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Journal of Virology, March 2000, p. 2210-2218, Vol. 74, No. 5
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Virus-Induced Abrogation of Transplantation Tolerance Induced by Donor-Specific Transfusion and Anti-CD154 Antibody

Raymond M. Welsh,1 Thomas G. Markees,2 Bruce A. Woda,1 Keith A. Daniels,1 Michael A. Brehm,1 John P. Mordes,2 Dale L. Greiner,2 and Aldo A. Rossini2,*

Departments of Pathology1 and Medicine,2 University of Massachusetts Medical School, Worcester, Massachusetts 01655

Received 6 August 1999/Accepted 1 December 1999

Treatment with a 2-week course of anti-CD154 antibody and a single transfusion of donor leukocytes (a donor-specific transfusion or DST) permits skin allografts to survive for >100 days in thymectomized mice. As clinical trials of this methodology in humans are contemplated, concern has been expressed that viral infection of graft recipients may disrupt tolerance to the allograft. We report that acute infection with lymphocytic choriomeningitis virus (LCMV) induced allograft rejection in mice treated with DST and anti-CD154 antibody if inoculated shortly after transplantation. Isografts resisted LCMV-induced rejection, and the interferon-inducing agent polyinosinic:polycytidylic acid did not induce allograft rejection, suggesting that the effect of LCMV is not simply a consequence of nonspecific inflammation. Administration of anti-CD8 antibody to engrafted mice delayed LCMV-induced allograft rejection. Pichinde virus also induced acute allograft rejection, but murine cytomegalovirus and vaccinia virus (VV) did not. Injection of LCMV ~50 days after tolerance induction and transplantation had minimal effect on subsequent allograft survival. Treatment with DST and anti-CD154 antibody did not interfere with clearance of LCMV, but a normally nonlethal high dose of VV during tolerance induction and transplantation killed graft recipients. We conclude that DST and anti-CD154 antibody induce a tolerant state that can be broken shortly after transplantation by certain viral infections. Clinical application of transplantation tolerance protocols may require patient isolation to facilitate the procedure and to protect recipients.

* Corresponding author. Mailing address: Diabetes Division, University of Massachusetts Medical School, Two Biotech, 373 Plantation St., Suite 218, Worcester, MA 01605. Phone: (508) 856-3800. Fax: (508) 856-4093. E-mail: Aldo.Rossini{at}umassmed.edu.

Journal of Virology, March 2000, p. 2210-2218, Vol. 74, No. 5
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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