High levels of CMV-IE-1-specific memory T cells are associated with less alloimmunity and improved renal allograft function Peter Nickel a,e, ⁎, Gantuja Bold a,e , Franziska Presber b , Didier Biti b , Nina Babel a,e , Stephanie Kreutzer b , Johann Pratschke c , Constanze Schönemann d , Florian Kern b , Hans-Dieter Volk b,e,f , Petra Reinke a,e,f a Department of Nephrology and Intensive Care, Charité Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany b Institute of Medical Immunology, Charité Campus Mitte, Charitéplatz 1,10117 Berlin, Germany c Department of Surgery, Charité Campus Virchow, Augustenburger Platz 1,13353 Berlin, Germany d HLA-Laboratory, Institute of Transfusion Medicine, Charité Campus Virchow, Augustenburger Platz 1,13353 Berlin, Germany e Interdisciplinary Transplant Research Group Nephrology/Medical Immunology, Charité Campus Mitte, Charitéplatz 1,10117 Berlin, Germany f Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Campus Virchow, Augustenburger Platz 1,13353 Berlin, Germany abstract article info Article history: Received 18 July 2008 Received in revised form 30 October 2008 Accepted 3 November 2008 Keywords: Immune monitoring Cytomegalovirus T cells ELISPOT Kidney transplantation Background: Cytomegalovirus (CMV) infection has been associated with allograft rejection in solid organ transplantation. However, the immunologic mechanisms behind this observation have not been elucidated. One proposed mechanism is direct cross-reactivity of antiviral T-cells with allogeneic MHC/peptide complexes, a process termed heterologous immunity. Another model favours indirect stimulation of alloimmunity by CMV-induced proinflammatory cytokines and upregulation of MHC class II and adhesion molecules. Recently, we found that protection from CMV disease was correlated with high levels of CMV- immediate early-1 (IE-1) specific IFN-γ-producing T-cell responses in heart and lung transplant recipients. The aim of this study was to define the relation of CMV-specific T-cell responses to acute rejection, donor- reactive memory T cells, and allograft function after kidney transplantation. Methods: To address this issue, IFN-γ-producing T-cell responses following ex-vivo stimulation with pools of overlapping peptides representing the CMV pp65 and IE-1 proteins, as well as donor-reactive IFN-γ- producing T-cells were determined at multiple time points before (pre-Tx) and during the first 6 months posttransplant (post-Tx) in 36 kidney transplant recipients using an enzyme linked immunoabsorbent spot assay (ELISPOT). Results: CMV-specific Tcells were not exclusively detectable in CMV seropositive patients, as 3/12 seronegative patients had significant pre- and post-Tx pp65/IE-1-specific T-cell responses. In patients with detectable anti- CMV antibody or T-cell responses, no difference in CMV-specific T-cell frequencies was found between patients with versus without acute rejection. However, early (week 1, r = 0.457, p = 0.037) and average IE-1-specific T-cell responses (r = - 0.415, p = 0.032) during 6 months post-Tx showed a significant inverse correlation with average post-Tx donor-reactive T-cell responses. Furthermore, average post-Tx IE-1-specific T-cell responses correlated significantly with 6 and 12 months glomerular filtration rate (GFR). In contrast, pp65-specific T-cell responses did not correlate with donor-reactive T cells or graft function. Only 2/36 patients developed CMV disease, both showing very weak IE-1-specific T-cell responses during the whole monitoring period. Conclusion: No evidence for heterologous immunity could be found in patients with high levels of CMV-specific T cells. On the contrary, less alloreactivity and improved graft function were found in patients with strong IE-1- specific T-cell responses. These results emphasize the importance of immediate early antigens (IE) as targets for T-cell immunity to CMV. We hypothesize that IE-1-specific T cells might effectively suppress IE-1-induced indirect effects such as inflammation and upregulation of MHC class II and adhesion molecules. © 2008 Elsevier B.V. All rights reserved. 1. Introduction Cytomegalovirus (CMV) contributes significantly to morbidity and mortality in bone marrow and solid organ transplantation [1]. Besides tissue-invasive disease, CMV has been implicated in the pathogenesis of acute and chronic rejection. Evidence for a role of CMV in allograft rejection derives from animal models and studies in transplant patients that demonstrated improved graft function and inhibition Transplant Immunology 20 (2009) 238–242 ⁎ Corresponding author. Department of Nephrology and Intensive Care, Charité Campus Virchow, Augustenburger Platz 1, D-13353 Berlin, Germany. Tel./fax: +49 1149 30 450 553 132/909. E-mail address: peter.nickel@charite.de (P. Nickel). 0966-3274/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.trim.2008.11.002 Contents lists available at ScienceDirect Transplant Immunology journal homepage: www.elsevier.com/locate/trim