Aim: Donor-specific HLA antibodies (DSA) are associated with rejecting kidney, heart, and lung transplants. However, the impact of DSA is controversial in the liver transplant literature. Here, we postulate that multiple insults, including DSA and non-HLA antibodies, contribute to injuries of liver allografts. We aim to examine the roles of these antibodies in T-cell mediated rejection (TCMR) of adult liver transplants.
Method: This study included post-transplant serum (n=103) with paired liver allograft biopsy from 78 adult liver transplant recipients. DSA was prospectively tested with Luminex Single Antigen beads (One Lambda). Banked post-transplant sera were retrospectively tested with Luminex for 60 non-HLA Abs panel (Werfen) and with ELISA for anti-angiotensin II type 1 receptor (AT1R) (One Lambda).
Results: TCMR was diagnosed in 59/103 (57%) biopsies, 33 were mild, 18 were moderate, and 8 were severe. Serums were collected at a mean of 2 ± 9 days after biopsy. DSA was positive in 95/103 (92%) cases with MFI>1K as a threshold, in 64/103 (62%) cases with MFI>5K as a threshold, but was not associated with TCMR. A panel of 18 Luminex non-HLA Abs were significantly associated with moderate-severe TCMR (MS-TCMR, n = 26) compared to negative-mild TCMR (NM-TCMR, n=77). A higher number of panel-18 non-HLA-Abs was found in serums paired with MS-TCMR than those with NM-TCMR (median [IQR]: 3[2 - 5] vs. 1[0 - 1], p<0.001). The risk for MS-TCMR was higher for the cases with the panel-18 non-HLA Abs≥3 than those with fewer Abs (HR=19.6 [6.0 - 64.8], p<0.001). The anti-AT1R Abs were elevated in serums paired with MS-TCMR than NM-TCMR (median [IQR]: 18.8[15.2 - 40.0] vs. 13.0[10.0 - 21.5] U/ml, p<0.01). Anti-AT1R Abs (>17U/ml) were associated with a higher risk for MS-TCMR (HR = 12.4[1.5 - 101.6], p=0.02). Significant association with MS-TCMR (p <0001, 6/7 cases) was observed in patients who exhibited triple-positive DSA (MFI>5K), panel-18 non-HLA Abs ≥3, and AT1R Ab (>17U/ml). In contrast, none of the 21 triple-negative cases had MS-TCMR (Table 1).
Conclusion: We found that non-HLA Abs, were associated with MS-TCMR in adult liver allograft biopsies, while DSA alone was not. The presence of multiple non-HLA Abs and DSA synergistically augmented the risk of MS-TCMR. The novel set of triple antibodies may be used to identify patients with elevated risk for rejection, prompt biopsy, and early intervention.
