Lung transplantation is the only definitive treatment modality for end stage pulmonary diseases. However, the lung is rejected more frequently than other solid organ allografts. The leading cause of death in lung allograft recipients is chronic rejection known as bronchiolitis obliterans (BO), and repeated acute rejection episodes are believed to culminate in BO. Donor major histocompatibility complex (MHC) antigens are the target and stimulus of the rejection response, and studies with other solid organ allografts have shown that immunizing the recipient orally with donor MHC prior to transplantation induces tolerance to the allograft. This phenomenon, known as oral tolerance induction, abrogates the rejection of many solid organs by suppressing or eliminating alloreactive T-lymphocytes but has not been investigated in lung transplantation. We have recently reported that in addition to donor MHC, the alpha-1 chain of type V collagen [a1pha 1 (V)] is also recognized as an antigen during lung allograft rejection. In the lung, type V collagen [col(V)] is located in the perivascular and peribronchiolar connective tissues; each are sites of inflammation which undergo extensive remodeling during the rejection response. Degradation/remodeling of col(V) is regulated mainly by matrix metalloproteinase-2 (MMP-2) and MMP-9. Since BO is believed to be the result of alloimmune activation in response to repeated presentation of donor-derived MHC peptides or MHC-like peptides, then allograft rejection could be perpetuated by a1pha 1(V)-peptides that are produced as a result of local MMP activity. Utilizing a rat model of lung transplantation in which F344 rat lungs (RT1lv1) are transplanted orthotopically into WRY (RT1l) recipient animals, we propose to test the hypothesis that oral immunization with col(V) induces immunological tolerance to lung allografts by examining the following specific aims:
Aim 1. Studies will examine the role of col(V) and its peptides as an antigen and tolerogen during acute rejection of lung allografts.
Aim 2. Studies will determine the ability of col(V) to induce oral tolerance and prevent the development of chronic rejection - BO.
Aim 3. MMP's contribute to the local release of col(V) peptides and, therefore, the pathology of the rejection response. MMP expression and activity will be examined in the transplanted lungs of naive and tolerant allograft recipients. Addtionally, systemic and local production of col(V) peptide during allograft rejection

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL069727-02
Application #
6528205
Study Section
Special Emphasis Panel (ZAI1-NN-I (M1))
Program Officer
Reynolds, Herbert Y
Project Start
2001-08-01
Project End
2004-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
2
Fiscal Year
2002
Total Cost
$221,445
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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