Relationship of Reconstituted Adaptive and Innate Cytomegalovirus (CMV)-Specific Immune Responses with CMV Viremia in Hematopoietic Stem Cell Transplant Recipients

• Published in: Clinical infectious diseases 2009-12, Vol.49 (12), p.1777-1783
• Main Authors: Barron, Michelle A., Gao, Dexiang, Springer, Kathryn L., Patterson, Julie A., Brunvand, Mark W, McSweeney, Peter A., Chang, Zeng, Barón, Anna E., Weinberg, Adriana
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Adult; Aged; ARTICLES AND COMMENTARIES; Biological and medical sciences; Blood; Bone marrow; Correlation analysis; Cytomegalovirus; Cytomegalovirus infections; Cytomegalovirus Infections - immunology; Disease risk; DNA polymerase; Female; Hematopoietic Stem Cell Transplantation - adverse effects; Humans; Immunity, Innate; Infections; Infectious diseases; Interferon; Killer Cells, Natural - immunology; Male; Medical sciences; Middle Aged; Morbidity; Natural killer cells; Stem cells; T cell receptors; T lymphocytes; Transplantation; Transplants & implants; Viral diseases; Viremia; Viremia - immunology; Viruses
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1086/648423

Background. Cytomegalovirus (CMV) is a major cause of morbidity in transplant recipients. An immunologic predictor of protection against CMV reactivation or disease is highly desirable. Methods. Thirty-eight allogeneic hematopoietic stem cell transplant recipients at risk of CMV disease were prospectively monitored using whole blood CMV-DNA polymerase chain reaction assay, lymphocyte proliferation assay (LPA), interferon γ enzyme-linked immunospot assay (ELISPOT), and flow cytometric enumeration of CMV-specific CD69+interferon (IFN)γ+CD4, CD8, natural killer cells, and γδ T cells. Results. Twenty-one subjects developed ⩾1 episode of CMV viremia and 4 developed disease during 360 days of follow-up. Among CMV-seropositive recipients, positive CMV-LPA before transplantation correlated with higher risk of developing viremia after transplantation (P=.02). In contrast, after transplantation, reconstitution of CMV-LPA was significantly associated with absence of CMV viremia over 360 days of follow-up (P=.04) and with faster clearance of viremia during individual episodes of CMV reactivation (P=.03). Reconstitution of CMV-specific natural killer cells was also associated with absence of CMV viremia over 360 days of study (P=.04) but not with faster clearance of viremia. CMV-specific CD4, CD8, γδ T cells, and ELISPOT values were not significantly different in viremic subjects, compared with the corresponding values in nonviremic subjects, at any time point. Conclusions. To our knowledge, this is the first study to prospectively compare multiple measures of innate and adaptive immune responses in hematopoietic stem cell transplant recipients with CMV viremia. The strongest immune correlates with protection against CMV viremia in hematopoietic stem cell transplant recipients are reconstitution of CMV-specific T cell memory responses (LPA) and recovery of natural killer cell function. In contrast, positive CMV-LPA before transplantation may be a marker of high risk of CMV reactivation after transplantation.