Delayed NK Cell Reconstitution and Reduced NK Activity Increased the Risks of CMV Disease in Allogeneic-Hematopoietic Stem Cell Transplantation

Abstract

Cytomegalovirus (CMV) infection has a significant impact in patients after allogeneic hematopoietic stem cell transplantation (HSCT). We investigated natural killer (NK) cell reconstitution and cytotoxic/cytokine production in controlling CMV infection, especially severe CMV disease in HSCT patients. Fifty-eight patients with acute myeloid leukemia (AML) who received allo-HSCT were included. We monitored NK reconstitution and NK function at baseline, 30, 60, 90, 120, 150, and 180 days after HSCT, and compared the results in recipients stratified on post-HSCT CMV reactivation (n = 23), non-reactivation (n = 24) versus CMV disease (n = 11) groups. The CMV disease group had a significantly delayed recovery of CD56dim NK cells and expansion of FcRγ-CD3ζ+NK cells started post-HSCT 150 days. Sequential results of NK cytotoxicity, NK cell-mediated antibody-dependent cellular cytotoxicity (NK-ADCC), and NK-Interferon-gamma (NK-IFNγ) production for 180 days demonstrated delayed recovery and decreased levels in the CMV disease group compared with the other groups. The results within 1 month after CMV viremia also showed a significant decrease in NK function in the CMV disease group compared to the CMV reactivation group. It suggests that NK cells’ maturation and cytotoxic/IFNγ production contributes to CMV protection, thereby revealing the NK phenotype and functional NK monitoring as a biomarker for CMV risk prediction, especially CMV disease.

Viral Infections in HSCT: Detection, Monitoring, Clinical Management, and Immunologic Implications

“…Furthermore, early NK response may have a favorable impact on the risk of CMV reactivation ( 36 ). There is a bidirectional relationship between NK recovery and CMV infection, since low NK level favors CMV reactivation and CMV reactivation shapes NK response, as specified in a subsequent section ( 46 ).…”

“…In experimental animal models, CMV proved to be the driver of the adapted NK response and adapted NK proved to be effective in clearing CMV at virus re-challenge, as could be hypothesized from clinical studies ( 171 ). The wide heterogeneity of HSCT settings and some contradictory results ( 46 ) raise the question as to whether CMV-linked features of NK response are invariably to be expected after every type of HSCT. For example, on a series of MUD HSCT recipients, a significant increase of NK bearing an adapted phenotype was limited to cases where BM was the stem cell source ( 158 ).…”

Modification of Monocyte Count and Subsets During Human Cytomegalovirus Replication in vivo and Glucocorticoid Therapy

“…The cause of monocytosis is primarily hematologic or infectious disease, but cytomegalovirus disease has not been described [13]. However, lymphocytosis with atypical lymphocytes is a well-known symptom in immunocompetent patients, but most of patients with active CMV replication are lymphopenic under the influence of NHL, HSCT or primary immunodeficiency (Table 2) [9,11]. High (up to 25% of WBC) monocyte percentage corresponds with such situation ( Figure 4B).…”

“…Contrary to rapid development of molecular background, basic understanding of physiology, symptomatology and differential diagnosis of CMV disease is still an open question [3,7,8]. Unfortunately, CMV reactivation is arbitrarily defined as CMV viremia > 1000 copies/mL in spite of the fact that viral particles may be in free form or within leukocytes and deep leukopenia may affect the absolute result [9]. Such studies show ambiguous results with nearly the same prevalence of CMV reactivation and no CMV infection in recipient positive donor-negative constellation (R+/D-) i.e.…”

“…No cytomegalovirus disease was observed in D-R-or D-R+ pairs, contrary to the accepted rule, that patients undergoing allo-HSCT, the use of a CMV (−) donor to a CMV (+) patient (R+/D-) have been associated with an increased risk for nonrelapse mortality and decreased survival [10]. Other infectious causes of pneumonitis or colitis in such immunodeficient patients were not analyzed and no patients with CMV disease developed relapse [9]. For the development of CMV disease not only the size of the viral load is crucial, but also the parameters of the host, such as IgG, leukocyte level, especially lymphopenia [11].…”