RESUMEN
In lung transplant recipients (LTRs), human cytomegalovirus (HCMV) DNAaemia could be associated with HCMV disease and reduced allograft survival. In the present study we analysed whether or not HCMV-specific granzyme B (Grz-B) responses indicating CD8(+) T cell cytotoxicity exert an impact on HCMV DNAaemia and relate to specific interferon (IFN)-γ secretion. HCMV-specific Grz-B responses were quantitated by enzyme-linked immunosorbent assay (ELISA) in 70 samples from 39 HCMV seropositive LTRs who were prospectively investigated for HCMV DNA plasma levels and IFN-γ kinetics using a standardized CD8(+) T cell assay (QuantiFERON®-CMV assay). In all LTRs who were protected from HCMV DNAaemia by early and persistent IFN-γ responses, Grz-B responses were also detected. In LTRs who developed episodes of HCMV DNAaemia, the Grz-B responses which were detected prior to viral DNA detection differed significantly in patients who experienced episodes with high (exceeding 1000 copies/ml) and low plasma DNA levels (P = 0·0290, Fisher's exact test). Furthermore, the extent of Grz-B release prior to viral DNAaemia correlated statistically with the detected levels of IFN-γ (P < 0·0001, Spearman's rank test). Of note, simultaneous detection of Grz-B and IFN-γ secretion was associated significantly with protection from high HCMV DNA plasma levels during the subsequent follow-up (P = 0·0057, Fisher's exact test), and this association was stronger than for IFN-γ detection alone. We conclude that, in addition to IFN-γ responses, Grz-B secretion by CD8(+) T cells is essential to control HCMV replication and a simultaneous measurement of IFN-γ and Grz-B could contribute to the immune monitoring of LTRs.
Asunto(s)
Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Citomegalovirus/genética , Citomegalovirus/inmunología , Granzimas/metabolismo , Trasplante de Pulmón/inmunología , Adulto , Anciano , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , ADN Viral/sangre , Femenino , Granzimas/sangre , Humanos , Interferón gamma/biosíntesis , Interferón gamma/sangre , Masculino , Persona de Mediana Edad , Carga ViralRESUMEN
In lung transplant recipients (LuTRs), human cytomegalovirus (HCMV) DNAemia may be associated with HCMV disease and reduced survival of the allograft. Because T cells are essential for controlling HCMV replication, we investigated in this prospective study whether the kinetics of plasma HCMV DNA loads in LuTRs are associated with HCMV-specific CD8+ T cell responses, which were longitudinally assessed using a standardized assay. Sixty-seven LuTRs were monitored during the first year posttransplantation, with a mean of 17 HCMV DNA PCR quantifications and 11.5 CD8+ T cell tests performed per patient. HCMV-specific CD8+ T cell responses displayed variable kinetics in different patients, differed significantly before the onset of HCMV DNAemia in LuTRs who subsequently experienced episodes of DNAemia with high (>1000 copies/mL) and low plasma DNA levels (p = 0.0046, Fisher's exact test), and were absent before HCMV disease. In HCMV-seropositive LuTRs, high-level DNAemia requiring preemptive therapy occurred more frequently when HCMV-specific CD8+ T cell responses fluctuated, were detected only after HCMV DNA detection, or remained undetectable (p = 0.0392, Fisher's exact test). Thus, our data indicate that HCMV-specific CD8+ T cells influence the magnitude of HCMV DNAemia episodes, and we propose that a standardized measurement of CD8+ T cell immunity might contribute to monitoring the immune status of LuTRs posttransplantation.