Fibro-obliterative disease of the airways and vessels is a key element of the chronic rejection process after heart and lung transplantation. Th17 cellular immune responses (IR) to the Α1 chain of collagen type V [col(V)] are strongly associated with development of bronchiolitis obliterans syndrome (BOS), and with both idiopathic pulmonary fibrosis (IPF) and coronary artery disease (CAD), fibro-obliterative diseases that are primary indications for lung or heart transplantation. We found that out of 99 patients awaiting lung transplantation 30% (24/99) exhibited a strong trans-vivo DTH response to col(V), and 53% of these expressed HLA-DRB1*1501 (DR15) (p=0.02, compared to the frequency of DR15 in controls). After transplantation, patients with HLA-DR1 and -DR17, but not -DR15, developed Th17 anti-col(V) responses most frequently (p=0.04 and 0.01 vs. controls, respectively). Interestingly, those patients who received a lung from a DR15+ donor were at significant risk of developing anti-col(V) responses (p=0.02) and BOS (p=0.03). To account for the apparent DR15 bias of IR to col(V), a peptide library of the triple helical region of the Α1(V) protein was screened for binding to HLA-DR1, -DR15, -DR17, and to the DR15- and DR17-associated DQ molecules, HLA-DQ2 and -DQ6. Out of 101 overlapping 15-mer peptides, 6 DR-binding and 2 DQ-binding peptides, were identified. The highest binding scores were found for 2 Α1(V) peptides that bound to HLA DR15, p799 (GIRGLKGTKGEKGED), and p1439 (LRGIPGPVGEQGLPG). Peptides p799 and p1439, which also bound weakly to DR1 but not to DR17, elicited TV-DTH swelling responses in DR1- or DR15-expressing col(V) reactive patients, whereas both binding and immunoreactivity of p1049 (KDGPPGLRGFPGDRG) was DR15-specific. An exception was found in the case of lung transplant patient L86 (HLA-DR1, -DR11; donor HLA-DR1, DR15), who responded not only to p799 and p1439, but also to p1049. The DTH response to a self-peptide that can be presented only by the donor HLA suggests donor derived APCs may contribute to de novo autoimmunity to Α1(V) after lung transplantation.

Conclusion: These studies establish an HLA-DR association in lung transplant patients with col(V) autoimmunity. These associations are not only limited to the recipient, but suggest a possible role for donor APCs, specifically HLA-DR15+ donors, in the initiation or development of BOS.

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