This research proposal will investigate the cause of bronchiolitis obiliterans syndrome (BOS), a common long term complication of the airways which develops in lung transplant recipients. This work will focus on the role of the immune system and cytomegalovirus (CMV) infection in the pathogenesis of BOS, so that precise strategies can be developed for its prevention. The hypothesis is that antibodies specific for donor HLA and/or endothelial antigens developed during the post-transplant period cause damage to the epithelium leading to the development of BOS, that CMV specific T cells play a role in augmenting epithelial changes of BOS, and furthermore, that selected CMV epitopes are recognized by such T cells. To test this hypothesis sera will prospectively analyzed by cytotoxicity as well as immunofluorescence for the development of antibodies to donor HLA and endothelial antigen in lung transplant patients. These findings will be compared to the timing of development of BOS. In addition, CMV positive lung transplant patients will have broncheoalveolar lavage fluid (BAL) analyzed for CMV reactive T-cells at various times after transplantation. Increased frequency of CMV reactive T-cells will be compared to the onset of BOS. Correlation between increased numbers of CMV specific T-cells and onset of BOS would implicate CMV infection as a cause of BOS. Reactive T- cells will then be cloned and examined for human leukocyte antigen (HLA) restriction and CMV peptide specificity. This will define the CMV antigenic epitopes recognized by lymphocytes from transplant patients with BOS.
| Smith, Michael A; Jaramillo, Andres; SivaSai, Krovvidi S R et al. (2002) Indirect recognition and antibody production against a single mismatched HLA-A2-transgenic molecule precede the development of obliterative airway disease in murine heterotopic tracheal allografts. Transplantation 73:186-93 |
| Smith, M A; Naziruddin, B; Poindexter, N J et al. (2000) Liver transplant recipient sera derived soluble HLA mediates allele specific CTL apoptosis. Transplantation 69:157-62 |
| Jaramillo, A; Smith, M A; Phelan, D et al. (1999) Temporal relationship between the development of anti-HLA antibodies and the development of bronchiolitis obliterans syndrome after lung transplantation. Transplant Proc 31:185-6 |
| Jaramillo, A; Smith, M A; Phelan, D et al. (1999) Development of ELISA-detected anti-HLA antibodies precedes the development of bronchiolitis obliterans syndrome and correlates with progressive decline in pulmonary function after lung transplantation. Transplantation 67:1155-61 |
