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* Department of Medical Microbiology and Immunology and
Department of Surgery, Surgical-Medical Research Institute, University of Alberta, Edmonton, Alberta, Canada
Hematopoietic chimerism is considered to generate robust allogeneic tolerance; however, tissue rejection by chimeras can occur. This "split tolerance" can result from immunity toward tissue-specific Ags not expressed by hematopoietic cells. Known to occur in chimeric recipients of skin grafts, it has not often been reported for other donor tissues. Because chimerism is viewed as a potential approach to induce islet transplantation tolerance, we generated mixed bone marrow chimerism in the tolerance-resistant NOD mouse and tested for split tolerance. An unusual multilevel split tolerance developed in NOD chimeras, but not chimeric B6 controls. NOD chimeras demonstrated persistent T cell chimerism but rejected other donor hematopoietic cells, including B cells. NOD chimeras also showed partial donor alloreactivity. Furthermore, NOD chimeras were split tolerant to donor skin transplants and even donor islet transplants, unlike control B6 chimeras. Surprisingly, islet rejection was not a result of autoimmunity, since NOD chimeras did not reject syngeneic islets. Split tolerance was linked to non-MHC genes of the NOD genetic background and was manifested recessively in F1 studies. Also, NOD chimeras but not B6 chimeras could generate serum alloantibodies, although at greatly reduced levels compared with nonchimeric controls. Surprisingly, the alloantibody response was sufficiently cross-reactive that chimerism-induced humoral tolerance extended to third-party cells. These data identify split tolerance, generated by a tolerance-resistant genetic background, as an important new limitation to the chimerism approach. In contrast, the possibility of humoral tolerance to multiple donors is potentially beneficial.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Alberta Diabetes Institute, Canadian Institutes of Health Research, and the Edmonton Civic Employees Charitable Assistance Fund. W.F.N.C. is supported by doctoral research studentships from the Muttart Diabetes Research and Training Centre and the Canadian Diabetes Association. A.M.J.S. and C.C.A. are supported by scholar awards from the Alberta Heritage Foundation for Medical Research.
2 Current address: Department of General Surgery, Xuan Wu Hospital, Capital University of Medical Science, Beijing, China 100053.
3 Address correspondence and reprint requests to Dr. Colin C. Anderson, 1074 Dentistry/Pharmacy Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2N8. E-mail address: colinand{at}ualberta.ca
4 Abbreviations used in this paper: BMT, bone marrow transplantation; KO, knockout; Treg, regulatory T.
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