NK Cell Receptor NKp46 Regulates Graft-versus-Host Disease

Hormas Ghadially,Meir Ohana,Moran Elboim,Roi Gazit,Chamutal Gur,Arnon Nagler,Ofer Mandelboim

doi:10.1016/j.celrep.2014.05.011

Hormas Ghadially, Meir Ohana + Show 5 more

Open Access

https://doi.org/10.1016/j.celrep.2014.05.011

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Abstract

SUMMARYHematopoietic stem cell transplantation (HSCT) is often the only curative treatment for a wide variety of hematologic malignancies. Donor selection in these diseases is crucial, given that transplanted cells can mediate not only the desired graft-versus-leukemia effect but also graft-versus-host disease (GVHD). Here, we demonstrate that in the absence of NKp46, a major killer receptor expressed by human and mouse natural killer (NK) cells, GVHD is greatly exacerbated, resulting in rapid mortality of the transplanted animals because of infection with commensal bacteria. Furthermore, we demonstrate that the exacerbated GVHD is the result of an altered ability of immune cells to respond to stimulation by immature dendritic cells. Because high and low expression of NKp46 on NK cells is observed in different individuals, our data indicate that choosing NKp46-high donors for the treatment of different hematologic malignancies might lead to better tumor eradication while minimizing GVHD.

Highlights

Hematopoietic stem cell transplantation (HSCT) is often the only curative treatment for a wide variety of hematologic malignancies
In many cases, it is impossible to achieve a complete identity of the major histocompatibility complex (MHC) class I proteins, and under these conditions, allogeneic HSCT is considered, which increases the chance of graft-versus-host disease (GVHD)
Since we have recently shown that NKp46 is involved in the killing of Immature dendritic cells (imDCs) and that in the absence of NKp46 (Ncr1) differences in the T cell responses are observed (Ghadially et al, 2013), we hypothesized that NKp46 could be involved in GVHD

Summary

Introduction

Hematopoietic stem cell transplantation (HSCT) is often the only curative treatment for a wide variety of hematologic malignancies. It is essential to select the most proper donor for HSCT, and in this regard it is important that the donor’s major histocompatibility complex (MHC) proteins will be as identical as possible to the patient’s. In many cases, it is impossible to achieve a complete identity of the MHC class I proteins, and under these conditions, allogeneic HSCT is considered, which increases the chance of GVHD. One of the biggest challenges of allogeneic HSCT is preventing GVHD while retaining the beneficial GVL effect. Natural killer (NK) cells mediate a strong GVL effect and play an important role in the rejection of allogeneic transplants (Ruggeri et al, 2006) and GVHD (Olson et al, 2010; Shlomchik et al, 1999)

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