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*
Department of Pathology,
Institute for Gene Therapy and Molecular Medicine, and the Recacati/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY 10029; and
Departments of Surgery and Bioengineering, University of Tokyo, Tokyo, Japan
Previous reports demonstrated that retroviral mediated gene
transfer of viral IL-10 (vIL-10) prolongs allograft survival by
decreasing donor-specific cytotoxic T lymphocyte precursor (CTLp) and
IL-2-secreting helper T lymphocyte precursor (HTLp) frequency within
graft-infiltrating cells (GIC). This report now shows that vIL-10
efficacy is dependent on CD4+ T cells, suggesting that
immunosuppression may involve a switch from a Th1 to a Th2
alloresponse. In support of this, anti-IL-4 or anti-murine
IL-10 (anti-mIL-10) mAbs, but not anti-IFN-
mAb,
administered at the time of vIL-10 gene transfer prevents enhanced
graft survival. Because Th switching involves APC function, GIC were
examined for their ability to present alloantigen. GIC from
vIL-10-treated grafts were shown to be mostly of recipient (CBA)
origin, yet were unable to elicit alloproliferative responses from
donor type (C57BL/6) or third party (BALB/c) responders. The inability
of vIL-10-treated GIC to stimulate the MLR was not due to the
generation of negative regulatory cells or the production of
immunosuppressive cytokines such as IL-4, mIL-10, or TGF
. Using
fractionated GIC subpopulations, the number of recipient type cells in
the allografts was modestly reduced by vIL-10 gene transfer, while
maintaining both APC phenotype and alloantigen presenting function.
Conversely, after vIL-10 gene transfer, donor type GIC were unable to
participate in direct alloantigen presentation. Therefore, local
immunosuppression induced by vIL-10 gene transfer is CD4 T cell and
IL-4 and mIL-10 dependent, and impairs direct alloantigen presentation
through an alteration of donor type APC
function.
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