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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070997-04
Application #
6897307
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Mondoro, Traci
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$342,000
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Hossain, Mohammad S; Roback, John D; Wang, Fengrong et al. (2008) Host and donor immune responses contribute to antiviral effects of amotosalen-treated donor lymphocytes following early posttransplant cytomegalovirus infection. J Immunol 180:6892-902
Hossain, Mohammad S; Roback, John D; Pollack, Brian P et al. (2007) Chronic GvHD decreases antiviral immune responses in allogeneic BMT. Blood 109:4548-56
Hossain, Mohammad Sohrab; Roback, John D; Lezhava, Levan et al. (2005) Amotosalen-treated donor T cells have polyclonal antigen-specific long-term function without graft-versus-host disease after allogeneic bone marrow transplantation. Biol Blood Marrow Transplant 11:169-80
Jordan, Catherine T; Roback, John D (2004) Separating antiviral and GVHD activities of donor T cells prior to bone marrow transplantation. Immunol Res 29:209-18
Roback, John D; Hossain, Mohammad S; Lezhava, Levan et al. (2003) Allogeneic T cells treated with amotosalen prevent lethal cytomegalovirus disease without producing graft-versus-host disease following bone marrow transplantation. J Immunol 171:6023-31