Potential clinical utility of monitoring cytomegalovirus-specific T lymphocytes in allogeneic stem cell transplantation

Abstract

Cytomegalovirus (CMV) remains an important cause of morbidity and mortality in organ and, particularly, allogeneic stem cell transplant (SCT) recipients, mostly due to reactivation of the virus. The advent of effective antiviral drugs, such as foscarnet and in particular ganciclovir (GCV) stimulated clinical trials to prevent CMV disease after allogeneic SCT. These studies have revealed marrow toxicity as a significant adverse effect of GCV. Consequently, preemptive treatment schedules were designed on monitoring of CMV viral load in order to administrate GCV therapy selectively to patients with active CMV infection. Currently, this approach is most widely used to prevent CMV disease. Human leukocyte antigen (HLA)-restricted, CMV-specific T-cell immunity plays an important role in protection against CMV disease post SCT. Most of the T-cell-mediated immune reactivity against CMV is directed against the structural phosphoprotein (pp) 65. Recently, direct visualization of CMV-specific T cells has become possible through flow cytometric analysis of tetramer-binding CD8 + T cells. Thus far, results of six studies in SCT and organ transplant recipients have shown that: (a) active CMV infection (≈ reactivation in most cases) triggers the CMV-specific immune response, as measured by peripheral blood counts of CMV-specific CD8 + T cells; (b) this response may dampen upon reduction of the CMV load; (c) GCV itself, while effective in reducing viral load, may at the same time blunt the CMV-specific immune response, as does concurrent immunosuppression for transplant rejection or graft-versus-host disease (GVHD). In comparison to organ transplant recipients, CMV-seropositive SCT recipients are at higher risk for CMV disease because their immune systems have to regenerate from the SCT grafts. The tetramer-based studies of allogeneic SCT recipients confirm earlier functional studies in that CMV-specific T cells present in the graft have a protective effect against recurrent CMV antigenemia and CMV disease. In allogeneic SCT recipients, the value of monitoring CMV-specific T cells for individual patient management should be addressed in further prospective studies.