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*
Surgical Research Laboratory, Department of Surgery, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA 02115;
The Dumont-University of California at Los Angeles Transplant Center, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095; and
Institute of Medical Immunology, Charité, Humboldt University Berlin, Germany
We have shown that features of infectious tolerance, as originally
described in thymectomized mice, may be applied to euthymic rat
recipients of heart transplants. We now report on studies aimed at
exposing mechanisms underlying the infectious tolerance pathway, with
emphasis on the role of thymus and alloantigen. Pretransplant
thymectomy diminished the efficacy of CD4-targeted therapy, with
donor-specific tolerance induced in 
50% of recipients. Thymus was
required for generation of regulatory T cells under the cover of CD4
mAb therapy and for the ability of these cells to confer infectious
tolerance. However, thymus was not mandatory to maintain an
infectious-permissive environment in cohorts of adoptively transferred
recipients. Intragraft expression of IL-2, IL-4, and IL-10 genes was
diminished in euthymic and thymectomized tolerant hosts. However,
grafts in the latter group showed significant IFN-
gene expression,
suggesting a less efficient down-regulation of Th1-like cells in the
absence of regulatory cells. Indeed, exogenous challenge with rIL-2 or
freshly alloactivated spleen cells recreated rejection in
thymectomized, but not euthymic, hosts, suggesting that a state of
cytokine-responsive anergy contributes to the "noninfectious" form
of tolerance in thymectomized rats. The infection-tolerant state did
not result from "graft adaptation," and regulatory T cells
restricted for the original alloantigen were exposed to its continuous
stimulation. The effective memory for suppression was dependent upon
persistent donor-specific alloantigen stimulation; it disappeared
within 3 weeks after its removal. Hence, both central and peripheral
immune mechanisms, orchestrated by the tolerizing alloantigen,
contribute to the infectious tolerance pathway in CD4 mAb-treated rat
transplant recipients.
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