Towards a myeloablative regimen with clinical potential: I. Treosulfan conditioning and bone marrow transplantation allow induction of donor-specific tolerance for skin grafts across full MHC barriers.
To investigate whether we could create a radiation-free conditioning regimen to induce permanent mixed and multilineage chimerism and donor-specific tolerance, we treated recipient mice with anti-T-cell antibodies, varying and fractionated doses of Treosulfan and fully MHC disparate bone marrow cells. Treosulfan is mainly used in the treatment of ovarian cancer. It is a structural analog of busulfan, but it does not induce severe hepatotoxicity or veno-occlusive disease at or above the maximum tolerated dose, lacks significant nonhematological toxicity and has limited organ toxicity. We report here the successful induction of permanent mixed multilineage chimerism and donor-specific tolerance as was proven by skin transplantation and IFN-gamma ELISPOT. In conclusion, because of its lower nonhematological toxicity, compared with other myeloablative regimens (eg irradiation or busulfan admin- istration), Treosulfan could be a better candidate for conditioning to induce donor-specific allograft tolerance.
van Pel
M
M
Laboratory for Vaccine Research, National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
van Breugel
D W J G
DW
Vos
W
W
Ploemacher
R E
RE
Boog
C J P
CJ
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000379:methods*; D002066:Busulfan / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D004353:Drug Evaluation, Preclinical; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006648:Histocompatibility; D006649:Histocompatibility Antigens; D007108:Immune Tolerance / Q000187:drug effects*; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D019653:Myeloablative Agonists / Q000008:administration & dosage*; D016038:Skin Transplantation / Q000276:immunology* / Q000379:methods; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous
D018906:Antineoplastic Agents, Alkylating; D006649:Histocompatibility Antigens; D019653:Myeloablative Agonists; C018404:treosulfan; D002066:Busulfan