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* Cellular and Molecular Immunology Laboratory, Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, MA 02114;
Laboratory of Immunogenetics and Transplantation, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; and
Department of Immunology, Lerner Research Institute, Cleveland, OH 44195
The role of immune response to tissue-specific Ags in transplant
rejection is poorly defined. We have previously reported that
transplantation of cardiac allografts triggers a CD4+ Th1
cell response to cardiac myosin (CM), a major contractile protein of
the heart, and that pretransplant activation of proinflammatory
CM-specific T cells accelerates rejection. In this study, we show that
administration of CM together with IFA (CM/IFA) can prevent acute
rejection of an allogeneic heart transplant. Prolongation of cardiac
graft survival is associated with activation of CM- and allo-specific T
cells secreting type 2 cytokines (IL-4, IL-5) and reduction of the
frequency of proinflammatory IFN-
-secreting (type 1) alloreactive T
cells. Blocking of IL-4 cytokine with Abs abrogates the prolongation.
CM/IFA treatment prevents acute rejection of MHC class I-mismatched,
but not fully mismatched grafts. However, if donor heart is devoid of
MHC class II expression, CM-IFA administration delays rejection of
fully allogeneic cardiac transplants. This finding suggests that the
effect of CM modulation depends on the type (direct vs indirect) and
strength of recipient’s CD4+ T cell alloresponse. Our
results underscore the important role of host immunity to
tissue-specific Ags in the rejection of an allograft. This study
demonstrates that modulation of the immune response to a
tissue-specific Ag can significantly prolong cardiac allograft
survival, an observation that may have important implications for the
development of novel selective immune therapies in
transplantation.
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