Lung transplantation is the only definitive therapy for many forms of end stage lung disease. However, survival of the transplant recipient is limited by chronic rejection, known as obliterative bronchiolitis (OB). Rejection episodes are initiated by recipient T cells recognizing donor major histocompatibility complexes (MHC). However, we have reported the rejection response also involves specific immunity to a native protein, type V collagen [col(V)], and that immunity to col(V) is a major risk factor for the development of OB. Therefore, lung transplant rejection is a disease if both allo- and autoimmunity. Immune responses require lymphocyte migration from the blood stream to lymph nodes followed by emigration of activated lymphocytes to sites of inflammation/injury. However, the mechanism of anti-col(V) lymphocyte migration and emigration into and from mediastinal lymph nodes and BALT, respectively, are unknown. In addition, recent studies implicate a novel group of T cells (Th-17) able to induce autoimmune disease in many organs, including the lung. However, the role of Th-17 cells in the pathogenesis of autoimmunity that occurs during lung transplant rejection has not been characterized. Recognition of donor alloantigens occurs via two pathways, direct and indirect;and the two types of rejection, acute and chronic, have been attributed to the activity each pathway, respectively. The current paradigm of direct and indirect allorecognition is based on the ability of donor antigen presenting cells (known as passenger leukocytes) and recipient-derived antigen presenting cells (APCs), respectively, to activate recipient T cells. However, the role of passenger leukocytes and somatic cells in lung grafts to mediate acute rejection and OB is unknown. Furthermore, the requirement for these cells to induce Tregs specific for donor antigens and col(V) has not been reported. Utilizing a rat model of lung transplantation, the current proposal tests the hypothesis that alloimmune-induced autoimmunity to col(V) mediates lung transplant destruction by examining the following specific aims:
Aim 1. To determine if the adhesion pathways utilized by col(V)-reactive lymphocytes for migration/emigration to mediastinal nodes and BALT are differentially regulated.
Aim 2. To determine the contribution of humoral and Th-17 cellular immunity to the pathogenesis of anti-col(V)-mediated pathology.
Aim 3. To determine the contribution of somatic cells and passenger leukocytes in the transplanted lung in development of Tregs and autoimmunity to col(V) during allograft rejection. This application will investigate the causes of lung transplant rejection which is the leading cause of death in lung transplant recipients. This application may also identify new areas that may allow for new treatments of this clinical problem.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067177-10
Application #
8113248
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Eu, Jerry Pc
Project Start
2001-05-01
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
10
Fiscal Year
2011
Total Cost
$364,887
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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