Murine Models Provide New Insights Into Pathogenesis of Chronic Graft-Versus-Host Disease in Humans.

Qingxiao Song,Defu Zeng,Paul J Martin,Xiaohui Kong

doi:10.3389/fimmu.2021.700857

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for hematologic malignancies, but its success is complicated by graft-versus-host disease (GVHD). GVHD can be divided into acute and chronic types. Acute GVHD represents an acute alloimmune inflammatory response initiated by donor T cells that recognize recipient alloantigens. Chronic GVHD has a more complex pathophysiology involving donor-derived T cells that recognize recipient-specific antigens, donor-specific antigens, and antigens shared by the recipient and donor. Antibodies produced by donor B cells contribute to the pathogenesis of chronic GVHD but not acute GVHD. Acute GVHD can often be effectively controlled by treatment with corticosteroids or other immunosuppressant for a period of weeks, but successful control of chronic GVHD requires much longer treatment. Therefore, chronic GVHD remains the major cause of long-term morbidity and mortality after allo-HCT. Murine models of allo-HCT have made great contributions to our understanding pathogenesis of acute and chronic GVHD. In this review, we summarize new mechanistic findings from murine models of chronic GVHD, and we discuss the relevance of these insights to chronic GVHD pathogenesis in humans and their potential impact on clinical prevention and treatment.

Highlights

Allogeneic hematopoietic cell transplantation offers a way to eliminate residual malignant cells and prevent relapse by taking advantage of the graft-versus-leukemia/lymphoma (GVL) activity of alloreactive donor T cells [1,2,3,4,5,6]
These results show that PSGL1loCD4+ Trm cell interaction with memory B cells in graft-versus-host disease (GVHD) target tissues contributes to perpetuation of chronic GVHD pathogenesis
With murine models of chronic GVHD, we have found that extrafollicular CD4+ T and B interactions and CD4+ Trm cells in the GVHD target tissues play critical roles in chronic GVHD pathogenesis, and these findings have been linked to chronic GVHD pathogenesis in humans through studies with humanized MHC−/−HLA-A2+DR4+ NSG mice and patient GVHD target tissues [47]

Summary

INTRODUCTION

Allogeneic hematopoietic cell transplantation (allo-HCT) offers a way to eliminate residual malignant cells and prevent relapse by taking advantage of the graft-versus-leukemia/lymphoma (GVL) activity of alloreactive donor T cells [1,2,3,4,5,6]. These models have elucidated the role of T-cell subsets and cytokines in acute GVHD pathogenesis [25,26,27,28,29,30,31,32,33,34,35,36]. We will describe how we have used identical allogeneic donor and recipient strain combinations to induce acute GVHD mediated by alloreactive T cells and to induce autoimmune-like chronic GVHD. In these models, acute and chronic GVHD can occur sequentially in murine recipients [46], similar to what most often occurs in humans [15]. We will summarize new insights into chronic GVHD pathogenesis through the murine models

A MURINE MODEL CAN REFLECT CHARACTERISTIC FEATURES OF CHRONIC GVHD IN PATIENTS

Findings

CONCLUSIONS