*Purpose: Lymphocytic bronchitis (LB) precedes chronic lung allograft dysfunction (CLAD). Peri-vascular (A-grade) and peri-bronchiolar (B-grade) lymphocytic inflammation are traditional markers of acute cellular rejection. The relationship of LB (Endobronchial or “E-score” rejection) to A- and B-grade pathologies is unclear. We hypothesized that LB would be associated with a distinct gene signature.

*Methods: We studied LB in two partially overlapping lung transplant recipient cohorts. Cohort 1 was defined by large airway brushes (6 LB cases and 18 post-transplant referents). Differential expression using DESeq2 was used for pathway analysis and to define an LB-associated metagene, as the normalized sum of counts for transcripts unregulated with a false discovery rate adjusted p-value of <0.1. Cohort 2 consisted of eight biopsy pairs for each of the A-, B-, and E- pathology subtypes matched with a pathology-free biopsy from the same subject. These biopsies were analyzed by multiplexed digital counting of immune RNA transcripts (NanoString). Metagene scores from biopsies with and without rejection were compared by paired t-tests for this LB metagene and previously published allograft rejection signatures.

*Results: Compared to referents, LB demonstrated upregulation of genes, including allograft rejection pathways, characterizing an LB-associated metagene (Cohort 1, Figure 1A). We observed statistically increased expression for this LB-associated metagene as well as three other established allograft rejection metagenes in rejection vs. paired non-rejection biopsies for both E-grade and A-grade subtypes, but not in the B- grade pathologies (Cohort 2, Figure 1B).

*Conclusions: Gene signatures characterizing transplant rejection were observed in E-grade rejection, overlapping with A- but not B-grade rejection. Gene expression-based categorization of allograft rejection may prove useful in monitoring lung allograft health.

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