This is a revision of a previously submitted proposal that was approved but not funded. Cytomegalovirus (CMV) is a common pathogen in lung transplant recipients and CMV disease has been shown to be one of the risk factors associated with bronchiolitis obliterans (BO), a major complication affecting more than 50% of long-term lung transplant recipients. The mechanism by which this occurs has not been elucidated. Clinically, CMV infection can persist within the allograft for several months. Using proliferative assays, we have demonstrated the persistence of """"""""primed"""""""" CMV-specific lymphocytes in bronchoalveolar lavages (BAL) several months following CMV disease. The presence of """"""""primed"""""""" rather than """"""""memory"""""""" cells within the allograft suggests an ongoing CMV induced lymphocyte activation which may indicate that the virus is not effectively cleared by the host immune response. In this proposal we address two questions: 1) why does the immune response to CMV persist in the graft of certain individuals? and what are the consequences of this persistence? These findings form the basis of the underlying hypothesis of this grant. Persistent CMV infection within the lung allograft initiates a chronic inflammatory process because of 1) a prolonged anti CMV-specific T helper response, 2) inefficient CMV-specific cytotoxic response, and 3) overabundance production of proinflammatory cytokines with in the allograft; the consequence of this host anti-CMV immune response is 4) the chronic activation of alveolar macrophages that induce tissue damage. The experiments described under specific aims 1-3 deal with the dysregulation of helper and cytotoxic responses of lung transplant recipients with chronic CMV infection.
Aim 1 - Determine the CMV-specific T helper response by assessing proliferation of BAL and PBL to soluble CMV antigens.
Aim 2 - Determine the CMV-specific cytolytic efficiency.
Aim 3 - Assess and quantitate the CMV-induced cytokine profile.
in Aim 4 we test the effect of CMV-driven response on alveolar macrophage (AM) activation.
Aim 4 - Characterize the activation state of alveolar macrophages (AM): a) assess the frequency of AM that express the activation markers 27E10 and AIF-1; b) detect the cytokine gene expression within AM spontaneously and IFN-gamma induced. These studies will provide valuable information regarding the immunological mechanisms underlying CMV disease. This will enable the development of better strategies for clinical management and newer therapeutic approaches for treatment and prevention of recurrent CMV and the development of BO in lung transplant recipients.
| Ahmed, M; Venkataraman, R; Logar, A J et al. (2001) Quantitation of immunosuppression by tacrolimus using flow cytometric analysis of interleukin-2 and interferon-gamma inhibition in CD8(-) and CD8(+) peripheral blood T cells. Ther Drug Monit 23:354-62 |
| Zeevi, A; Morel, P; Spichty, K et al. (1998) Clinical significance of CMV-specific T helper responses in lung transplant recipients. Hum Immunol 59:768-75 |
