Bone marrow transplantation in miniature swine: IV. development of myeloablative regimens that allow engraftment across major histocompatibility barriers

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Studies of the myeloablative regimens capable of permitting successful BMT across MHC barriers in miniature swine have been performed. To minimize graftversus-host disease (GVHD), engraftment was studied in the FI→P combination (i.e., MHC homozygous [“parental”] swine receiving bone marrow from one-haplo-type matched MHC heterozygous [[“FI[”] 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 FI→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 [650×2]). Both of these regimens were also confirmed to permit engraftment between heterozygous donors and recipients sharing a single common haplotype (“FI↠FI“). The regimen of 1300 cGy (650×2) 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 allogeneic BMT and GVHD in this large animal preclinical model. © 1993 by Williams and Wilkins.

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