Immune Features of Disparate Liver Transplant Outcomes in Female Hispanics With Nonalcoholic Steatohepatitis

Rebecca A Sosa; Allyson Q Terry; Takahiro Ito; Bita V Naini; Ying Zheng; Harry Pickering; Jessica Nevarez-Mejia; Ronald W Busuttil; David W Gjertson; Jerzy W Kupiec-Weglinski; Elaine F Reed; Fady M Kaldas

doi:10.1097/TXD.0000000000001550

Immune Features of Disparate Liver Transplant Outcomes in Female Hispanics With Nonalcoholic Steatohepatitis

Transplant Direct. 2023 Oct 20;9(11):e1550. doi: 10.1097/TXD.0000000000001550. eCollection 2023 Nov.

Authors

Rebecca A Sosa^{1

2}, Allyson Q Terry¹, Takahiro Ito³, Bita V Naini¹, Ying Zheng^{1

2}, Harry Pickering¹, Jessica Nevarez-Mejia¹, Ronald W Busuttil³, David W Gjertson^{1

2}, Jerzy W Kupiec-Weglinski^{1

3}, Elaine F Reed^{1

2}, Fady M Kaldas³

Affiliations

¹ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
² UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Los Angeles, CA.
³ Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Abstract

Background: Nonalcoholic steatohepatitis (NASH) is a severe immune-mediated stage of nonalcoholic fatty liver disease that is rapidly becoming the most common etiology requiring liver transplantation (LT), with Hispanics bearing a disproportionate burden. This study aimed to uncover the underlying immune mechanisms of the disparities experienced by Hispanic patients undergoing LT for NASH.

Methods: We enrolled 164 LT recipients in our institutional review board-approved study, 33 of whom presented with NASH as the primary etiology of LT (20%), with 16 self-reported as Hispanic (48%). We investigated the histopathology of prereperfusion and postreperfusion biopsies, clinical liver function tests, longitudinal soluble cytokines via 38-plex Luminex, and immune cell phenotypes generated by prereperfusion and postreperfusion blood using 14-color flow cytometry and enzyme-linked immunosorbent assay.

Results: Hispanic LT recipients transplanted for NASH were disproportionately female (81%) and disproportionately suffered poor outcomes in the first year posttransplant, including rejection (26%) and death (38%). Clinically, we observed increased pro-inflammatory and apoptotic histopathological features in biopsies, increased AST/international normalized ratio early posttransplantation, and a higher incidence of presensitization to mismatched HLA antigens expressed by the donor allograft. Experimental investigations revealed that blood from female Hispanic NASH patients showed significantly increased levels of leukocyte-attracting chemokines, innate-to-adaptive switching cytokines and growth factors, HMGB1 release, and TLR4/TLR8/TLR9/NOD1 activation, and produced a pro-inflammatory, pro-apoptotic macrophage phenotype with reduced CD14/CD68/CD66a/TIM-3 and increased CD16/CD11b/HLA-DR/CD80.

Conclusions: A personalized approach to reducing immunological risk factors is urgently needed for this endotype in Hispanics with NASH requiring LT, particularly in females.

Abstract

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