NOD2/CARD15 Variants of Donor and Recipient as Critical Risk Factors for the Development of Bronchiolitis Obliterans Syndrome after Allogeneic Stem Cell Transplantation.
Authors: Hildebrandt Gerhard , Wolff Daniel , Hertenstein Bernd , Greinix Hildegard T. , Rogler Gerhard , Brenmoehl Julia , Schulz Christian , Dickinson Anne M. , Andreesen Reinhard , Holler Ernst 
Published: April 2020

Abstract
Bronchiolitis obliterans syndrome (BOS) is a life-threatening complication after allogeneic stem cell transplantation (SCT), that affects primarily small airways. BOS mortality is high and risk factors and pathophysiology have yet to be defined. Experimental data from BOS in heterotopic traecha transplant models suggest, that both bronchial epithelial cell (EC) integrity as well as an alloantigen-reactive T cell response are involved. We recently reported an association of single nucleotide polymorphisms (SNPs) of the NOD2/CARD15 gene resulting in a diminished NF- κB response to bacterial cell wall products with increased acute graft versus host disease (GVHD) severity and transplant-related mortality. As NOD2/CARD15 is expressed not only in monocytes/macrophages and intestinal EC but also in bronchial EC, we hypothesized that NOD2/CARD15 variants contribute to changes in host defense and alloreaction leading to BOS. We analyzed the association of NOD2/CARD15 SNPs (SNP 8, 12, 13) with the occurrence of BOS within 244 donor/recipient (D/R) pairs of patients (pts) receiving allogeneic SCT. Follow-up was performed for a mean of 1243±172 days (range: 327–2149). BOS was diagnosed by pathology or by functional airway obstruction (FEV1&lt;/= 80% of predicted).
12 pts developed BOS with a mean time point of diagnosis at 678±112 days after SCT (range: 186–1407). Incidence of BOS rose from 1.7% (3/174) in D/R pairs without mutated SNPs to 10.0% (6/60) in pairs with mutated alleles in either donor or recipient (p=0.01) and to 25.0% (3/12) in pairs with mutated alleles in both donor and recipient (p=0.009). In addition, in D/R pairs developing BOS, NOD2/CARD15 variants were observed at higher frequencies (donor: 60.0% vs. 12.9%, p=0.001; recipient: 50.0% vs. 15.0%; p=0.007). 50% of pts with BOS died between day +327 and day +1582 (mean: 844±195), whereas 6 pts are still alive (mean follow-up: 1642±170 days). Survival did not differ between pts with BOS in relation to the presence/absence of NOD2/CARD15 mutations. Finally, we analyzed whether other transplant-related parameters contributed to the incidence of BOS. Conditioning regimen intensity, stem cell source, donor type (matched unrelated donor vs. HLA-identical sibling), recipient age, donor or recipient gender, and acute GVHD were not associated with BOS development, whereas chronic GVHD was confirmed as a risk factor for BOS (p=0.01). Interestingly, NOD2/CARD15 mutations did not associate with chronic GVHD (p=0.19). Our data indicate that NOD2/CARD15 mutations of donor or recipient increase the risk of developing BOS after allogeneic SCT, which may be due to impaired macrophage function, to impaired defence mechanisms of bronchial epithelial cells, or to other pathways still unknown. Further, future risk assessment before SCT using NOD2/CARD15 typing may help identifying patients at higher risk for BOS and improve clinical outcome after allogeneic SCT.