This is an application for a Career Development Award (CDA-2) for Dr. John Greenland, a staff physician in the Pulmonary and Critical Care Section of the San Francisco VA Medical Service who is establishing himself as an investigator in patient-oriented research into the immunology of lung transplantation. This CDA-2 award will provide Dr. Greenland with the necessary support to accomplish the following goals: (1) to improve the understanding of predictors of chronic lung rejection, (2) to acquire theoretical and practical skills in bioinformatics and advanced T cell immunology, (3) to establish the mechanistic foundations for future interventional trials to improve post-lung transplant surveillance, and (4) to establish an independent clinical research career focused on lung transplantation immunology. To achieve these goals, Dr. Greenland has assembled a mentoring team consisting of (1) primary mentor Dr. George Caughey, an internationally respected authority in pulmonary immunology with a track record of mentoring translational researchers, (2) Dr. David Daikh, a recognized translational T cell immunologist, (3) Dr. Qizhi Tang, an expert in human transplant immunology; and (4) Dr. Jeffrey Golden, who has over 25 years of experience with clinical research in lung transplantation. Additionally, he will benefit from tutorials and mentorship from Drs. Nick Jewell, Scott Boyd, and Kirk Jones, in biostatistics, bioinformatics, and pathology, respectively; and research support from Drs. Lewis Lanier and Mark Ansel. The proposed research expands on Dr. Greenland's recently published findings that lymphocytic bronchitis (LB) on post-lung transplant surveillance biopsy predicts the development of chronic rejection in the form of bronchiolitis obliterans syndrome (BOS). The proposed study will establish a prospective cohort of lung transplant recipients to achieve the following specific aims: (1) determine the phenotype and specificity of infiltrating T cells in LB, (2) assess regulatory, humoral, and innate lymphocyte responses during LB, and (3) prospectively assess LB as a predictor of BOS. These studies will make use of next-generation flow cytometry and sequencing techniques to characterize immune responses in peripheral blood, airway brushings and biopsies, and bronchoalveolar lavage fluid from patients undergoing post-transplant surveillance bronchoscopy. A better understanding of LB may allow it to become an important biomarker for the development of BOS, while understanding LB in the context of the post-lung transplantation donor-specific immune response will lead to new tools for optimizing immunosuppression and inducing tolerance.

Public Health Relevance

Establishing a clinical research program in lung transplant immunology at the San Francisco VAMC will advance the VHA goal of improving access for veterans to lung transplantation. The proposed research focuses on the development of new tests for early detection of rejection in transplanted lungs that may allow caregivers to intervene before there is permanent damage. This study may lead to a better understanding of why some patients reject transplanted lungs and suggest approaches to prevent rejection from degrading the performance of transplanted lungs. Improving care following lung transplantation will have a direct impact on the health of veterans, a population that is disproportionately affected by end-stage lung diseases.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (IK2)
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Veterans Affairs Medical Center San Francisco
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Greenland, John R; Chong, Tiffany; Wang, Angelia S et al. (2018) Suppressed calcineurin-dependent gene expression identifies lung allograft recipients at increased risk of infection. Am J Transplant 18:2043-2049
Calabrese, Daniel R; Chong, Tiffany; Wang, Angelia et al. (2018) NKG2C natural killer cells in bronchoalveolar lavage are associated with cytomegalovirus viremia and poor outcomes in lung allograft recipients. Transplantation :
Greenland, John R (2018) Where the Chromosome Ends: Telomeres and CMV Risk in Lung Transplant Recipients. Am J Respir Crit Care Med :
Singer, Jonathan P; Soong, Allison; Bruun, Allan et al. (2018) A mobile health technology enabled home-based intervention to treat frailty in adult lung transplant candidates: A pilot study. Clin Transplant 32:e13274
Calabrese, Daniel R; Florez, Rebecca; Dewey, Katherine et al. (2018) Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients. Clin Transplant 32:e13332
Baldwin, Matthew R; Singer, Jonathan P; Huang, Debbie et al. (2017) Refining Low Physical Activity Measurement Improves Frailty Assessment in Advanced Lung Disease and Survivors of Critical Illness. Ann Am Thorac Soc 14:1270-1279
Faust, Hilary E; Golden, Jeffrey A; Rajalingam, Raja et al. (2017) Short lung transplant donor telomere length is associated with decreased CLAD-free survival. Thorax 72:1052-1054
Greenland, J R; Sun, H; Calabrese, D et al. (2017) HLA Mismatching Favoring Host-Versus-Graft NK Cell Activity Via KIR3DL1 Is Associated With Improved Outcomes Following Lung Transplantation. Am J Transplant 17:2192-2199
Singer, J P; Katz, P P; Soong, A et al. (2017) Effect of Lung Transplantation on Health-Related Quality of Life in the Era of the Lung Allocation Score: A U.S. Prospective Cohort Study. Am J Transplant 17:1334-1345
Xu, Xiang; Greenland, John R; Gotts, Jeffrey E et al. (2016) Cathepsin L Helps to Defend Mice from Infection with Influenza A. PLoS One 11:e0164501

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