Cytomegalovirus Immune Reconstitution Occurs in Recipients of Allogeneic Hematopoietic Cell Transplants Irrespective of Detectable Cytomegalovirus Infection

Abstract

The question of when immune reconstitution of cytomegalovirus (CMV)-specific CD8 T cells occurs after hematopoietic cell transplantation and, more specifically, to which CMV targets this immunity is likely to be directed remains poorly understood. The dependence of immune reconstitution on CMV reactivation is even less clear. To better understand these events, 44 CMV-seropositive HLA-A*0201 subjects were followed up at approximately days 40, 90, 120, 150, 180, and 360 after hematopoietic cell transplantation for CMV immunity as measured by 2 types of assays: (1) an HLA-A*0201 tetramer-binding assay for both CMV pp65 (pp65) and immediate-early 1 (IE-1) or (2) intracellular cytokine interferon gamma responses induced by pp65 or IE-1-derived peptides. To verify the reliability of IE-1-specific assays relative to the pp65-based assays, a pilot study first compared the development of IE-1-specific immunity in a subgroup by using multiple HLA-A*0201-restricted peptides, and then these recipients were followed up for 1 year for immunologic function and for CMV infection. The IE-1-specific response occurred to each of the 3 HLA-A*0201-restricted peptides studied (IE-1-256, -297, and -316), and there was no predominant IE peptide response. However, the immunodominant HLA-A*0201-restricted pp65 peptide was recognized significantly more frequently than these IE-1 peptides. When this was compared with the occurrence of CMV infection, the overall immune reactivity, as measured by the mean or median number of CD8+ T cells reactive to either pp65 or IE-1 peptides by intracellular cytokine or tetramer binding assay, was not significantly different in those with and without CMV infection. For patients who demonstrated reconstituted immunity to CMV at 1 year, all were reconstituted by 6 months, and the timing of the first observed immune reactivity to either of the pp65 or the IE peptides was not different in those with and without detectable CMV infection.

Early reconstitution of effector memory CD4+ CMV-specific T cells protects against CMV reactivation following allogeneic SCT

“…The most likely explanation for this finding is viral reactivation in the early post transplant period could lead to the expansion of effector memory CMV-specific CD4 þ T-cell populations even in the absence of clinically detectable viraemia. 34 As viral reactivation becomes controlled, reversion of Agspecific populations into central memory and resting memory phenotype could then occur. Alterations in general immune homeostasis in the early post transplant period may also impact on the cytokine profile of effector populations.…”

Monitoring cytomegalovirus IE‐1 and pp65‐specific CD4+ and CD8+ T‐cell responses after allogeneic stem cell transplantation may identify patients at risk for recurrent CMV reactivations

“…1 Tcell responses in the absence of CMV reactivation had already been noted by others (33). The absence of CMVspecific CD4…”

Clearance of CMV viremia and survival after double umbilical cord blood transplantation in adults depends on reconstitution of thymopoiesis

“…Detection of CMV effectors without detectable CMV viremia was previously observed after HSC transplantation and was attributed to occult CMV reactivation. 39,43 These observations raise intriguing questions about the mechanisms that may regulate the ability of CMV effectors to successfully fight the virus and clear CMV viremia in some but not all the patients. We determined that patients with higher levels of CD3 ϩ and CD8 ϩ T cells in general, and the CD8 ϩ CD45RA ϩ subset in particular, had higher numbers of IFN-␥-producing CMV effectors at 6 months after transplantation.…”