Cytomegalovirus (CMV) is the most common opportunistic infection in solid organ transplant recipients, particularly lung transplant recipients (LTRs). As a member of the herpesvirus family, it establishes a state of chronic infection after acute primary infection. Active CMV infection, including pneumonitis, is associated with direct allograft injury and dysfunction in LTRs, along with episodes of acute and chronic rejection. At highest risk for acute primary CMV (defined by detection of de novo CMV replication) disease are CMV-seronegative recipients of lung allografts from CMV-seropositive donors (D+/R""""""""). However, the acquisition of de novo adaptive T cell viral immunity during primary infection and its impact on viral control following infection, particularly in the lung allograft, remains poorly understood. The overall objective of this proposal is to further explore the basic cellular mechanisms of CMV-specific immunity and viral control in the distinct compartments of the lung allograft and blood of LTRs. This will be accomplished specifically by 1) determining whether CMV-specific T cell responses and viral loads are increased in the lung allograft compared to the blood during primary infection and 2) determining whether CMV-specific T cell responses at the time of primary infection correlate with viral control in the lung allograft and blood compartments during chronic infection. Studies will be performed on T cells from the blood and lung allograft of an already sizeable and growing cohort of D+/R- LTRs in whom primary CMV infection is detected via diligent screening. Studies will utilize techniques including multi-parameter flow cytometry of cells obtained from the blood and lung allograft and subjected to in vitro restimulation with CMV antigens derived from the major CMV antigens pp65 and IE1, along with CMV lysate coupled with intracellular cytokine staining, MHC class I CMV tetramers, and determination of compartmental CMV viral loads by quantitative PCR. ?
Public health will benefit from these studies by a better understanding of how the immune system fights a common virus called CMV. People with a normal immune system usually do not have trouble with CMV, but people with problems in their immune system (like people with a lung transplant) can have significant trouble with the virus. These studies will help us learn how to better deal with CMV in people with lung transplants. ? ? ?
| Pipeling, Matthew R; John, Emily R; Orens, Jonathan B et al. (2011) Primary cytomegalovirus phosphoprotein 65-specific CD8+ T-cell responses and T-bet levels predict immune control during early chronic infection in lung transplant recipients. J Infect Dis 204:1663-71 |
