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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2002-03-0872.
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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3400-3407
TRANSPLANTATION
Combined effects of calcineurin inhibitors or sirolimus with
anti-CD40L mAb on alloengraftment under nonmyeloablative
conditions
Patricia A. Taylor,
Christopher J. Lees,
Jessica M. Wilson,
Michael J. Ehrhardt,
Matthew T. Campbell,
Randolph J. Noelle, and
Bruce R. Blazar
From the University of Minnesota Cancer Center and
Department of Pediatrics, Division of Bone Marrow Transplantation,
Minneapolis, MN; and the Department of Microbiology, Dartmouth Medical
College, Hanover, NH.
The immunosuppressive drugs, cyclosporine A (CsA), tacrolimus, or
sirolimus, were analyzed as single agents and in combination with
anti-CD40L monoclonal antibody (mAb) for their effects on alloengraftment in mice conditioned with minimal total body irradiation (TBI). Whereas anti-CD40L mAb facilitated chimerism, neither sirolimus nor CsA resulted in substantial alloengraftment. However,
sirolimus was synergistic with anti-CD40L mAb for inducing donor
chimerism. Contrary to expectations, CsA, a T-cell receptor
(TCR) signaling inhibitor, did not abrogate anti-CD40L
mAb-facilitated engraftment but rather increased engraftment in
anti-CD40L mAb-treated mice. Although tacrolimus alone or with
anti-CD40L mAb resulted in similar levels of donor chimerism, donor
T-cell reconstitution was very low in tacrolimus-treated mice. At 1 week after transplantation, CsA decreased thymic numbers more
profoundly than sirolimus or tacrolimus in anti-CD40L mAb-treated
recipients. In contrast, only sirolimus resulted in a decrease in host
splenic T-cell numbers in anti-CD40L mAb-treated recipients.
Importantly, sirolimus and anti-CD40L mAb induced profound donor
tolerance with 100% acceptance of donor skin grafts placed early after
bone marrow transplantation (BMT). In contrast, anti-CD40L mAb
alone or in combination with CsA resulted in 12% or less donor skin
graft acceptance early (1 month) and 60% or less later (3 months)
after BMT. These data have clinical relevance and indicate that
immunosuppressive pharmacologic agents enhance anti-CD40L
mAb-facilitated alloengraftment and tolerance induction under
nonmyeloablative conditioning.
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