Isoforms of human leukocyte antigen-G and their inhibitory receptors in human kidney allograft acceptance † Juan Wu a , Wei Zhang a , Pedro Hernandez-Lopez b , Edward Fabelo b , Mehul Parikh b , Laura L. Mulloy b , Anatolij Horuzsko a, * a Center for Molecular Chaperone/Radiobiology and Cancer Virology, Department of Medicine, Medical College of Georgia, Augusta, GA 30912, USA b Division of Nephrology, Hypertension, and Transplant Medicine, Department of Medicine, Medical College of Georgia, Augusta, GA 30912, USA ARTICLE INFO Article history: Received 25 June 2009 Accepted 30 July 2009 Available online 5 August 2009 Keywords: Inhibitory receptors Dendritic cells Kidney allograft T cells Tolerance Transplantation ABSTRACT Novel therapeutic strategies such as the modulation of dendritic cell and T-cell function have exhibited great potential in clinical transplantation. Human leukocyte antigen (HLA)-G is a molecule that plays a significant role in establishing complex mechanisms to protect semiallogeneic fetuses from rejection by the maternal immune system. 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 the modulation of immune responses to improve allogeneic graft survival in clinical transplantation. Experimental data from several groups as well as our data from experiments involving HLA-G-mediated human tolerogenic dendritic cells in vitro and receptor transgenic mice in vivo indicate that different isoforms of HLA-G have various immunomodulatory effects through the inhibitory receptors. This knowledge is crucial in understanding mechanisms of prolongation of allograft survival. The analyses of HLA-G isoforms and inhibitory receptors in patients with kidney allograft and the relationship among different isoforms of HLA-G, inhibitory receptors, their mediated immunoregulation, and graft acceptance or failure will be discussed here.  2009 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. 1. Introduction The induction of immune tolerance continues to be an impor- tant goal of clinical organ and tissue transplantation [1–5]. The immunological acceptance of a fetal semiallograft during preg- nancy is a natural model of immune tolerance, and its underlying mechanisms can be exploited to prevent allograft rejection in clin- ical transplantation. Human leukocyte antigen (HLA)-G is a human, nonclassical major histocompatibility complex (MHC) molecule expressed in immune-privileged sites and is responsible in large part for the development of maternal tolerance to genetically dif- ferent fetal tissues. Evidence indicates that HLA-G protects the fetus from attack by natural killer cells (NKs), macrophages, den- dritic cells (DCs), monocytes, and T cells by interacting with inhib- itory receptors, such as immunoglobulin-like transcript (ILT)-2 and ILT4, and modifying cell functions [6 –9]. 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 ILTs make HLA-G very important in fundamental approaches for the modulation of immune responses to improve allogeneic graft survival in clinical transplantation. We have developed models to dissect the mechanisms of tolero- genic function of HLA-G in vitro and in vivo. Our studies revealed that allogeneic skin graft survival is significantly prolonged or the allograft is accepted in transgenic mice expressing inhibitory re- ceptors and treated with HLA-G1 [10 –12]. Because HLA-G has the potential to upregulate the expression of inhibitory receptors and HLA-G has been reported in patients with organ transplants and might be associated with allograft survival [13] and because our data support that the HLA-G5 dimer form mediates the strongest inhibitory signal [14], we predict that the level of HLA-G5 dimer plays a critical role in patients with prolongation of kidney allograft survival. We propose that different isoforms of HLA-G mediate distinct inhibition of immune responses via ILT receptors in pa- tients with kidney transplants. We determined the levels and effi- ciency of inhibitory signaling of HLA-G5 monomers and dimers in patients with kidney allograft and the relationship between differ- ent isoforms of HLA-G and graft acceptance or failure. In addition, the interaction of a strong HLA-G ligand and ILTs promotes induc- tion of regulatory T cells and myeloid-derived suppressor cells (MDSCs) with suppressive activity [15,16]. We determined the * Corresponding author. E-mail address: ahoruzsko@mcg.edu (A. Horuzsko). † All patients gave their informed consent to this study, which was approved by the Institutional Review Board of the Medical College of Georgia. A.H. has patents pending on HLA-G. Human Immunology 70 (2009) 988 –994 Contents lists available at ScienceDirect 0198-8859/09/$32.00 - see front matter  2009 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.humimm.2009.07.023