Potential of HLA-G for Transplantation

Project: Research project

Project Details

Description

Abstract
Novel therapeutic strategies such as modulation of dendritic cell and T cell functions have shown great
potential in clinical transplantation. HLA-G is a molecule that plays a significant role in establishing complex
mechanisms to protect semi-allogeneic fetuses from rejection by the maternal immune system. The tolerogenic
potential of HLA-G is mediated by its exclusive binding to the inhibitory receptors on immunocompetent cells
that modulate cell functions. However, the mechanisms by which HLA-G modulates the function of dendritic
cells and T cells are thus far incompletely understood. The unique characteristics of both cell surface and
soluble isoforms of HLA-G, the formation of disulfide-bonded dimers with the potential to augment inhibitory
receptor signaling, and the function of HLA-G as a preferential ligand for the immunoglobulin-like transcript
receptors make HLA-G very important in fundamental approaches for modulation of immune responses to
improve allogeneic graft survival in clinical transplantation. This application will address the cellular and
molecular mechanisms of tolerization of dendritic cells and the expansion and enhancement function of
myeloid-derived suppressor cells mediated by HLA-G, leading to the prolongation of allograft survival. The
long-term goal of this research is to determine the mechanisms of modulation of dendritic cells, myeloid-
derived suppressor cells, and T cells by HLA-G, and to design a highly potent HLA-G-based immunotherapy
against allograft rejection. We have developed models to determine the mechanisms of tolerogenic function of
HLA-G in vitro and in vivo. The central hypothesis of this application, which is based on our published
and strong preliminary data from experiments involving HLA-G-mediated human tolerogenic dendritic
cells in vitro and receptor transgenic mice in vivo, is that different isoforms of HLA-G have various
immunomodulatory effects through the inhibitory receptors, and that knowledge of this can be crucial
in designing the most potent form of HLA-G. This hypothesis is reflected in the study of the mechanism of
tolerization of dendritic cells (Specific Aim 1) and mechanisms of prolongation of allograft survival mediated by
HLA-G and inhibitory receptors on myeloid-derived suppressor cells (Specific Aim 2). Data obtained from these
studies will reveal the potential of HLA-G in modulation of immune responses and will aid in development of
novel strategies for translation into the clinic to improve allograft survival in patients and treat graft-versus-host
disease, allergy, and autoimmune diseases
StatusNot started

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