IgG4 Subclass Class 2 Donor Specific Antibody (DSA) is Associated with Subclinical Rejection in Stable Pediatric Liver Transplant (LT) Recipients with Normal Liver Tests

A. Jackson¹, S. Kanaparthi², B. Burrell³, D. Lucas⁴, R. Vega⁴, A. J. Demetris⁵, S. Feng⁶

¹Surgery, Duke University, Durham, NC, ²The Immune Tolerance Network, Bethesda, MD, ³Immune Tolerance Network, Bethesda, MD, ⁴Medicine, Johns Hopkins University, Baltimore, MD, ⁵Pathology, University of Pittsburgh, Pittsburgh, PA, ⁶Surgery, University of California San Francisco, San Francisco, CA

Meeting: 2019 American Transplant Congress

Abstract number: 41

Keywords: HLA antibodies, Liver, Pediatric, Rejection

Session Information

Session Name: Concurrent Session: Liver: Immunosuppression and Rejection

Session Type: Concurrent Session

Date: Sunday, June 2, 2019

Session Time: 2:30pm-4:00pm

Presentation Time: 2:42pm-2:54pm

Location: Room 312

*Purpose: DSA is a known biomarker of allograft rejection, yet injury phenotype and potential differ across organs. Among pediatric LT recipients entering iWITH (NCT01638559), an immunosuppression withdrawal trial, eligibility biopsies segregated into 3 histological phenotypes (Feng et al. Gastroenterology, 2018). We investigated DSA IgG subclass and assignment to Cluster 1, characterized by interface activity and tissue gene expression profile of T-cell mediated rejection (TCMR), vs Clusters 2 (fibrosis alone; no TCMR) or 3 (no inflammation or fibrosis; no TCMR).

*Methods: Sera from 129 subjects (67 boys; 40 living donor) were tested using LabScreen® Single Antigen™ HLA beads, α-IgG and α-IgG subclass-antibodies. DSA defined by HLA epitopes and thresholds of: IgG >2000 MFI and IgG subclass > mean autologous-HLA MFI. Cluster 1 was correlated with clinical and class II DSA features in uni- and multi-variable analyses. DSA IgG subclass sum was examined in 2 ways: absolute MFI and %IgG subclass. %IgGX was calculated by dividing [IgGX MFI] by [IgG1MFI+IgG2MFI+IgG3MFI+IgG4MFI].

*Results: Among 129 subjects, 24 (19%), 39 (30%) and 66 (51%) were assigned to clusters 1, 2 and 3, respectively. 65 subjects (50%) tested positive for total IgG class II DSA. IgG1 was most common, present in 64 or 98% of all subjects, compared to IgG2 (42; 65%), IgG3 (49; 75%) and IgG4 (47; 72%). Cluster 1 vs 2 or 3 had the highest proportion of subjects with IgG4 >2000 MFI (Fig 1A) and ≥5% IgG4 (Fig 1B). Among subjects in Clusters 1, 2 and 3, IgG4 MFI was >2,000 for 37% (9/24), 5% (2/39) and 5% (3/66) while IgG4 was ≥5% for 50% (12/24), 18% (7/39) and 11% (7/66), respectively. In models with deceased donor and ALT, IgG4 MFI (OR 20.79; 95%CI 4.38, 98.69; p=.0001) and ≥5% IgG4 DSA (OR 8.99; 95%CI 2.70, 29.92; p=.0003) were strongly associated with Cluster 1 assignment (Figs 1C+D).

*Conclusions: IgG4 class II DSA was strongly associated with subclinical chronic liver injury characterized by interface activity and a tissue transcriptional profile of TCMR in pediatric LT recipients. IgG4 DSA reflects an evolved humoral response, consistent with the observed chronic injury phenotype. Subclass determination may non-invasively risk-stratify clinically and biochemically stable transplant recipients.

To cite this abstract in AMA style:

Jackson A, Kanaparthi S, Burrell B, Lucas D, Vega R, Demetris AJ, Feng S. IgG4 Subclass Class 2 Donor Specific Antibody (DSA) is Associated with Subclinical Rejection in Stable Pediatric Liver Transplant (LT) Recipients with Normal Liver Tests [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/igg4-subclass-class-2-donor-specific-antibody-dsa-is-associated-with-subclinical-rejection-in-stable-pediatric-liver-transplant-lt-recipients-with-normal-liver-tests/. Accessed May 11, 2025.

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