CD28 and KIR2D receptors as sensors of the immune status in heart and liver transplantation R.M. Blanco-GarcÎa a , M.R. LÔpez-A ´ lvarez a,b , I.P. Garrido c , G. Salgado-Cecilia a , J.A. Campillo a,b , J.M. BolarÎn a , I. Legaz a , M. Muro a,b , A.M. GarcÎa-Alonso a,b , M.V. MartÎnez-SÂnchez a , J.M. de la PeÒa Moral d , D.A. Pascual-Figal c , M.R. A ´ lvarez-LÔpez a,b , M. Miras b,e , A. Minguela a,b, * a Immunology Service, University Hospital Virgen de la Arrixaca, El Palmar, Murcia, Spain b Centro de Investigaciòn Biomèdica en Red de enfermedades hepàticas y digestivas (CIBERehd), University Hospital Virgen de la Arrixaca, El Palmar, Murcia, Spain c Cardiology, University Hospital Virgen de la Arrixaca, El Palmar, Murcia, Spain d Pathology, University Hospital Virgen de la Arrixaca, El Palmar, Murcia, Spain e Digestive Medicine Services, University Hospital Virgen de la Arrixaca, El Palmar, Murcia, Spain ARTICLE INFO Article history: Received 7 February 2011 Accepted 7 June 2011 Available online 22 June 2011 Keywords: Heart transplantation Liver transplantation CD28 KIR2D CMV HCV ABSTRACT Viral infections and cellular acute rejection (AR) condition immunosuppressive therapy and compromise the evolution of allografts. Immune monitoring can be useful for ascertaining rejection and for differentiating allo-reaction from activation induced by infections. This work analyzes the usefulness of monitoring the expression of CD28 and KIR2D receptors in peripheral blood T lymphocytes by flow cytometry, to ascertain the immune response in heart and liver transplant recipients. In both types of transplant, the up-regulation of CD28 in CD4 + lymphocytes in the periods of greatest AR frequency indicates an effective allo-response, whereas the post-transplantation emergence of circulating CD8 + CD28 - and CD8 + CD28 - KIR2D + T cells correlates with better early clinical results. Cytomegalovirus (CMV) infection, but not hepatitis C virus (HCV) or other infections, abrogated both CD28 up-regulation and CD8 + CD28 - KIR2D + T-cell expansion. Our results show that monitoring the expression of CD28 and KIR2D receptors on T lymphocytes might be considered as sensors of the immune status of heart and liver recipients.  2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. 1. Introduction The use of immunosuppressive drugs has made it possible for allogeneic transplantation to become the best clinical solution for numerous terminal diseases. However, both excessive and long- term use of these drugs lead to undesirable effects that condition patient survival. To minimize this collateral damage immune mon- itoring has appeared as a complementary tool to help clinicians to deal with these drugs. Heart graft requires tight immunosuppres- sive regimens [1], whereas liver shows better acceptance [2]. Nev- ertheless, in both types of transplant, viral infections and cellular acute rejection (AR) are clinical situations that condition immuno- therapy administration, compromising graft stability. Cytomegalo- virus (CMV) is the most common viral infection after solid organ transplantation [3]. In heart transplantation (HT), CMV infection increases the incidence and severity of AR and is intimately in- volved in the development of cardiovascular pathology [4], so that early anti-CMV prophylaxis is commonly used. In liver transplan- tation (LT), CMV infection seems to reduce graft survival [5], whereas anti-CMV prophylaxis reduces graft rejection [6] and im- proves patient survival [7]. The most challenging issue nowadays in LT is the post-transplantation recurrence of cirrhosis induced by the hepatitis C virus (HCV) [8]. Generally, AR has no detrimental impact on overall graft or patient survival [9 –11]. However, in HCV-infected liver recipients, AR increases the risk of death [12,13] and AR misdiagnosis increases the risk of HCV-recurrence [13]. Therefore, it is extraordinarily important to differentiate AR from viral infections when recipients show abnormal graft functioning [14,15]. Histopathology is considered the gold standard method for that purpose. Unfortunately, access to the grafted heart is basically limited to the septum, and, in LT, differentiation of HCV recurrence from AR has limited reliability [16]. Previous data from our liver transplant series demonstrated that the expression of CD28 on CD4 + peripheral blood T cells seemed to be an AR diagnosis parameter not influenced by hepatitis B virus (HBV), HCV, or CMV infections useful to discriminate between acute rejection and the cellular activation induced by viral re- infection of the liver graft [17–19]. It is well known that complete and efficient allogenic response requires a second co-stimulatory signal, mainly triggered by CD28, that renders lymphocytes fully activated [18,20]. However, chronic stimulation and aging lead to increased proportions of T lymphocytes with lack of CD28 expres- * Corresponding author. E-mail address: alfredo.minguela@carm.es (A. Minguela Puras). Human Immunology 72 (2011) 841-848 Contents lists available at SciVerse ScienceDirect 0198-8859/11/$32.00 - see front matter  2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.humimm.2011.06.004