q000494:pharmacology / Q000528:radiation effects; D005914:Globins / Q000172:deficiency / Q000235:genetics; D006082:Graft Enhancement, Immunologic / Q000379:methods*; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006183:H-2 Antigens / Q000276:immunology; D007364:Intercalating Agents / Q000494:pharmacology* / Q000528:radiation effects; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010777:Photochemistry; D017319:Photosensitizing Agents / Q000494:pharmacology* / Q000528:radiation effects; D011828:Radiation Chimera; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects / Q000637:transplantation*; D013789:Thalassemia / Q000601:surgery*; D014184:Transplantation, Homologous / Q000009:adverse effects / Q000276:immunology*
chemical_list: D011564:Furocoumarins; D006183:H-2 Antigens; C024755:H-2K(K) antigen; C032876:H-2Kb protein, mouse; D007364:Intercalating Agents; D008222:Lymphokines; D017319:Photosensitizing Agents; D005914:Globins; C118577:amotosalen