Submitted February 4, 2009
Accepted April 4, 2009
Impact of donor CMV-status on viral infection and reconstitution of multi-function CMV-specific T-cells in CMV-positive transplant recipients
Wendi Zhou, Jeff Longmate, Simon F. Lacey, Joycelynne M. Palmer, Ghislaine Gallez-Hawkins, Lia Thao, Ricardo Spielberger, Ryotaro Nakamura, Stephen J. Forman, John A. Zaia, and Don J. Diamond*
Division of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, CA, United States
Division of Information Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, United States
Department of Virology, Beckman Research Institute of the City of Hope, Duarte, CA, United States
Department of Hematology and HCT, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
* Corresponding author; email: ddiamond{at}coh.org.
Reconstitution of cytomegalovirus (CMV)-specific CD8+ T-cells are essential to the control of CMV infection in CMV-positive recipients (R+) after allogeneic hematopoietic stem cell transplantation (HCT). Six-color flow cytometry was used to assess the functional profile of CMV-specific CD8+ T-cells in 62 of 178 R+ HCT recipients followed virologically for CMV reactivation. R+ recipients receiving grafts from CMV-negative (D-) donors (D-/R+) reconstituted fewer multi-functional CD8+ T-cells expressing TNF-
, MIP-1
, and CD107 in addition to IFN-
, compared to D+/R+ recipients. Unlike mono-functional CD8+ T-cells secreting IFN-, which were abundantly generated during CMV reactivation in D-/R+ recipients, the relative lack of multi-functional CD8+ T-cells persisted until at least 1-year post-HCT. D-/R+ recipients were more likely to require recurrent and prolonged use of antivirals. These findings were robust to statistical adjustment for pre-transplant factors, as well as for post-transplant factors including GVHD and its treatment by steroids. Our analyses suggest that D+/R+ transplants, on average, generate higher levels of multi-functional CMV-specific T-cells and require less antiviral therapy compared to D-/R+ HCT recipients. These results highlight the benefit of D+ donors in improving outcomes of R+ HCT recipients by reducing the duration and recurrent need of antiviral treatment, aided by increased levels of multi-functional CMV-specific T-cells.
