Humoral Risk Factors Associated to Allograft Dysfunction after Lung Transplantation: The Alert of Non-HLA Auto Antibody and HLA-Donor Specific Antibody (DSA) with Non-DSA HLA Antibody

Abstract

<h3>Purpose</h3> Growing evidence has indicated the negative impact of non-HLA auto antibody (NHAuAb) on organ transplantation. Donor specific antibody (DSA) after lung transplantation (LuT) has been observed frequently with de novo Non-DSA (dN-DSA) HLA antibody. This study investigates the deleterious role of post-LuT NHAuAb and dN-DSA synergism to DSA in allograft damage. <h3>Methods</h3> We retrospectively analyzed NHAuAb and de novo DSA (dDSA)/dN-DSA data collected from the recipients who underwent LuT during 2012-2016. NHAuAbs were detected using LABScreen™ Autoantibody (>95% non-sensitized subjects as cut-off). HLA antibody was tested by LABScreen™ SAB (MFI≥ 1000 as cut-off). Clinical Antibody Mediated Rejection (cAMR, with acute graft dysfunction) and Chronic Lung Allograft Dysfunction (CLAD) were assessed for LuT outcomes. <h3>Results</h3> CXCL9, AURKA, REG3A, IFNγ, FLRT2, GDNF, HNRNPK, CXCL10, PLA2R, and Collagen IV detected from 111 patients' sera drawn at DSA peak phase showed significant association to total AMR, but only FLRT2 (P<0.001), GDNF, and CXCL10 (P<0.05) were remarkably correlated to cAMR (Table 1a). Preformed & persistent LG3, PECR, PKC-Z (P<0.001) and de novo ENO1, GAPDH, Lamin-B, TubulinA1B (p<0.05) identified from 113 patients' sera drawn around CLAD time, demonstrated strong correlation to the occurrence of CLAD (Table 1b). Patients with dDSA & dN-DSA had significantly higher incidence of cAMR than the patients with only dDSA (p<0.001, Table 1c). <h3>Conclusion</h3> Distinct clinical phases presented specific NHAuAb profiles. Multiple NHAuAbs, especially LG3, PKC-Z, and PECR which were preformed & persistent, promoted chronic graft dysfunction. HLA-dDSA augmented by dN-DSA (most likely through shared targeting epitopes) and NHAuAbs of FLRT2, GDNF, and CXCL10 were related to acute graft injury. These HLA and non-HLA humoral risk factors warrant timely enhanced immune therapy to prevent final allograft failure.