Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis

Abstract

Protection from cytomegalovirus (CMV) disease in immunocompromised hosts has been shown to correlate with recovery of the host virus- specific CD8+ T-cell response. The administration of ganciclovir to immunosuppressed transplant recipients as antiviral prophylaxis has reduced the early risk of CMV disease, but late disease is observed with increased frequency, suggesting that recovery of the CMV-specific T-cell responses necessary for protective immunity may be delayed in these patients. Therefore, we evaluated reconstitution of CMV-specific T-cell responses in 47 bone marrow transplant (BMT) recipients entered on a randomized placebo-controlled study of ganciclovir. The study drug was initiated at a mean of 24 days after BMT. At day 30 to 40, a minority of patients had recovery of T-cell immunity to CMV and the frequency of reconstitution was equivalent in patients randomized to ganciclovir or placebo. The failure of ganciclovir to effect early reconstitution may reflect the short duration of treatment. Early recovery was associated with the infusion of BM from a CMV seropositive donor (P = .07 for CD8+ cytotoxic T cell (CTL), P = .04 for CD4+ Th). Between day 40 and day 90, recovery of deficient CD8+ and CD4+ CMV- specific T-cell responses occurred in the majority of individuals that received placebo, but in a minority of ganciclovir recipients. Two cases of late-onset CMV disease occurred in ganciclovir recipients. In all patients, the presence of a CTL response to CMV conferred protection from subsequent CMV disease (P = .005), and these protective CTL responses are shown to be specific for structural virion proteins similar to the responses in immunocompetent CMV seropositive individuals. These data confirm the importance of CMV-specific T-cell responses and suggest that a delay in recovery of these responses as a result of ganciclovir prophylaxis may contribute to the occurrence of late CMV disease.

Efficacy and Safety of Valganciclovir vs. Oral Ganciclovir for Prevention of Cytomegalovirus Disease in Solid Organ Transplant Recipients

“…However, the issue of whether antiviral prophylaxis alters CMV‐specific immune‐reconstitution is controversial. Indeed, while ganciclovir prophylaxis has been reported to delay the recovery of CMV‐specific T‐cell responses in bone marrow transplant recipients (29), ganciclovir treatment during primary viremia has been reported to assist in the rapid induction, maintenance and stabilization of CMV‐specific cellular immune responses in SOT recipients (30). It is also important to note that ganciclovir‐treated patients in the present study attained higher plasma ganciclovir exposures than would be expected from previous pharmacokinetic studies in SOT patients (mean AUC 0–24 h , 28.0 vs. 20.7 μg/h/mL) (16) and therefore the difference in degree of exposure after valganciclovir and ganciclovir was not as great as has been reported previously (16).…”

Population analysis of antiviral T cell responses using MHC class I-peptide tetramers

“…Use of such reagents in a whole blood‐based, 96‐well plate format for rapid processing could take them closer to clinical applications, where such tests have so far remained very much research tools. Because the samples may be stored under appropriate conditions and batched, this could in future be an efficient way of performing studies of T cell‐based immunity in a range of settings including treatment or vaccination of viral infections [25] or tumours [26] and transplantation [16,27].…”

Cellular responses to cytomegalovirus in immunosuppressed patients: circulating CD8+ T cells recognizing CMVpp65 are present but display functional impairment

“…The introduction of new techniques to visualize antigen‐specific T lymphocytes offers unique possibilities to characterize the cellular immune response to defined antigens of viruses and tumour cells. Cytotoxic (CD8 + ) and helper (CD4 + ) T lymphocytes are of crucial importance in the acute phase of viral diseases and for keeping lifelong viral infections, such as cytomegalovirus (CMV), in a latent phase [1–4]. However, in order to understand the mechanisms of reactivated CMV infection in immunosuppressed patients, the precise role of these antigen specific T lymphocytes remains to be fully explored.…”