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Development of Antidonor Antibody Directed Toward Non–Major Histocompatibility Complex Antigens in Tolerant Animals

Scalea, Joseph R.1; Villani, Vincenzo1; Gillon, Bradford C.1; Weiner, Joshua1; Gianello, Pierre2; Turcotte, Nicole1; Arn, John Scott1; Yamada, Kazuhiko1; Sachs, David H.1,3

doi: 10.1097/TP.0000000000000249
Basic and Experimental Research

Background: The clinical significance of antibodies directed against antigens other than major histocompatibility complex (MHC) antigens is poorly understood, and there are few large animal models in which such antibodies can be examined. We studied, both retrospectively and prospectively, the development of antibodies to non-MHC antigens in tolerant miniature swine.

Methods: Our database was assessed for cases of antidonor antibody formation in tolerant animals over the last 20 years. Flow cytometry, absorption assays, and familial analyses for inheritance pattern of the gene(s) potentially responsible for the antibody reactivities were carried out, and an animal determined to be negative for this reactivity was immunized by a skin graft and subcutaneous injections of peripheral blood monocyte cells from an antigen-positive donor.

Results: Sixteen of 469 tolerant animals tested were found to have developed antidonor antibodies. These antibodies were found to be specific for the same, presumably single, non-MHC antigen. Familial analyses indicated that the gene encoding this antigen was expressed in an autosomal-dominant manner in approximately 95% of the herd. In a prospective study, antidonor antibodies with the same specificity as those observed retrospectively were successfully induced in an antigen-negative animal after immunization with peripheral blood monocyte cells.

Conclusion: To our knowledge, this is the first report of the development of antibodies to a highly prevalent, non-MHC antigen present on peripheral blood mononuclear cells and developing in tolerant animals without signs of graft dysfunction. Considering the concern often raised by the appearance of antidonor antibodies in transplant recipients, these data could have important implications for clinical transplantation.

1 Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

2 Catholic University of Louvain, Belgium.

3 Address correspondence to: David H. Sachs, M.D., Transplantation Biology Research Center, Massachusetts General Hospital, MGH-East, Bldg. 149-9019, 13th Street, Boston, MA, 02129.

This work was sponsored by a grant from the American Society of Transplantation (awarded to J.R.S.), and NIAID 5U19AI102405, RO1AI084903, and 5P01AI45897.

The authors declare no conflicts of interest.

E-mail: david.sachs@tbrc.mgh.harvard.edu

J.R.S., V.V., B.C.G., J.W., P.G., and K.Y. participated in the performance of the research. J.R.S. participated in research design. J.R.S., V.V., N.T., J.S.A., and D.H.S. participated in data analysis. J.R.S., V.V., and D.H.S. participated in the writing of the article. D.H.S. is responsible for research design.

Received 18 February 2014. Revision requested 28 February 2014.

Accepted 14 April 2014.

© 2014 by Lippincott Williams & Wilkins