Lung transplantation is a life-saving option for selected patients with end-stage lung disease. Chronic allograft rejection (bronchiolitis obliterans syndrome, or BOS) is the major limitation to long-term survival, yet its pathogenesis is poorly understood and current therapies, including potent immunosuppressive agents, are largely ineffective. The diagnosis of BOS currently depends on clinical recognition and decline in pulmonary function. These markers may manifest changes only after BOS has become established, and the lack of precision in the clinical diagnosis leads either to inadequate treatment or inappropriate treatment with immunosuppressive agents, exposing the patient to the risk of lethal infection. A non-classical HLA class I molecule, HLA-G, first discovered in the fetal cells of the placenta that interact with maternal immune cells, may have a 'tolerogenic'function in heart, kidney, and liver transplantation, where HLA-G expression is associated with graft survival. However, the role of HLA-G in lung transplant survival has never been studied, and the relationship between HLA-G genotype and expression of HLA protein of the transplanted lung and host in the development of BOS is completely unknown. The airway mucosa is uniquely sited to mediate the tolerance of the transplanted lung as it represents a major site of interaction between the allograft and the external environment. HLA-G expression by the mucosa may mediate local and circulating immune cells in lung and thus modulate the response to infection and rejection. We propose that both circulating HLA-G and HLA-G expressed in the transplanted lung help to protect the allograft from rejection. We further propose that HLA-G genotype in both donor and host influence levels of HLA-G expression. To address this paradigm we propose the following specific aims:
Aim #1. Loss of circulating sHLA-G, and/or loss of HLA-G in the allograft, is associated with clinical symptoms of rejection in patients following lung transplantation. We hypothesize that circulating HLA-G can be detected in patients after lung transplantation, that low levels are associated with greater number of acute rejection episodes in the first year, and that decreased levels of HLA-G pre-date the onset of rejection. We also hypothesize that the airway epithelium in situ and in culture express HLA-G.
Aim #2. Levels of expression of circulating HLA-G, and HLA-G in the allograft, depend upon the genotype of the host and the donor, respectively. We hypothesize that HLA-G genotype influences peripheral levels of sHLA-G prior to lung transplant, that the genotype of both the allograft and of the recipient contribute to concentrations of circulating HLA-G, and that genotypes associated with a low expression of HLA-G will be associated with a higher risk for rejection. Understanding the expression of HLA-G in lung transplant patients and the genetic determinants of expression may translate into an earlier, more certain diagnosis of BOS and lead to be better understanding of immune tolerance in lung transplantation.
Lung transplantation is a life-saving option for selected patients with end-stage lung disease, but rejection of the new lung limits long-term survival. A potent regulator of the immune system, HLA-G, may have a role in protecting the transplanted lung from the host immune system. We propose that HLA-G in the blood and in the new lung of the transplant patient help to protect the allograft from rejection: if true, our application will lead the way for future, large-scale clinical trials that will determine the usefulness of HLA-G as a marker for transplant rejection and perhaps as a life-saving therapy for transplant patients.
| White, Steven R; Floreth, Timothy; Liao, Chuanhong et al. (2014) Association of soluble HLA-G with acute rejection episodes and early development of bronchiolitis obliterans in lung transplantation. PLoS One 9:e103643 |
| Floreth, Timothy; Stern, Eric; Tu, Yingli et al. (2011) Differentiated transplant derived airway epithelial cell cytokine secretion is not regulated by cyclosporine. Respir Res 12:44 |
| White, S R; Loisel, D A; McConville, J F et al. (2010) Levels of soluble human leukocyte antigen-G are increased in asthmatic airways. Eur Respir J 35:925-7 |
