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The ability of natural tolerance to be applied to allogeneic tissue: determinants and limits

DOI: 10.1186/1745-6150-2-10

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We found that internal transplants mismatched for a single minor-H antigen and 'healed-in' before immune system development were not ignored but instead induced natural tolerance. In contrast, multiple minor-H or MHC mismatched transplants did not consistently induce natural tolerance unless they carried chimerism generating passenger lymphocytes. To determine whether the systemic nature of passenger lymphocytes was required for their tolerizing capacity, we generated a model of localized vs. systemic donor lymphocytes. We identified the peritoneal cavity as a site that protects allogeneic lymphocytes from killing by NK cells, and found that systemic chimerism, but not chimerism restricted to the peritoneum, was capable of generating natural tolerance.These data provide an explanation for the variable results with pre-immunocompetence transplants and suggest that natural tolerance to transplants is governed by the systemic vs. localized nature of donor antigen, the site of transplantation, and the antigenic disparity. Furthermore, in the absence of systemic lymphocyte chimerism the capacity to establish natural tolerance to allogeneic tissue appears strikingly limited.This article was reviewed by Matthias von Herrath, Irun Cohen, and Wei-Ping Min (nominated by David Scott).Reviewed by Matthias von Herrath, Irun Cohen, and Wei-Ping Min (nominated by David Scott). For the full reviews, please go to the Reviewers' comments section.Transplantation of donor cells/tissues prior to the development of recipient immunocompetence theoretically provides the greatest opportunity to achieve donor specific tolerance (for our definition of key terms, such as tolerance, see Additional File 1). All of the tolerance processes that occur for self-reactive T cells are potentially available for donor reactive T cells, and in most cases the transplant has time to heal-in prior to encountering the recipient's immune system, potentially eliminating or reducing the APC activating signals fr


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