title: Bone marrow transplantation in miniature swine: IV. Development of myeloablative regimens that allow engraftment across major histocompatibility barriers.
abstract: Studies of the myeloablative regimens capable of permitting successful BMT across MHC barriers in miniature swine have been performed. To minimize graft-versus-host disease (GVHD), engraftment was studied in the F1-->P combination (i.e., MHC homozygous ["parental"] swine receiving bone marrow from one-haplotype matched MHC heterozygous ["F1"] donors). Animals given total body irradiation (TBI) up to 1100 cGy, 10 cGy/min, in a single dose failed to engraft. Increasing the dose rate led to unacceptable extramedullary toxicity without improving engraftment. Eleven different fractionated TBI regimens were tested in this F1-->parent model. At all of the dose rates tested, a total dose of less than 1000 cGy was insufficient for engraftment, and a total dose of 1400 cGy led to unacceptable toxicity. Between these extremes, a window was defined in which engraftment could be obtained without unacceptable extramedullary toxicity utilizing 2 equally divided fractions of TBI delivered 24 hr apart. The addition of 50 mg/kg cyclophosphamide i.v. to fractionated TBI (1150 cGy total dose [500 + 650]) also permitted engraftment, with decreased incidence of interstitial pneumonitis as compared to fractionated TBI (1300 cGy total dose [650 x 2]). Both of these regimens were also confirmed to permit engraftment between heterozygous donors and recipients sharing a single common haplotype ("F1-->F1"). The regimen of 1300 cGy (650 x 2) also permitted engraftment in completely MHC mismatched BMT, but with subsequent death from GVHD. These studies of the myeloablative regimens permitting engraftment across defined MHC barriers in miniature swine provide a basis for further studies of allogenic BMT and GVHD in this large animal preclinical model.
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital, Boston 02129.
authors.forename: C V
authors.initials: CV
authors.lastname: Smith
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: P C
authors.initials: PC
authors.lastname: Guzzetta
authors.forename: K
authors.initials: K
authors.lastname: Nakajima
authors.forename: T M
authors.initials: TM
authors.lastname: Sundt
authors.forename: A
authors.initials: A
authors.lastname: Mixon
authors.forename: T R
authors.initials: TR
authors.lastname: Spitzer
authors.forename: M A
authors.initials: MA
authors.lastname: Eckhaus
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects / Q000528:radiation effects / Q000601:surgery; D016026:Bone Marrow Transplantation / Q000276:immunology; D003520:Cyclophosphamide / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects / Q000528:radiation effects; D006086:Graft vs Host Disease / Q000150:complications / Q000517:prevention & control; D017563:Lung Diseases, Interstitial / Q000188:drug therapy; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008775:Methylprednisolone / Q000627:therapeutic use; D013552:Swine; D013556:Swine, Miniature
chemical_list: D000900:Anti-Bacterial Agents; D003520:Cyclophosphamide; D008775:Methylprednisolone