Development of ELISA-detected anti-HLA antibodies precedes the developmentof bronchiolitis obliterans syndrome and correlates with progressive decline in pulmonary function after lung transplantation

Background Development of anti-HLA antibodies after lung transplantation (L T) is thought to play an important role in the etiology of bronchiolitis ob literans syndrome (BOS), However, a cause-effect relationship between anti- HLA antibodies and EOS has not been established. This study was conducted t o determine the temporal relationship between the development of anti-HLA a ntibodies and BOS after LT, and to determine the antigenic specificity of t he antibodies developed in BOS patients. Methods, Sera from 15 BOS+ LT patients and 12 BOS- LT patients were obtaine d before LT and collected again at 6, 12, 24, 38, and 48 months after LT. A nti-HLA antibodies were detected by the PRA-STAT ELISA system and by comple ment-dependent cytoxicity assays. Anti-HLA reactivity was further character ized by flow cytometry and absorption/elution with human platelets. Results. When analyzed by ELISA, 10 of 15 BOS+ patients developed anti-HLA antibodies, whereas 0 of 12 BOS- patients developed anti-HLA antibodies (P< 0.001). When analyzed by complement-dependent cytotoxicity, only 2 of 15 BO S+ patients developed anti-HLA antibodies and 1 of 12 BOS- patients develop ed anti-HLA antibodies (P=0.99), There was a significant difference of 20.1 months between the time of anti-HLA antibody detection and the time of BOS diagnosis (P=0.005), A progressive decrease in pulmonary function correlat ed with a progressive increase in the anti-HLA reactivity 36 months after L T, The anti-HLA reactivity was directed to one of the donor HLA class I ant igens and to other unrelated HLA class I antigens, No anti-HLA reactivity w as found against HLA class II molecules. Conclusions. Our study indicates that anti-HLA class I antibodies play an i mportant role in the pathogenesis of BOS and that monitoring of anti-HLA cl ass I antibody development by a highly sensitive assay such as the PRA-STAT ELISA after LT can provide an early identification of an important subset of LT patients with an increased risk of developing BOS.