Background: In lung and heart transplant patients, chronic rejection manifests as fibro-obliteration of airways and vessels resulting in bronchiolitis obliterans syndrome (BOS) or cardiac allograft vasculopathy (CAV) respectively. One cause of this fibro-obliteration is the development of CD4-Th17 based autoimmune responses to the α1 chain of Collagen Type V (ColV). It was recently demonstrated that Th17 responses to ColV pre-exist in all normal healthy hosts, but are under strict control by CD39+ Treg cells. Heart or lung pathologies that cause end stage organ dysfunction (such as CAD, IPF) tend to disrupt this equilibrium, leading to uncontrolled anti-ColV Th17 responses when the patient presents for transplantation. HLA-DR analysis of pre-lung transplant patients, revealed a DR15 bias in ColV reactivity. Post-lung transplant, DR15 on the donor side, but not the recipient, was associated with the development of ColV reactivity. Thus, we sought to determine if the donor DR influences immune responses after transplantation.

Hypothesis: Murine heart or lung transplantation between DR transgenic mice (DR15 to DR1) will result in chronic rejection and the development of ColV autoimmunity.

Results: Murine heterotopic cardiac transplantation was performed between an IAb Null B6 DR15 donor and an IAb Null B6 A2/DR1 recipient. 60% (3/5) of the recipient mice developed acute rejection around day 21 post-transplant, while the remaining mice maintained a very low steady heart beat until day 100 post-transplant, developing chronic rejection. Strong reactivity to ColV, as measured by a trans-vivo assay, was demonstrated in both the acute and chronic rejecters. Additionally, responses were also noted to the donor DR (DR15) but not self (A2/DR1) nor the IAb peptide p599. However, the peptide response varied between the two groups. At day 21 post transplant, responses were noted only to the intact ColV but not the respective DR peptides. However, at day 100 post transplant, responses were noted to the DR1 restricted (p629), DR15 restricted (p1049) as well as the DR1/15 shared (p799 and p1439) peptides.

Conclusion: These results indicate that the donor DR does influence the immune responses in the recipient. Furthermore, the DR transgenic mice provide a viable transplant model to study ColV autoimmunity following heterotopic cardiac transplantation.

CITATION INFORMATION: Agashe V, Zhou Y, Jankowska-Gan E, Burlingham W. HLA-DR Based Murine Transplant Model for Studying Collagen Type V Autoimmunity in Chronic Allograft Rejection. Am J Transplant. 2017;17 (suppl 3).

« Back to 2017 American Transplant Congress