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Prepublished online as a Blood First Edition Paper on May 15, 2003; DOI 10.1182/blood-2003-02-0586.
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Blood, 1 September 2003, Vol. 102, No. 5, pp. 1920-1926
TRANSPLANTATION
Mechanisms of donor-specific transfusion tolerance: preemptive induction of clonal T-cell exhaustion via indirect presentation
Sergio A. Quezada,
Bruce Fuller,
Lamis Z. Jarvinen,
Mercedes Gonzalez,
Bruce R. Blazar,
Alexander Y. Rudensky,
Terry B. Strom, and
Randolph J. Noelle
From the Department of Microbiology & Immunology, Dartmouth Medical
School, Lebanon, NH; the Division of Bone Marrow Transplantation, University
of Minnesota, Minneapolis, MN; the Howard Hughes Institute, University of
Washington, Seattle, WA; and the Beth Israel Deaconess Medical Center,
Department of Medicine, Harvard, Boston, MA.
Induction of transplantation tolerance to alloantigens without general
immunosuppression remains an enduring challenge. Injecting a donor-specific
transfusion (DST) of spleen cells together with blocking  CD154 antibody
prior to graft transplantation is an effective way to induce long-lived graft
acceptance. Using a novel T-cell receptor (TCR) transgenic (Tg) model of
CD4+ T-cell–mediated rejection, this study sheds new insights
into the cellular basis for enhanced graft survival induced by DST and
CD154. The study shows that DST and CD154 induce an early,
robust, abortive expansion of the Tg T cells that results in profound anergy.
This is contrasted with the more delayed, regional, productive response
elicited by an allogeneic graft. Studies show that the induction of tolerance
to the allograft induced by DST is mediated by indirect presentation by host
antigen-presenting cells. Based on these observations, we conclude that DST
and CD154 preemptively tolerize the alloreactive T-cell compartment to
prohibit subsequent responses to the immunogenic allograft.
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