Mapping a DSA-Negative ABMR-Like State in Lung Transplants That is Highly Associated with NK Cells

PurposeABMR is now recognized as frequently DSA -ve in kidney (AJT 2022;22:1976) and heart (JHLT 2022: 41:334) transplants and has little short-term impact on survival when TCMR is absent. We studied if lung transplants also manifest a DSA -ve ABMR-like state.MethodsWe studied 896 transbronchial biopsies (TBB) from 672 patients (INTERLUNG ClinicalTrials.gov: NCT02812290) using genome-wide microarrays. Only 3% were diagnosed as clinical ABMR by the centers. We developed new rejection-associated transcript sets and studied their expression in TBB using PCA and archetypal analysis.ResultsWe identified four groups (fig 1a): R1 no rejection, n=493; R2 TCMR n=94; and R3 ABMR-like, n=238; 71 R4 biopsies with low surfactant were removed from analysis. ABMR-like biopsies were only 24% DSA +ve, similar to no rejection (26%); TCMR was 42% DSA +ve. Negative PC2 was associated with graft loss, reflecting TCMR (fig 1a). In genome-wide analysis, the top 20 genes associated with the ABMR-like state were all highly expressed in NK cells (table 2); IFNG-inducible transcripts were also increased in ABMR-like biopsies and TCMR. The ABMR-like state was not associated with CLAD, and had no effect on three-year graft survival (fig 1b). R2 TCMR was associated with increased three-year graft loss (fig a,b), as was clinical CLAD (fig 1c); TCMR was especially deleterious when associated with CLAD (fig 1d).ConclusionLung transplants frequently manifest a DSA -ve pure ABMR-like state, highly associated with NK cell transcripts and IFNG-inducible transcripts, that has little impact on short term survival (similar to DSA -ve ABMR in kidney and heart transplants). ABMR is now recognized as frequently DSA -ve in kidney (AJT 2022;22:1976) and heart (JHLT 2022: 41:334) transplants and has little short-term impact on survival when TCMR is absent. We studied if lung transplants also manifest a DSA -ve ABMR-like state. We studied 896 transbronchial biopsies (TBB) from 672 patients (INTERLUNG ClinicalTrials.gov: NCT02812290) using genome-wide microarrays. Only 3% were diagnosed as clinical ABMR by the centers. We developed new rejection-associated transcript sets and studied their expression in TBB using PCA and archetypal analysis. We identified four groups (fig 1a): R1 no rejection, n=493; R2 TCMR n=94; and R3 ABMR-like, n=238; 71 R4 biopsies with low surfactant were removed from analysis. ABMR-like biopsies were only 24% DSA +ve, similar to no rejection (26%); TCMR was 42% DSA +ve. Negative PC2 was associated with graft loss, reflecting TCMR (fig 1a). In genome-wide analysis, the top 20 genes associated with the ABMR-like state were all highly expressed in NK cells (table 2); IFNG-inducible transcripts were also increased in ABMR-like biopsies and TCMR. The ABMR-like state was not associated with CLAD, and had no effect on three-year graft survival (fig 1b). R2 TCMR was associated with increased three-year graft loss (fig a,b), as was clinical CLAD (fig 1c); TCMR was especially deleterious when associated with CLAD (fig 1d). Lung transplants frequently manifest a DSA -ve pure ABMR-like state, highly associated with NK cell transcripts and IFNG-inducible transcripts, that has little impact on short term survival (similar to DSA -ve ABMR in kidney and heart transplants).