IgG4 donor-specific HLA antibody profile is associated with subclinical rejection in stable pediatric liver recipients

Abstract

The impact of donor-specific HLA antibody (DSA) following liver transplantation remains controversial. We hypothesized DSA IgG subclass characteristics, compared to total DSA IgG, might correlate with specific histopathological phenotype(s) of subclinical graft injury. We therefore studied 129 stable, arguably "clinically ideal," pediatric liver recipients at the time of a screening biopsy to enter an immunosuppression withdrawal trial. Sixty-five (50%) subjects tested positive for class II DSA.IgG subclass profile was characterized by mean fluorescence intensity (MFI) and normalized subclass composition (>5%). A prominent IgG4 DSA profile was strongly correlated with greater HLA mismatch, a histopathological phenotype characterized by the presence of interface activity (with variable degrees of fibrosis), and a transcriptional profile of attenuated T cell-mediated rejection. Specifically, compared to those without class II DSA, those with IgG4 class II DSA MFI sum >2000 exhibited an odds ratio (OR) of 20.79 (95% confidence interval [CI] 4.38-98.69) and IgG4 subclass composition >5% exhibited an OR of 8.99 (95% CI 2.70-29.9). Our data suggest that IgG4 DSA may serve as a useful biomarker to identify, among clinically and biochemically stable liver transplant recipients, a subset with histological and transcriptional features indicative of an active, suboptimally controlled alloimmune response. K E Y W O R D S alloantibody, clinical research/practice, histocompatibility, immunosuppressive regimensminimization/withdrawal, liver transplantation/hepatology, pediatrics, rejection: subclinical S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Jackson AM, Kanaparthi S, Burrell BE, et al. IgG4 donor-specific HLA antibody profile is associated with subclinical rejection in stable pediatric liver recipients. Am

Sensitization in transplantation: Assessment of risk (STAR) 2019 Working Group Meeting Report

“…Rather, HLA IgG1 and IgG3 are the predominant subclasses associated with graft rejection and graft loss 36‐40 . Although preformed IgG3 DSAs may be associated with risk of acute rejection, DSAs of the IgG2 and IgG4 subclasses are not associated with absence of rejection (i.e., these subclasses are not demonstrably benign) 36,41 . This may be due to the fact that IgG4 arises from repeated antigen stimulation such as is seen in allergy or chronic infection and that the γ2 and γ4 genes are further downstream on the germline and often only produced after sequential switching from other γ immunoglobulins 28,42‐45 .…”

“…[36][37][38][39][40] Although preformed IgG3 DSAs may be associated with risk of acute rejection, DSAs of the IgG2 and IgG4 subclasses are not associated with absence of rejection (i.e., these subclasses are not demonstrably benign). 36,41 This may be due to the fact that IgG4 arises from repeated antigen stimulation such as is seen in allergy or chronic infection and that the γ2 and γ4 genes are further downstream on the germline and often only produced after sequential switching from other γ immunoglobulins. 28,[42][43][44][45] Importantly, current reagents to determine IgG subclasses in the context of HLA-SAB assays have cross-reactivity/lack of specificity.…”

Management of the Sensitized Cardiac Transplantation Recipient

“…It is possible to have a negative CDC-XM in the presence of DSA when the antibody titer is too low to activate complement or when the antigen is expressed at low levels on the donor's lymphocytes (e.g., HLA-Cw, -DQ, -DP) [24] and also the DSA may be of a subtype that does not activate complement (e.g., IgG2 and IgG4). Although the risk of hyperacute rejection is low in these situations, the risk of accelerated acute, acute, and/or chronic rejection is increased compared to recipients who are transplanted without DSA [25].…”

Strategies for Deliberate Induction of Immune Tolerance in Liver Transplantation: From Preclinical Models to Clinical Application

“…These binding abilities have the potential to trigger functions such as antibody-dependent cell cytotoxicity, cytokine production, intracellular signaling, and initiation of cell recruitment and degranulation with various immune mediators (macrophages, NK cells, neutrophils, and B cells) (82). Jackson et al recently examined whether DSA IgG subclass characteristics could identify subjects whose liver allografts exhibit subclinical graft injury with samples from a multicenter IS withdrawal study for pediatric LT recipients (iWITH, NCT01638559) (83). They reported that the HLA-class II IgG4 DSA profile was associated with a higher HLA mismatch, a subclinical histopathological phenotype characterized by interface activity, and a tissue transcriptional profile of rejection.…”