Immune cells and immunosuppression in a porcine bronchial model of obliterative bronchiolitis

Background. To study obliterative bronchiolitis (OB), we have developed a porcine heterotopic bronchial model. Allografts obliterate within 3 weeks, the immunosuppression cyclosporine (CsA)-azathioprine (AZA)-methylprednisolone (MP) delays OB, but OB is prevented when AZA is switched to 40-0-(2-hydroxy-ethyl)-rapamycin (RAD). To characterize our model, we studied immune cells under various immunosuppressive conditions. Methods. The groups studied were autografts (U), allografts (A), and allografts given either CsA-RAD-MP (R), or CsA-AZA-MP (C). The implants were harvested at 3, 7, 10, 14, 21, 30, 60, and 90 days after transplantation. Epithelial damage and obliteration were graded histologically, and the number of CD4, CD8, MHC class II expressing cells, macrophages, and B lymphocytes were counted (mean + SEM)/high-power visual field. Results. In group U, normal epithelium was regained with no obliteration and only few immune cells. In group A, consistent with initially acute ejection, an influx of CD4 (105+23), CD8 (166+23), and class II (92+20) cells was seen up to day 21, when total obliteration preceded by epithelial destruction had already developed. Some macrophages were seen and B cells were scarce. In group R, epithelial damage and obliteration were insignificant, but moderate numbers of CD4, CD8, and class II cells were seen. In group C, epithelial damage and obliteration were only delayed, but the immune cell response was clearly blunted. Conclusions. In our model, rejection with significant immune cell influx was still active when obliteration was total in nontreated allografts. In immunosuppressed allografts, decrease in the number of immune cells alone did prevent OB. These results support OB being T-cell mediated. RAD may have additional important effects on growth factors and proliferation in prevention of OB.