Regulatory T Cells in the Immunodiagnosis and Outcome of Kidney Allograft Rejection

Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2013, Article ID 852395, 7 pages http://dx.doi.org/10.1155/2013/852395 Review Article Regulatory T Cells in the Immunodiagnosis and Outcome of Kidney Allograft Rejection O. Franzese,1 A. Mascali,2 A. Capria,3 V. Castagnola,2 L. Paganizza,2 and N. Di Daniele2 1 Division of Pharmacology, Department of Medicine of the Systems, University of Rome “Tor Vergata” Rome, Italy Division of Nephrology, Department of Medicine of the Systems, University of Rome “Tor Vergata” Rome, Italy 3 Division of Internal Medicine, Department of Medicine of the Systems, University of Rome “Tor Vergata” Rome, Italy 2 Correspondence should be addressed to A. Mascali; Received 1 February 2013; Revised 2 May 2013; Accepted 2 June 2013 Academic Editor: Anne M. Stevens Copyright © 2013 O. Franzese et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Acute rejection (AR) is responsible for up to 12% of graft loss with the highest risk generally occurring during the first six months after transplantation. AR may be broadly classified into humoral as well as cellular rejection. Cellular rejection develops when donor alloantigens, presented by antigen-presenting cells (APCs) through class I or class II HLA molecules, activate the immune response against the allograft, resulting in activation of naive T cells that differentiate into subsets including cytotoxic CD8+ and helper CD4+ T cells type 1 (TH1) and TH2 cells or into cytoprotective immunoregulatory T cells (Tregs). The immune reaction directed against a renal allograft has been suggested to be characterized by two major components: a destructive one, mediated by CD4+ helper and CD8+ cytotoxic T cells, and a protective response, mediated by Tregs. The balance between these two opposite immune responses can significantly affect the graft survival. Many studies have been performed in order to define the role of Tregs either in the immunodiagnosis of transplant rejection or as predictor of the clinical outcome. However, information available from the literature shows a contradictory picture that deserves further investigation. 1. Introduction Acute rejection (AR) is responsible for up to 12% of graft loss with the highest risk generally occurring during the first six months after transplantation [1]. Patient monitoring following the transplant includes physical examination, blood and urine tests, and tissue biopsy. Rejection can often be histologically diagnosed before any variation of results obtained with laboratory tests. Many centers have introduced periodic biopsy surveillance protocols; however, to date, the clinical impact of a monitoring strategy based on biopsies is not clear [2, 3]. AR may be broadly classified into humoral and cellular rejections. In particular, antibody-mediated rejection is characterized by the presence of an antibody infiltration into the transplanted kidney, targeting HLA antigens on the peritubular and glomerular capillary endothelia, which results in complement activation, cytokine and chemokine release, and induction of adhesion molecules. This inflammatory response leads to platelet aggregation and leukocyte infiltration, which eventually contribute to the pathogenesis of acute lesions such as glomerulitis, peritubular capillaritis, microthrombi, and vessel necrosis [4]. New insights are now available into the mechanisms responsible for the immune response directed against a transplanted organ. Cellular rejection develops when donor alloantigens, presented by antigen-presenting cells (APCs) through class I or class II HLA molecules, activate the immune response against the allograft, resulting in activation of naive T cells that differentiate into subsets including cytotoxic CD8+ and helper CD4+ T cells type 1 (TH1) and TH2 cells or into cytoprotective immunoregulatory T cells (Tregs) [5]. CD4+ and CD8+ T cells infiltrate into the transplanted kidney, where they release cytokines and chemokines, causing cell death either directly or indirectly [6]. The immune reaction directed against a renal allograft has been suggested to be characterized by two major components: a destructive one mediated by CD4+ helper and CD8+ 2 Clinical and Developmental Immunology Naive CD4+ T cell Thymus gland T-Bet Gata3 ROR𝛾t Foxp3 Foxp3 Th1 Th2 Th17 iTreg nTreg Foxp3 Inflammation TCR engagement Other Mature resting Treg (quiescent) Foxp3 Tolerance Helper response Figure 1: Origin and activation of Treg. cytotoxic T cells and a protective response mediated by Tregs. The balance between these two opposite immune responses can significantly affect the graft survival [7]. Many studies have been performed in order to define the role of Tregs either in the immunodiagnosis of transplant rejection or as predictor of the clinical outcome. However, information available from the literature shows a contradictory picture that deserves further investigation. In this paper, we will analyze the possible role of Tregs in T-cell-mediated transplant rejection as useful biomarker for the immunological monitoring of the kidney transplantation outcome. 2. Principal Mechanisms of T-Cell-Mediated AR Transplant rejection is the consequence of the recipient’s alloimmune response and consists of manifested deterioration or complete function loss of the transplanted organ. From a physiopathological point of view, AR involves both cell-mediated and antibody-mediated immunities. Both cellular and humoral responses result in the allorecognition of foreign antigens which leads to immunocompetent cell activation and the orchestration of an effector response. This process ultimately results in the damage of the transplanted organ and the graft loss, both of which can show an early or late onset, as well as a striking or gradual development. Different cell types are involved in the graft rejection including T and B cells, macrophages, plasma cells, eosinophils, and neutrophils. T cells play a crucial role either in mounting and/or regulating alloreactive responses. The main targets of cell-mediated damage are the tubular epithelium and the endothelium. Generally acute allograft rejection starts (origins ?) when the recipient’s T cells recognize the donor alloantigens presented by APCs. In particular, donor antigens are carried by immature dendritic cells from the transplanted organ to the recipient’s draining lymph nodes and spleen, in a journey which induces their transformation into mature APCs [8]. After the homing of APCs to lymphoid organs, the allorecognition of foreign antigens leads to T cell activation followed by differentiation into different subpopulations (Figure 1) and the return to the graft, where they play a fundamental role in destroying the transplanted organ. T cell infiltration into t (...truncated)