During the period of immune reconstitution following allogeneic hematopoietic progenitor cell transplantation (HPCT), infections with cytomegalovirus (CMV) and other opportunistic pathogens produce significant morbidity and mortality. Adoptive transfer of donor CD8+ T-lymphocytes can protect the HPCT recipient from infectious complications and thus represents a powerful adjunct or alternative to antiviral drugs. However, adoptive immunotherapy is rarely used clinically due to lengthy and expensive in vitro protocols required to eliminate alloreactive T-cells that can produce lethal graft-versus-host disease (GvHD). Using a clinically-relevant murine bone marrow transplant (BMT) model in which F1 (C57BL/6 x BALB/c; H-2b/d) recipients of allogeneic C57BL/6 (H-2b) transplants are exquisitely sensitive to lethal murine CMV (MCMV) infections, we have identified a simple clinically-applicable method for adoptive antiviral immunotherapy with allogeneic (C57BL/6) lymphocytes: ex vivo pretreatment with S-59 psoralen and UVA light eliminates their GvHD potential without compromising antiviral immune function. We propose to utilize this model to address the following objectives: number 1) dissect the immune defects that predispose allogeneic BMT recipients to lethal MCMV infection, number 2) define the requirements for successful adoptive immunotherapy using S-59/UVA-treated MHC mis-matched lymphocytes, including the cell types required for effective immunotherapy (CD4 and/or CD8 T-cells); and, number 3) determine the effects of adoptive immunotherapy on short- and long-term immune responsiveness of the recipient. These studies will form a preclinical foundation for a novel method of adoptive antiviral immunotherapy that is simple, rapid, and should be broadly applicable to immunocompromised recipients of allogeneic HPCT. Furthermore, these investigations will provide an improved understanding of the defects that render allogeneic HPCT recipients susceptible to lethal infections.
