title: Bone marrow chimerism and tolerance induced by single-dose cyclophosphamide.
abstract: BACKGROUND
  Establishment of hematopoietic chimerism is the most stable strategy for donor-specific tolerance. Safer pretreatment regimens are needed for clinical application. We evaluated the efficacy of a simple protocol using cyclophosphamide (CYP) on induction of chimerism and organ transplant tolerance across major histocompatibility complex (MHC) barriers in the rat.
  
  
  METHODS
  Bone marrow cells from BN (RT1(n)) donors were infused to LEW (RT1(l)) recipients on day 0 after a single injection of CYP at various doses on day -1. Donor-derived hematopoietic chimerism was evaluated by flowcytometry. The recipients received BN or third party (BUF) heart allografts on day 100.
  
  
  RESULTS
  While pretreatment with 200 mg/kg of CYP induced high levels of hematopoietic chimerism, six of eight recipients died of severe graft-versus-host-disease (GVHD). CYP at dose of 150 mg/kg induced 36.5 +/- 24.1% of donor-derived chimerism on day 10, and sustained macrochimerism was seen until day 100 without GVHD. Pretreatment with 100 mg/kg of CYP resulted in only transient chimerism (4.8 +/- 5.2%) which disappeared by day 20. In the recipients with 50 mg/kg of CYP, donor bone marrow cells were rapidly rejected and no chimerism was observed. The recipients with 150 mg/kg of CYP accepted BN heart allografts (>100 days x 5), while rejecting BUF allografts by day 12 (n = 4). BN heart allografts were rejected in the recipients with 100 (MST: 57 days, n = 5) and 50 mg/kg (MST: 7 days, n = 5) of CYP.
  
  
  CONCLUSIONS
  A single dose of CYP can induce hematopoietic chimerism across MHC-barriers. The dose of 150 mg/kg seems to be optimal to induce organ transplant tolerance without developing GVHD.
authors.affiliation: First Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Okayama
authors.forename: Saiho
authors.initials: S
authors.lastname: Ko
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Kanehiro
authors.forename: Hideki
authors.initials: H
authors.lastname: Kanokogi
authors.forename: Michiyoshi
authors.initials: M
authors.lastname: Hisanaga
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ohashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sho
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Nagao
authors.forename: Naoya
authors.initials: N
authors.lastname: Ikeda
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Kanamura
authors.forename: Satoru
authors.initials: S
authors.lastname: Akashi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D003520:Cyclophosphamide / Q000276:immunology / Q000494:pharmacology*; D016027:Heart Transplantation / Q000276:immunology; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology*; D008285:Major Histocompatibility Complex / Q000276:immunology; D023421:Models, Animal; D051381:Rats; D011917:Rats, Inbred Lew; D018183:Transplantation Chimera / Q000276:immunology*; D023001:Transplantation Tolerance / Q000187:drug effects* / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D003520:Cyclophosphamide