Cytotoxic Pathways in Allogeneic Hematopoietic Cell Transplantation.

Wei Du,Xuefang Cao

doi:10.3389/fimmu.2018.02979

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for hematologic malignancies, and other hematologic and immunologic diseases. Donor-derived immune cells identify and attack cancer cells in the patient producing a unique graft-vs.-tumor (GVT) effect. This beneficial response renders allo-HCT one of the most effective forms of tumor immunotherapy. However, alloreactive donor T cells can damage normal host cells thereby causing graft-vs.-host disease (GVHD), which results in substantial morbidity and mortality. To date, GVHD remains as the major obstacle for more successful application of allo-HCT. Of special significance in this context are a number of cytotoxic pathways that are involved in GVHD and GVT response as well as donor cell engraftment. In this review, we summarize progress in the investigation of these cytotoxic pathways, including Fas/Fas ligand (FasL), perforin/granzyme, and cytokine pathways. Many studies have delineated their distinct operating mechanisms and how they are involved in the complex cellular interactions amongst donor, host, tumor, and infectious pathogens. Driven by progressing elucidation of their contributions in immune reconstitution and regulation, various interventional strategies targeting these pathways have entered translational stages with aims to improve the effectiveness of allo-HCT.

Highlights

Allogeneic hematopoietic cell transplantation is a potentially curative treatment for leukemia, lymphoma, and other hematologic malignancies
Olson et al showed that co-injection of donor natural killer (NK) cells with alloreactive T cells decreased host graft-vs.-host disease (GVHD) severity by reducing cytokine production, T cell activation, and proliferation, via a mechanism that involved T cell apoptosis induced by NK cells through the Fas ligand (FasL) and perforin pathways [74]
Our study suggests a novel function for Spi6, which contributes to GzmBindependent protection of intestinal epithelial cells in murine GVHD [110]

Summary

Introduction

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for leukemia, lymphoma, and other hematologic malignancies. A number of pathways have been described for allogeneic T cell-mediated cytotoxicity, including Fas/Fas ligand (FasL), perforin/granzymes, and cytokines such as tumor necrosis factor α (TNFα), interferon γ (IFNγ), and TNF-related apoptosis-inducing ligand (TRAIL) [27,28,29] (Figure 1). We postulate that the perforin/granzyme and Fas/FasL pathways comprise alternative and required mechanisms for T cell-mediated cytotoxic function in the context of allo-HCT.

Results

Conclusion