title: Addition of treosulfan to a nonmyeloablative conditioning regimen results in enhanced chimerism and immunologic tolerance in an experimental allogeneic bone marrow transplant model.
abstract: Treosulfan (L-threitol-1,4-bismethanesulfonate) is an alkylating agent with routine clinical application in the treatment of ovarian cancer. In this murine study we show that this drug also has the ability to deplete primitive hematopoietic stem cells in a dose-dependent manner as determined by the cobblestone area-forming cell assay and is similar to its parent compound busulfan. Because busulfan is frequently used as part of the conditioning regimen before stem cell transplantation, we investigated an alternative nonmyeloablative protocol in an allogeneic bone marrow transplantation model in which low-dose treosulfan was added to an immune-suppressive regimen consisting of T cell-depleting antibodies, fludarabine, and thymic irradiation. Although this treatment protocol produced minimal myelosuppression, the addition of treosulfan proved to be important for allowing stable multilineage and mixed chimerism in C57BL/6 recipients of major histocompatibility complex-mismatched B10.A bone marrow without evidence of graft-versus-host disease. Donor lymphocyte infusion performed at 10 weeks after bone marrow transplantation had the effect of transforming the state of mixed chimerism to full donor-type cells, again without evidence of graft-versus-host disease. Donor-specific immunologic tolerance in the mixed chimeric animals was indicated by the acceptance of donor-type and rejection of third-party skin grafts. Thus, low-dose treosulfan may be considered as a useful component of a truly nonmyeloablative conditioning protocol in providing for mixed hematopoietic chimerism and, consequently, in establishing a platform for adoptive immunotherapy.
authors.affiliation: Department of Hematology, Erasmus University, Rotterdam, The Netherlands.
authors.forename: Rob E
authors.initials: RE
authors.lastname: Ploemacher
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Johnson
authors.forename: Elwin J C
authors.initials: EJ
authors.lastname: Rombouts
authors.forename: Kenol
authors.initials: K
authors.lastname: Etienne
authors.forename: G Robbin
authors.initials: GR
authors.lastname: Westerhof
authors.forename: Joachim
authors.initials: J
authors.lastname: Baumgart
authors.forename: Mary E
authors.initials: ME
authors.lastname: White-Scharf
authors.forename: Julian D
authors.initials: JD
authors.lastname: Down
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D001853:Bone Marrow / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000379:methods; D002066:Busulfan / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D008297:Male; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning / Q000379:methods
chemical_list: D018906:Antineoplastic Agents, Alkylating; C018404:treosulfan; D002066:Busulfan