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Blood, 1 February 2007, Vol. 109, No. 3, pp. 1307-1315.
Prepublished online as a Blood First Edition Paper on October 3, 2006; DOI 10.1182/blood-2006-05-022772.
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Submitted May 17, 2006
Accepted September 19, 2006
Preformed antibody, not primed T cells, is the initial and major barrier to bone marrow engraftment in allosensitized recipients
Patricia A Taylor, Michael J Ehrhardt, Matthew M Roforth, Jessica M Swedin, Angela Panoskaltsis-Mortari, Jonathan S Serody, and Bruce R Blazar*
Cancer Center and Department of Pediatrics, Division of BMT, University of Minnesota, Minneapolis, MN
Lineberger Comprehensive Cancer Center, Univeristy of North Carolina, Chapel Hill, NC
* Corresponding author; email: blaza001{at}tc.umn.edu.
Multiply-transfused individuals are at higher risk for BM rejection. We show that whereas allosensitization resulted in the priming of both cellular and humoral immunity, preformed antibody was the major barrier to engraftment. The generation of cross-reactive alloantibody led to rejection of BM of a different MHC-disparate strain. Imaging studies indicated that antibody-mediated rejection was very rapid (<3 hours) in primed recipients while T cell-mediated rejection in non-primed mice took >6 days. Antibody-mediated BM rejection was not due to a defect in BM homing as rejection occurred despite direct intra-BM infusion of donor BM. Rejection was dependent upon host FcR+ cells. BM cells incubated with serum from primed mice were eliminated in non-primed recipients indicating that persistent exposure to high titer antibody was not essential for rejection. High donor engraftment was achieved in a proportion of primed mice by mega-BM cell dose, in vivo T cell-depletion, and high dose immunoglobulin infusion. The addition of splenectomy to this protocol only modestly added to the efficacy of this combination strategy. These data demonstrate both rapid alloantibody-mediated elimination of BM by host FcR+ cells and priming of host anti-donor T cells and suggest a practical strategy to overcome engraftment barriers in primed BMT individuals.
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