This is a Career Development Grant to allow the PI protected time for formal education, mentored laboratory work and development of a research approach. My new research pathway requires additional mentored and didactic learning, despite my extensive prior training and experience. In my over three years at UCLA I have learned new laboratory techniques that are common in the field of transplant immunology. I have become competent at FACS and analysis of such data. The complex, longitudinal studies that I propose to undertake will require statistical analysis techniques with which I am not yet familiar. Moreover, more time is needed to develop a solid laboratory background, and such experience is best gained in a mentored environment. A mentored research environment thus allows protected time for me to undertake formal instruction, to continue to apply for grant funding, and to establish myself as a translational transplant researcher. The K23 is designed to meet these goals. My Career Development Plan includes formal, graduate level, biostatistical coursework as a part of the UCLA K30 program, which will lead to a Masters in Clinical Research. More advanced courses will be taken within the Department of Biostatistics that focus on analysis of complex, longitudinal data with many covariates, which is the sort of data to be developed in the research plan. Courses outside of UCLA will focus on furthering my FACS skills and analysis of such data. The Environment and Mentors that we have put together is truly phenomenal. The resources available to me at UCLA will ensure that the aims in this grant, which includes my growth as an independent researcher, are met. My mentors have a combined history of mentoring scores of successful researchers and have solid grant support for the duration of my proposal. This is truly a multi-disciplinary approach to research and training, which is precisely the approach that science itself is more often taking. The research plan is focused on lymphocytes, chemokines, cytokines and long-term graft survival. Lung transplantation is a therapeutic option for end-stage lung disorders. Long-term survival is largely dependent upon recipients remaining free of bronchiolitis obliterans syndrome (BOS). BOS affects over 60% of lung transplant recipients within five years after transplantation and imparts a 3-year mortality of >50%. Despite BOS being a major obstacle to long-term survival post-lung transplantation, there is presently no effective means of early detection nor effective treatment strategy. We have recently found that lung transplant recipients with increased frequencies of Treg within the bronchoalveolar lavage fluid do not develop BOS. The frequencies of BAL Treg correlated with BAL levels of the CCR7 ligand CCL21, which itself appears to protect against BOS. We further identified a subset of Treg, CCR7+/CD45RA- memory Treg, that identify individuals protected from chronic allograft rejection. Our hypothesis is that these CCR7+/CD45RA- memory Treg promote an allograft milieu which protects lung allograft recipients against BOS. The overall objective of this application is to determine if a) BALF CCR7+ /CD45RA- mTreg can identify lung transplant recipients at reduced risk of future BOS development and b) if BALF protein levels of the CCR7 ligands correlate with protection from BOS and with frequencies of this Treg subset. Our long-term objective is to determine the immune mechanisms that drive BOS, so as to prolong survival and improve quality of life after lung transplantation. The successful completion of these aims will improve understanding of the mechanisms behind Treg accumulation within the lung allograft and will ultimately lead to the development of novel biologics to promote protection against BOS.

Public Health Relevance

to Public Health Lung transplantation is an option for end-stage lung disease, but is complicated by chronic allograft rejection (BOS). Despite its major obstacle to long-term survival, there is presently no effective means of early detection, prevention, or treatment strategies. Identification of a Treg subset responsible for preventing BOS and elucidation of the mechanism whereby such Treg are recruited to and maintained within the allograft will allow for novel therapeutic and treatment modalities to prolong post-lung transplant survival.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL102220-04
Application #
8586341
Study Section
Special Emphasis Panel (ZHL1-CSR-X (O1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2011-01-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$152,406
Indirect Cost
$11,289
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
DerHovanessian, A; Weigt, S S; Palchevskiy, V et al. (2016) The Role of TGF-β in the Association Between Primary Graft Dysfunction and Bronchiolitis Obliterans Syndrome. Am J Transplant 16:640-9
Miele, Catherine H; Schwab, Kristin; Saggar, Rajeev et al. (2016) Lung Transplant Outcomes in Systemic Sclerosis with Significant Esophageal Dysfunction. A Comprehensive Single-Center Experience. Ann Am Thorac Soc 13:793-802
Gregson, Aric L (2016) Infectious Triggers of Chronic Lung Allograft Dysfunction. Curr Infect Dis Rep 18:21
Husain, Shahid; Sole, Amparo; Alexander, Barbara D et al. (2016) The 2015 International Society for Heart and Lung Transplantation Guidelines for the management of fungal infections in mechanical circulatory support and cardiothoracic organ transplant recipients: Executive summary. J Heart Lung Transplant 35:261-82
DerHovanessian, Ariss; Todd, Jamie L; Zhang, Alice et al. (2016) Validation and Refinement of Chronic Lung Allograft Dysfunction Phenotypes in Bilateral and Single Lung Recipients. Ann Am Thorac Soc 13:627-35
Allyn, Paul R; Duffy, Erin L; Humphries, Romney M et al. (2016) Graft Loss and CLAD-Onset Is Hastened by Viral Pneumonia After Lung Transplantation. Transplantation 100:2424-2431
Gregson, A L; Wang, X; Injean, P et al. (2015) Staphylococcus via an interaction with the ELR+ CXC chemokine ENA-78 is associated with BOS. Am J Transplant 15:792-9
Gregson, Aric L; Hoji, Aki; Injean, Patil et al. (2015) Altered Exosomal RNA Profiles in Bronchoalveolar Lavage from Lung Transplants with Acute Rejection. Am J Respir Crit Care Med 192:1490-503
Hsiue, Peter P; Gregson, Aric L; Injean, Patil et al. (2014) Variation in antibiotic prophylaxis selection for coronary artery bypass graft procedures in an era of increasing methicillin-resistant Staphylococcus aureus prevalence. Infect Control Hosp Epidemiol 35:737-40
McKinnell, J A; Cannella, A P; Injean, P et al. (2014) Adjunctive glucocorticoid therapy for non-HIV-related pneumocystis carinii pneumonia (NH-PCP). Am J Transplant 14:982-3

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