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* Institute for Cellular Therapeutics and
James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202
There is an increased risk of failure of engraftment following nonmyeloablative conditioning. Sensitization resulting from failed bone marrow transplantation (BMT) remains a major challenge for secondary BMT. Approaches to allow successful retransplantation would have significant benefits for BMT candidates living with chronic diseases. We used a mouse model to investigate the effect of preparative regimens at primary BMT on outcome for secondary BMT. We found that conditioning with TBI or recipient T cell lymphodepletion at primary BMT did not promote successful secondary BMT. In striking contrast, successful secondary BMT could be achieved in mice conditioned with anti-CD154 costimulatory molecule blockade at first BMT. Blockade of CD154 alone or combined with T cell depletion inhibits generation of the humoral immune response after primary BMT, as evidenced by abrogation of production of anti-donor Abs. The humoral barrier is dominant in sensitization resulting from failed BMT, because almost all CFSE-labeled donor cells were killed at 0.5 and 3 h in sensitized recipients in in vivo cytotoxicity assay, reflecting Ab-mediated cytotoxicity. CD154:CD40 costimulatory blockade used at primary BMT promotes allogeneic engraftment in secondary BMT after engraftment failure at first BMT. The prevention of generation of anti-donor Abs at primary BMT is critical for successful secondary BMT.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grants R01 DK069766 and 5RO1 HL063442; Juvenile Diabetes Research Foundation Grants 1-2005-1037 and 1-2006-1466; Department of the Navy, Office of Naval Research; Department of the Army, Office of Army Research; Commonwealth of Kentucky Research Challenge Trust Fund; W. M. Keck Foundation; and Jewish Hospital Foundation.
This research was supported in part by National Institutes of Health Grants R01 DK52294 and HL63442; Juvenile Diabetes Research Foundation; Department of Defense: Department of the Navy, Office of Naval Research; Department of Defense: Office of Army Research; W. M. Keck Foundation; Commonwealth of Kentucky Research Challenge Trust Fund; Jewish Hospital Foundation; and University of Louisville Hospital, National Foundation to Support Cell Transplant Research.
2 Address correspondence and reprint requests to Dr. Suzanne T. Ildstad, Director, Institute for Cellular Therapeutics, Jewish Hospital Distinguished Professor of Transplantation, Professor of Surgery, University of Louisville, 570 South Preston Street, Suite 404, Louisville, KY 40202-1760. E-mail address: stilds01{at}louisville.edu
3 Abbreviations used in this paper: BMT, bone marrow transplantation; BMC, bone marrow cell; DC, dendritic cell; FCXM, flow cross-match assay; MFI, mean fluorescence intensity; TBI, total body irradiation.
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