RESUMEN
A high-risk epitope mismatch (REM) (found in DQA1∗05 + DQB1∗02/DQB1∗03:01) is associated with de novo donor specific antibodies after lung transplantation (LTx). Chronic lung allograft dysfunction (CLAD) remains a barrier to LTx survival. This study aimed to measure the association between DQ REM and the risk of CLAD and death after LTx. A retrospective analysis of LTx recipients at a single center was conducted between January 2014 and April 2019. Molecular typing at human leucocyte antigen-DQA/DQB identified DQ REM. Multivariable competing risk and Cox regression models were used to measure the association between DQ REM, time-to-CLAD, and time-to-death. DQ REM was detected in 96/268 (35.8%), and DQ REM de novo donor specific antibodies were detected in 34/96 (35.4%). CLAD occurred in 78 (29.1%), and 98 (36.6%) recipients died during follow-up. When analyzed as a baseline predictor, DQ REM status was associated with CLAD (subdistribution hazard ratio (SHR), 2.19; 95% confidence interval [CI], 1.40-3.43; P = .001). After adjustment for time-dependent variables, DQ REM dn-DSA (SHR, 2.43; 95% CI, 1.10-5.38; P = .029) and A-grade rejection score (SHR, 1.22; 95% CI, 1.11-1.35; P = <.001), DQ REM status was not independently associated with CLAD. DQ REM was not associated with death (hazard ratio, 1.18; 95% CI, 0.72-1.93; P = .51). Classification of DQ REM may identify patients at risk of poor outcomes and should be incorporated into clinical decision-making.
Asunto(s)
Isoanticuerpos , Trasplante de Pulmón , Humanos , Epítopos , Estudios Retrospectivos , Antígenos HLA-DQ , Pulmón , Trasplante de Pulmón/efectos adversos , Rechazo de Injerto/etiología , AloinjertosRESUMEN
BACKGROUND: The Westran pig has been purposely inbred for use in xenotransplantation. The herd originated in the wild from a limited gene pool and has been inbred by repeated full-sib matings for nine generations. METHODS: The aim of this study was to evaluate the level of inbreeding by functional assays, such as bi-directional MLR and reciprocal skin grafts between herd members, and by genetic analysis using highly polymorphic genetic markers to calculate the level of inbreeding. RESULTS: The MLR between herd members were non-reactive whereas there was a prompt response to third party pig lymphocytes, indicative of a normal immune responsiveness in Westran pigs but isogenicity of the major histocompatibility complex. Skin grafts between male siblings or female sibling skin grafts on male recipients showed prolonged survival but with few exceptions did not survive beyond 100 days suggesting that by the fifth generation the Westran herd was still mismatched at minor histocompatibility antigens. This level of functional inbreeding was confirmed by microsatellite analysis of highly polymorphic markers, which showed that 52 of 53 chromosomally dispersed markers were fixed by the ninth generation. This level of fixation was consistent with 19 to 20 generations of full-sibling inbreeding. The calculated inbreeding coefficient at generation 10 was 0.98159. CONCLUSIONS: This analysis confirms that the Westran pig is highly inbred and we propose that analysis of chromosomally dispersed highly polymorphic markers is an accurate and reproducible method for assessing the level of inbreeding of a pig herd.