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240: Acquisition of CMV-specific CD8+ T cell memory during primary CMV infection in lung transplant recipients
S146
Abstracts
would allow risk stratification of individual LTR with regard to CMV reactivation. Methods and Materials: A longitudinal cohort of LTR were recruited from the time of transplantation and followed prospectively for one year. All CMV “at-risk” patients received 5 months antiviral prophylaxis. CMV load was assessed in the blood and BAL at the time of routine bronchoscopic evaluation. At these same time points, QuantiFERON®-CMV was used to detect CMV CD8⫹ T-cell immunity in the blood by measuring IFN-g secreted from stimulated T-cells previously exposed to CMV. Results: 250 samples were collected from 49 LTR (CMV D⫹/R-, n ⫽ 11; D⫹/R⫹, n ⫽ 21; D-/R⫹, n ⫽ 9; D-/R-, n ⫽ 9). As expected CMV-specific T-cell immunity was not detected in any of the CMV D-/R- LTR. CMV-specific CD8⫹ T cells could be detected in all CMV ⫹ve LTR and although the levels varied between patients, the presence of CMV-specific immunity appeared protective against significant CMV reactivation. In CMV “at-risk” LTR levels of CMV immunity generally increased with time from transplant and this was particularly marked following an episode of CMV reactivation where levels of CMV immunity often reset at a significantly higher level compared with baseline. CMV reactivation episodes were most likely in the CMV mismatched LTR, particularly once antiviral prophylaxis was ceased, and in these patients QuantiFERON®-CMV tracked the development of the primary immune response to CMV (median 33wks post-tx). Conclusions: The ability of the QuantiFERON®-CMV assay to measure CMV-specific CD8⫹ T-cell function provides significant insights into the dynamics of CMV reactivation and immunity in LTRs, and offers the potential for improved CMV risk stratification and individualised antiviral prophylaxis in the future. Research Funding; Cellestis.
240 ACQUISITION OF CMV-SPECIFIC CD8ⴙ T CELL MEMORY DURING PRIMARY CMV INFECTION IN LUNG TRANSPLANT RECIPIENTS M.R. Pipeling,1 E.E. West,1 C.M. Osborne,2 S.A. Migueles,2 M. Connors,2 J.F. McDyer,1 1Medicine, Johns Hopkins University, Baltimore, MD; 2National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD Purpose: Primary CMV infection in lung transplant recipients (LTRs) is associated with increased morbidity and mortality. Methods and Materials: Using peptides of the major CMV antigens pp65 and IE1, and CMV MHC class I tetramers, we assessed 7 D⫹RLTRs for the development of CMV-specific CD8⫹ T cell responses during primary CMV infection in the lung allograft and PBMC. Results: A significant expansion of CD8⫹ T cells occurs in the lung during acute CMV pneumonitis and can be detected in the bronchoalveolar lavage (BAL) fluid at the time of diagnosis, as shown in fig. 1. This correlates with high frequencies of de novo CMV-specific CD8⫹IFN-␥⫹ effector T cells in the BAL (fig. 2) and PBMC. Further, CMV tetramer⫹ CD8⫹ T cells bearing the IL-7R (CD127) are detectable in the lung and blood at this time. As in murine models of primary viral infection, CMV-specific CD8⫹IFN-␥⫹ effector T cells contract in the BAL and PBMC in the transition from active to latent infection, though long-term CMV-specific CD8⫹ T cell memory persists long after active infection. Conclusions: Together, these data support the notion that the primary CD8⫹ T cell response to active CMV infection is a dynamic process that begins with the acquisition and expansion of CMVspecific CD8⫹ effectors, and progresses toward the establishment and maintenance of long-term CD8⫹ T cell memory at airway mucosal sites within the lung allograft in addition to the blood.
The Journal of Heart and Lung Transplantation February 2007
241 ASYMPTOMATIC CMV VIREMIA IS ASSOCIATED WITH ADVERSE OUTCOMES FOLLOWING LUNG TRANSPLANTATION D.M. Lyu,1 M. Nicolls,1 M.R. Zamora,1 1Pulmonary Sciences and Critical Care Medicine, Univ. of Colorado Health Sciences Center, Denver, CO Purpose: CMV is a significant cause of morbidity and mortality after lung transplantation (LTX). Preemptive prophylaxis is advocated as an effective CMV prevention strategy. However, this is predicated on the assumption that development of asymptomatic CMV viremia does not adversely affect allograft function. Immune activation is seen in normal hosts with latent CMV infections. We sought to determine whether asymptomatic CMV viremia (AV) adversely affects lung allograft function. Methods and Materials: We reviewed the records of 172 consecutive pts undergoing LTX from 3/01 to 10/05. Pts were excluded from analysis if they did not survive 6 mos (n⫽12) or couldn’t tolerate antiviral agents (n⫽7). CMV cases were matched to control pts in consecutive fashion by the indication for LTX, time post-LTX and CMV donor/recipient serostatus. All pts received CMV prophylaxis with CMV-IVIG and 6 mos of oral valganciclovir (VGCV) and followed for CMV infection (over 600 copies/ml) by whole blood quantitave PCR. Pts with viral loads over 3000 copies/ml received a single dose of CMV-IVIG and 3 wks of VGCV. Outcome indicators were the incidence of acute rejection within 90 days of the CMV episode and the incidence of BOS. Results: 47 pts developed asymptomatic CMV viremia; 15 received antiviral therapy (AVT) for viral loads over 3000 copies/ml and 19 developed CMV disease. Compared to case-matched controls, pts with AV had an increased incidence of acute rejection within 90 days after their CMV episode (13/32 AV vs 12/66 CONT, p ⫽ .047). Treatment of AV resulted in an AR incidence similar to the controls (5/15 vs 12/66). 1 year freedom from AR after CMV was decreased in AV vs CONT (p ⫽ .01) or AVT pts. The incidence of BOS was increased in AV vs CONT pts (14/32 vs 11/62, p ⫽ .013) out to 36 months of follow-up. No significant differences were found in survival between groups.
Abstracts
would allow risk stratification of individual LTR with regard to CMV reactivation. Methods and Materials: A longitudinal cohort of LTR were recruited from the time of transplantation and followed prospectively for one year. All CMV “at-risk” patients received 5 months antiviral prophylaxis. CMV load was assessed in the blood and BAL at the time of routine bronchoscopic evaluation. At these same time points, QuantiFERON®-CMV was used to detect CMV CD8⫹ T-cell immunity in the blood by measuring IFN-g secreted from stimulated T-cells previously exposed to CMV. Results: 250 samples were collected from 49 LTR (CMV D⫹/R-, n ⫽ 11; D⫹/R⫹, n ⫽ 21; D-/R⫹, n ⫽ 9; D-/R-, n ⫽ 9). As expected CMV-specific T-cell immunity was not detected in any of the CMV D-/R- LTR. CMV-specific CD8⫹ T cells could be detected in all CMV ⫹ve LTR and although the levels varied between patients, the presence of CMV-specific immunity appeared protective against significant CMV reactivation. In CMV “at-risk” LTR levels of CMV immunity generally increased with time from transplant and this was particularly marked following an episode of CMV reactivation where levels of CMV immunity often reset at a significantly higher level compared with baseline. CMV reactivation episodes were most likely in the CMV mismatched LTR, particularly once antiviral prophylaxis was ceased, and in these patients QuantiFERON®-CMV tracked the development of the primary immune response to CMV (median 33wks post-tx). Conclusions: The ability of the QuantiFERON®-CMV assay to measure CMV-specific CD8⫹ T-cell function provides significant insights into the dynamics of CMV reactivation and immunity in LTRs, and offers the potential for improved CMV risk stratification and individualised antiviral prophylaxis in the future. Research Funding; Cellestis.
240 ACQUISITION OF CMV-SPECIFIC CD8ⴙ T CELL MEMORY DURING PRIMARY CMV INFECTION IN LUNG TRANSPLANT RECIPIENTS M.R. Pipeling,1 E.E. West,1 C.M. Osborne,2 S.A. Migueles,2 M. Connors,2 J.F. McDyer,1 1Medicine, Johns Hopkins University, Baltimore, MD; 2National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD Purpose: Primary CMV infection in lung transplant recipients (LTRs) is associated with increased morbidity and mortality. Methods and Materials: Using peptides of the major CMV antigens pp65 and IE1, and CMV MHC class I tetramers, we assessed 7 D⫹RLTRs for the development of CMV-specific CD8⫹ T cell responses during primary CMV infection in the lung allograft and PBMC. Results: A significant expansion of CD8⫹ T cells occurs in the lung during acute CMV pneumonitis and can be detected in the bronchoalveolar lavage (BAL) fluid at the time of diagnosis, as shown in fig. 1. This correlates with high frequencies of de novo CMV-specific CD8⫹IFN-␥⫹ effector T cells in the BAL (fig. 2) and PBMC. Further, CMV tetramer⫹ CD8⫹ T cells bearing the IL-7R (CD127) are detectable in the lung and blood at this time. As in murine models of primary viral infection, CMV-specific CD8⫹IFN-␥⫹ effector T cells contract in the BAL and PBMC in the transition from active to latent infection, though long-term CMV-specific CD8⫹ T cell memory persists long after active infection. Conclusions: Together, these data support the notion that the primary CD8⫹ T cell response to active CMV infection is a dynamic process that begins with the acquisition and expansion of CMVspecific CD8⫹ effectors, and progresses toward the establishment and maintenance of long-term CD8⫹ T cell memory at airway mucosal sites within the lung allograft in addition to the blood.
The Journal of Heart and Lung Transplantation February 2007
241 ASYMPTOMATIC CMV VIREMIA IS ASSOCIATED WITH ADVERSE OUTCOMES FOLLOWING LUNG TRANSPLANTATION D.M. Lyu,1 M. Nicolls,1 M.R. Zamora,1 1Pulmonary Sciences and Critical Care Medicine, Univ. of Colorado Health Sciences Center, Denver, CO Purpose: CMV is a significant cause of morbidity and mortality after lung transplantation (LTX). Preemptive prophylaxis is advocated as an effective CMV prevention strategy. However, this is predicated on the assumption that development of asymptomatic CMV viremia does not adversely affect allograft function. Immune activation is seen in normal hosts with latent CMV infections. We sought to determine whether asymptomatic CMV viremia (AV) adversely affects lung allograft function. Methods and Materials: We reviewed the records of 172 consecutive pts undergoing LTX from 3/01 to 10/05. Pts were excluded from analysis if they did not survive 6 mos (n⫽12) or couldn’t tolerate antiviral agents (n⫽7). CMV cases were matched to control pts in consecutive fashion by the indication for LTX, time post-LTX and CMV donor/recipient serostatus. All pts received CMV prophylaxis with CMV-IVIG and 6 mos of oral valganciclovir (VGCV) and followed for CMV infection (over 600 copies/ml) by whole blood quantitave PCR. Pts with viral loads over 3000 copies/ml received a single dose of CMV-IVIG and 3 wks of VGCV. Outcome indicators were the incidence of acute rejection within 90 days of the CMV episode and the incidence of BOS. Results: 47 pts developed asymptomatic CMV viremia; 15 received antiviral therapy (AVT) for viral loads over 3000 copies/ml and 19 developed CMV disease. Compared to case-matched controls, pts with AV had an increased incidence of acute rejection within 90 days after their CMV episode (13/32 AV vs 12/66 CONT, p ⫽ .047). Treatment of AV resulted in an AR incidence similar to the controls (5/15 vs 12/66). 1 year freedom from AR after CMV was decreased in AV vs CONT (p ⫽ .01) or AVT pts. The incidence of BOS was increased in AV vs CONT pts (14/32 vs 11/62, p ⫽ .013) out to 36 months of follow-up. No significant differences were found in survival between groups.