Contents lists available at ScienceDirect Human Immunology journal homepage: www.elsevier.com/locate/humimm Soluble HLA-G pre-transplant levels to identify the risk for development of infection in heart transplant recipients Daria Bortolotti a , Valentina Gentili a , Antonella Rotola a , Luciano Potena b , Roberta Rizzo a, ⁎ a Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy b Cardiovascular Department, University of Bologna, Bologna, Italy ARTICLE INFO Keywords: HLA-G Infection Heart transplantation ABSTRACT Infection is still a leading cause of death during the first year after heart transplantation. We evaluated the pre- transplant levels of HLA (Human Leukocyte antigen) – G molecules as a means of identifying heart recipients at risk of serious infections. We prospectively analyzed 122 adult heart transplant (HT) recipients. Serum samples were collected before transplantation and analyzed for sHLA-G levels by ELISA assay. The clinical follow-up period lasted 5 years. Clinical outcomes were bacterial infections requiring intravenous anti-microbial agents, cytomegalovirus (CMV) disease, and fungal infections requiring therapy. We found that 39 patients (32%) de- veloped at least 1 serious bacterial infection. Higher pre-transplant sHLA-G levels were a risk factor for serious infection (above median value 5.4 ng/ml; relative risk 3.70; 95% confidence interval 1.03–12.64; p = 0.043). Patients with high levels of pre-transplant sHLA-G are also characterized by a lower overall survival at 5 years (p = 0.017), with microbial infections as major causes of death. No association was observed with the devel- opment rejection episode. Early monitoring of sHLA-G molecules proved useful for the identification of heart recipients who are at risk of serious infections. 1. Introduction Both solid organ and hematopoietic stem cell transplantation re- present life-saving therapies for patients with end stage organ failure or severe haematological malignancies, respectively. However, genetic incompatibilities between donor and recipient, in particular among classical human leukocyte antigen (HLA) class I (HLA-A, -B, -C) and class II (HLA-DR, -DQ, -DP) molecules, lead to a powerful allo-response by the adaptive and/or innate immune system, which has to be con- trolled by immunosuppressive drugs. Despite the development of modern immunosuppressive strategies, the induction of such reactions cannot always be completely prevented, and acute or chronic rejection remains a major complication in transplantation. The positive effects of the immunosuppressive agents, obligatory for the prevention of organ rejection, have been tempered by the negative effects of these same therapies, leading to various infections that range in both frequency and severity [1]. Newer immune-modulating agents have been developed, increasing the number of therapies that prevent organ rejection, mainly in heart transplanted patients [2]. However, this has simultaneously created newer unwanted opportunities for pathogens to cause infectious com- plications [2]. These adverse effects are the result of their negative impact on both the cellular and humoral arms of the heart transplanted recipient's immune system. Fortunately, newer diagnostic laboratory methods have also added much-needed capacity to identify the pre- sence and types of pathogens, often early enough in the heart trans- planted recipient’s course to prevent or mitigate severe infection [3]. However, it seems important to understand the mechanisms at the basis of a different follow-up of heart transplanted patients in term of in- fection outcome and transplant survival. HLA-G is a non classical HLA class I molecules with a naturally tolerance-inducing function [4]. This molecule is operative in preg- nancy, which is the only true physiological situation of tolerance to- wards a semiallograft [5]. HLA-G belongs to non classical HLA class I family. Although it shares some structural similarities with classical HLA class I, several important differences render HLA-G unique among HLA class I molecules: it displays a low allelic variation, a restricted peptide repertoire, an unusually high diversity of molecular structures due to alternative splicing of the mRNA [6,7], and a restricted ex- pression under physiological conditions. HLA-G has originally been https://doi.org/10.1016/j.humimm.2019.10.003 Received 18 July 2019; Received in revised form 8 October 2019; Accepted 16 October 2019 Abbreviations: HLA, human leukocyte antigen; RR, relative risk; m.v., median value; CI, confidence interval; ILT, immunoglobulinlike transcript; DC, dendritic cell; CsA, cyclosporine; PRED, prednisone; ISHLT, International Society for Heart and Lung Transplantation; CMV, cytomegalovirus; HT, heart transplant ⁎ Corresponding author at: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Via Luigi Borsari, 46-44121 Ferrara, Italy. E-mail address: rbr@unife.it (R. Rizzo). Human Immunology xxx (xxxx) xxx–xxx 0198-8859/ © 2019 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. Please cite this article as: Daria Bortolotti, et al., Human Immunology, https://doi.org/10.1016/j.humimm.2019.10.003