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Dumont-University of California Los Angeles Transplant Center, Department of Surgery, University of California Los Angeles School of Medicine, Los Angeles, CA 90095;
Institute of Medical Immunology, Humboldt University, Berlin, Germany; and
Institute of Medical Biochemistry, University of Rostock, Rostock, Germany
We have previously shown that the tolerant state in allograft
recipients can be maintained and perpetuated by an "infectious" T
cell-dependent regulatory mechanism. Hence, 1) treatment of LEW rats
with RIB-5/2, a CD4 nondepleting mAb, produces indefinite survival of
LBNF1 cardiac allografts; 2) donor-specific tolerance can
be then transferred by spleen cells into new cohorts of test allograft
recipients; and 3) putative regulatory CD4+ Th2-like cells
are instrumental in this tolerance model. We now report on studies
aimed at exposing mechanisms underlying the infectious tolerance
pathway, with emphasis on the interactions between intragraft
adenovirus-IL-4 gene transfer and systemic infusion of regulatory cells
from tolerant hosts. Unlike individual treatment regimens, adjunctive
therapy with adenovirus-IL-4 and suboptimal doses of regulatory spleen
cells was strongly synergistic and extended donor-type test cardiac
allograft survival to about 2 mo. RT-PCR-based expression of intragraft
mRNA coding for IL-2 and IFN-
remained depressed, whereas that of
IL-4 and IL-10 reciprocally increased selectively in the combined
treatment group, data supported by ELISA studies. In parallel, only
adjunctive treatment triggered intragraft induction of molecules with
anti-oxidant (HO-1) and anti-apoptotic
(Bcl-xL/Bag-1) but not with pro-apoptotic (CPP-32)
functions, both in the early and late posttransplant phases. Hence,
systemic infusion of regulatory cells potentiates the effects of local
adenovirus-IL-4 gene transfer in transplant recipients. Th2-driven
up-regulation of protective molecule programs at the graft site, such
as of anti-oxidant HO-1 and/or anti-apoptotic
Bcl-xL and Bag-1, may contribute, at least in part, to the
maintenance of the infectious tolerance pathway in transplant
recipients.
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