title: Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation.
abstract: Reconstitution of cellular immunity by 3 months after hematopoietic stem cell transplantation (HSCT) is a critical determinant of the long-term success of the transplantation. We analyzed the factors affecting recovery of cytomegalovirus (CMV)-specific CD4+ and CD8+ function at 3 months after HSCT by univariate and multivariable analyses including source of stem cells (bone marrow vs peripheral blood stem cells [PBSCs]), age, sex, graft-versus-host disease (GVHD), steroid use, conditioning regimens, ganciclovir use, HLA matching, circulating CMV antigenemia, absolute CD4+ and CD8+ counts, and donor CMV serology. High-dose steroids and CD4+ count less than 100 x 10(9)/L were significant predictors of impaired CD4+ functional recovery in the multivariable analysis. High-dose steroids, bone marrow as a source of stem cells, and CD8+ count less than 50 x 10(9)/L were associated with impaired CD8+ function in the multivariable analysis. Steroids were found to impair both CD4+ and CD8+ function in a dose-dependent manner. In the absence of high-dose steroids, low-level subclinical CMV antigenemia was found to stimulate both CD4+ and CD8+ functional recovery in recipients of ganciclovir prophylaxis. There was no difference in immune reconstitution between those who received prophylactic ganciclovir versus antigenemia-guided pre-emptive therapy. Thus, absolute CD4+ and CD8+ counts less than 100 x 10(9)/L and 50 x 10(9)/L, respectively; bone marrow as the source of stem cells; and high-dose steroid use all predict delayed recovery of functional T-cell immunity at 3 months after transplantation. Subclinical CMV reactivation while on ganciclovir appears to be a potent stimulator of T-cell function. These findings have implications for vaccination and adoptive-immunotherapy strategies in this population.
authors.affiliation: Fred Hutchinson Cancer Research Center, and the University of Washington, Seattle, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Hakki
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Riddell
authors.forename: Jan
authors.initials: J
authors.lastname: Storek
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Carter
authors.forename: Terry
authors.initials: T
authors.lastname: Stevens-Ayers
authors.forename: Patrick
authors.initials: P
authors.lastname: Sudour
authors.forename: Kristen
authors.initials: K
authors.lastname: White
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
authors.forename: Michael
authors.initials: M
authors.lastname: Boeckh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003587:Cytomegalovirus / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007223:Infant; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D013997:Time Factors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous / Q000379:methods*
chemical_list: D000998:Antiviral Agents; D015774:Ganciclovir