Lung transplantation is the final therapeutic option for select patients with end-stage lung disease. However, obliterative bronchiolitis (OB), or chronic airway rejection, limits its long-term success and occurs despite calcineurin-inhibitor based immunosuppressive regimens. The pathogenesis of this disease remains unclear. While significant evidence points towards a role for type 1 T cell responses in the development of OB, several studies in lung transplant recipients have suggested that type 17 T cell responses are also important in the disease, and there is evidence in murine transplant models that type 17 responses are increased in mice that express no T-bet, a transcription factor important in the development of type 1 responses. In addition, preliminary data suggests the cyclosporine A, a calcineurin-inhibitor used widely in recipients of solid organ transplant to prevent rejection, inhibits T-bet expression in vitro. The purpose of this project is to investigate the effects of T-bet deficiency on the balance between type 1 and type 17 responses and airway rejection. Using a murine model of airway transplant (murine heterotopic tracheal transplant model) that results in obliterative airway disease (OAD) reminiscent of OB, 2 major questions will be answered: (1) Does absolute T-bet deficiency result in preferential priming for type 17 T cell responses that are sufficient for OAD induction?, and (2) Does CSA create a relative T-bet deficiency in vivo that potentiates type 17 responses which can be stimulated with LPS to participate in OAD pathogenesis?. The first question will be answered by characterizing allospecific T cell responses (via use of flow cytometry) and resultant allograft pathology of T-bet -/- recipients compared to wild-type recipients. T cells from T-bet-/- mice will also be adoptively transferred into lymphocyte deficient tracheal transplant recipients to test whether these cells are sufficient for OAD induction and to define their effector responses. The second question will be answered by treating wild-type recipients of tracheal transplant with CSA and characterizing resultant T cell effector responses and allograft pathology. The hypothesis here is that with the addition of an LPS stimulus to the CSA-treated recipient (via placing the allograft in an LPS solution prior to transplantation), type 17 T cell responses will be enhanced and will overcome CSA mediated OAD attenuation. If the hypothesis is true, this could explain one mechanism by which rejection occurs despite calcineurin-inhibitor based immunosuppressive regimens. The long-term objective is to improve outcomes in lung-transplant recipients by elucidating the cellular mechanisms involved in the pathogenesis of obliterative bronchiolitis and identifying potential therapeutic targets.
The T cell responses that participate in the pathogenesis airway rejection and the regulation of these T cell responses will be further defined through this research. As a result of this project and others that aim to elucidate cellular mechanisms of airway rejection in animal models, translational studies can be designed in human lung transplant recipients and potential therapeutic targets identified to prevent the limits that obliterative bronchiolitis exerts on long-term survival in these patients. In addition, this research may be applicable to rejection in other solid organ transplants and to any disease process involving the type 17 response.
|Dodd-o, J M; Lendermon, E A; Miller, H L et al. (2011) CD154 blockade abrogates allospecific responses and enhances CD4(+) regulatory T-cells in mouse orthotopic lung transplant. Am J Transplant 11:1815-24|