Cytomegalovirus‐Specific Cellular Immune Responses and Viremia in Recipients of Allogeneic Stem Cell Transplants

Abstract

The immune suppression inherent in allogeneic stem cell transplantation (SCT) offers a favorable environment for infection by opportunistic agents, such as human cytomegalovirus (CMV). Despite the application of potent antiviral prophylaxis, patients remain at risk for CMV infection until adequate immunity is restored. CMV-specific CD8(+) T cell counts were monitored, using HLA-A2 tetrameric complexes, to establish the level of immune response to the viral phosphoprotein UL83 in patients after allogeneic SCT. Correlating this with viral replication and clinical status shows that the level of tetramer-positive T cells provides an assessment of CMV immune reconstitution after stem cell transplantation. Most patients with seropositive donors did reconstitute long-term CMV immunity, unless prolonged immunosuppression to control graft-versus-host disease was induced. Together with polymerase chain reaction testing, this technique provides measurable parameters that can be a guide to therapeutic decision making and can form the basis of CMV immunotherapy.

Functional analysis of cytomegalovirus-specific T lymphocytes compared to tetramer assay in patients undergoing hematopoietic stem cell transplantation

“…These results showed that CMV disease could occur after HSCT even in patients with 410/ml CMV-specific CTL as evaluated by tetramer assay, which has been considered to be sufficient to protect against CMV infection. [5][6][7] CMV-specific CTL emerged immediately following the detection of antigenemia in most patients, suggesting that CMV infection can be a trigger for the recovery of CMV-specific immunity. However, UPN9 had recovery of CMV-specific CTL at day 60 even though his CMV antigenemia and CMV DNA as evaluated by PCR were negative throughout the course.…”

“…For this purpose, tetramer-based monitoring of CMV-specific cytotoxic T-cells (CTL) has been widely performed in patients with an HLA-A02 or HLA-B07 serotype. [3][4][5][6][7][8][9][10][11] Some of the results have demonstrated that the reconstitution of CMV-specific CTL as evaluated by quantitative tetramer to levels 410-20/ml is adequate for protection against CMV infection. [5][6][7] However, some patients with CMV-specific CTL above this level still experience CMV reactivation.…”

“…[3][4][5][6][7][8][9][10][11] Some of the results have demonstrated that the reconstitution of CMV-specific CTL as evaluated by quantitative tetramer to levels 410-20/ml is adequate for protection against CMV infection. [5][6][7] However, some patients with CMV-specific CTL above this level still experience CMV reactivation. 9 It has also been reported that the cellular response to CMV in immunosuppressed patients reflects functional impairment, 10 and CMV reactivation following HSCT has been shown to be associated with the presence of dysfunctional CMV-specific T-cells.…”

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

“…In contrast, studies consistently report that almost all D 1 /R 1 transplantations show early and sustained reconstitution of pp65 tetramer positive T cells. [84][85][86][87] Reactivation during pregnancy HCMV infection in utero is estimated at between 0.4% and 0.7% of live births in the United States and a similar rate in European countries. 18 While the greatest risk for HCMV disease of the foetus is accepted to be primary infection of naive mothers, the risk of maternal-to-fetal transmission is substantially lower in seropositive women, 88 suggesting that pre-existing immunity is beneficial.…”

Functional impairment of human T-lymphocytes following PHA-induced expansion and retroviral transduction: implications for gene therapy

“…43 After tetramer staining, in some experiments, antigen-specific CTL-IFN␥ secretion was induced with specific peptide (10 M) and 3 g/ml anti-CD28 antibody (37°C, 6 h, with 3 M monensin; Calbiochem, La Jolla, CA, USA). Intracellular staining with monoclonal antibodies against IFN␥, perforin and granzyme A (BD Pharmingen) and their isotype controls was performed after cell permeabilization with Cytofix/Cytoperm Kit (BD Pharmingen).…”