Viral abrogation of stem cell transplantation tolerance causes graft rejection and host death by different mechanisms

Tolerance-based stem cell transplantation using sublethal conditioning is being considered for the treatment of human disease, but safety and efficacy remain to be established. We have shown that mouse bone marrow recipients treated with sublethal irradiation plus transient blockade of the CD40-CD154 costimulatory pathway develop permanent hematopoietic chimerism across allogeneic barriers. We now report that infection with lymphocytic choriomeningitis virus at the time of transplantation prevented engraftment of allogeneic, but not syngeneic, bone marrow in similarly treated mice. Infected allograft recipients also failed to clear the virus and died. Postmortem study revealed hypoplastic bone marrow and spleens. The cause of death was virus-induced IFN-alphabeta. The rejection of allogeneic bone marrow was mediated by a radioresistant CD8(+)TCR-alphabeta(+)NK1.1(-) T cell population. We conclude that a noncytopathic viral infection at the time of transplantation can prevent engraftment of allogeneic bone marrow and result in the death of sublethally irradiated mice treated with costimulation blockade. Clinical application of stem cell transplantation protocols based on costimulation blockade and tolerance induction may require patient isolation to facilitate the procedure and to protect recipients.