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BACKGROUND: Two pathways of antigen presentatin have been proposed as important mediators of immunological events in allograft recipients; direct allo-recognition of intact, cell-associated antigen and indirect presentation of reprocessed soluble HLA-derived peptides. We investigated the hypothesis that differences in the mode of donor antigen presentation may correlate with clinical outcome of lung allografts.
METHODS: Serum and PBL samples were collected from lung allograft recipients at regular intervals which corresponded with routine monitoring time points for bronchoalveolar lavage with biopsy and pulmonary function assessment. Serum levels of soluble, donor derived HLA were determined by ELISA. Leukocytes of donor origin were identified by genomic PCR from samples of PBMCs followed by Southern hybridisation using oligonucleotide probes. Donor and recipient cells were differentiated using SRY and/or HLA-DR mismatches between donor and recipient.
RESULTS: The release of large quantities of soluble, donor-derived HLA (10-35 ng/ml) in the peripheral blood was found to be significantly correlated (p < 0.001) with graft loss as the result of acute rejection or bronchiolitis obliterans sydrome (BOS). In contrast, patients with a good post-transplant course released low, but detectable levels of soluble donor HLA (2-5 ng/ml) into the peripheral circulation. Rare cells of donor origin were identified in the peripheral circulation of patients with a good graft outcome. Furthermore, a significant negative correlation was identified between the release of soluble HLA into the periphery and our recent findings of maintenance of high numbers of donor-derived leukocytes within the lung graft itself and a good lung allograft outcome (p < 0.05; r = -0.4).
CONCLUSIONS. The results from this study strongly support the proposal that differences in the form of antigen available and the mechanism of antigen presentation may influence the outcome of lung transplantation. Conditions that favor the indirect pathway of allo-antigen presentation, i.e. rapid replacement of donor by host antigen presenting cells within the graft and high levels of donor soluble HLA prevail in patients with poor outcome, while favorable outcome was associated with conditions that favor a direct pathway response (high persistence of donor cells in graft and periphery and low levels of soluble donor HLA).