In the modern era, organ transplantation has proven increasingly important as a solution to severe or end- stage diseases of the kidney, heart and liver, but unfortunately the results of lung transplantation have lagged considerably in terms of patient and graft survival rates. One of the main contributors to this poorer outcome is the development of primary graft dysfunction (PGD) within the first few days of lung transplantation. Dr. Jason Christie at UPenn has been studying the pathophysiology underlying PGD for the past decade, and has NIH- funded clinical studies underway in which blood samples are being collected pre- and post-lung transplantation in adults. An important new concept in immunology is that FOXP3+ T-regulatory (Treg) cells are key to normal regulation of immune responses, and that decreased Treg function likely contributes, clinically, to many forms of autoimmunity and inflammation. We hypothesize that pre-existing defects in Treg numbers or function, or defects in Treg numbers or function as a result of lung transplantation, may contribute to the development of PGD. We propose to test this hypothesis by assessing patients undergoing study in the underlying NIH-funded study of Dr. Christie that will last until 2014, using state-of-the art tests of Treg function that we have developed.
Aim 1) of this ancillary study will assess aspects of Treg numbers and/or function pre-operatively and seek to ask whether any changes in Treg function are associated with increased rates or severity of PGD.
Aim 2) of this ancillary study will asses whether the development of PGD in the very early post-Tx period is associated with decreased Treg numbers and/or function. Our studies will provide the first information on this clinically highly significant problem in lung Tx. Our findings, using samples obtained from 3 active lung transplant centers (Columbia, Indiana, Penn), may lead to new diagnostic or therapeutic interventions involving Treg cells therapies, or use of agents to enhance Treg function, in the very early post-operative period so as to overcome, or markedly decrease, the incidence and severity of PGD post-lung transplantation.

Public Health Relevance

We will determine whether abnormalities in a key population of circulating lymphocytes called T-regulatory (Treg) cells affects the very early outcomes of lung transplants in patients with severe lung diseases. We will assess whether problems with Tregs occur pre- or post-transplant using blood samples already being collected as part of an NIH-funded clinical study of lung transplant recipients. Our studies may identify new diagnostic or therapeutic options to decrease the high morbidity and mortality rates currently associated with clinical lung transplantation. ! !

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL114468-03
Application #
8676591
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Eu, Jerry Pc
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Diamond, Joshua M; Akimova, Tatiana; Kazi, Altaf et al. (2014) Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction. Am J Respir Crit Care Med 189:567-75