Transplant tolerance: new insights and strategies for long-term allograft acceptance.

Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2013, Article ID 210506, 15 pages http://dx.doi.org/10.1155/2013/210506 Review Article Transplant Tolerance: New Insights and Strategies for Long-Term Allograft Acceptance Paulina Ruiz,1,2 Paula Maldonado,1 Yessia Hidalgo,1 Alejandra Gleisner,1 Daniela Sauma,1,3 Cinthia Silva,1 Juan Jose Saez,1 Sarah Nuñez,1 Mario Rosemblatt,1,3,4 and Maria Rosa Bono1 1 Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, 7800024 Santiago, Chile Programa de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile, 8380453 Santiago, Chile 3 Fundacion Ciencia y Vida, 7780272 Santiago, Chile 4 Facultad de Ciencias Biologicas, Universidad Andres Bello, 8370146 Santiago, Chile 2 Correspondence should be addressed to Maria Rosa Bono; Received 30 January 2013; Revised 12 April 2013; Accepted 13 April 2013 Academic Editor: Nicolaus Kroger Copyright © 2013 Paulina Ruiz 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. One of the greatest advances in medicine during the past century is the introduction of organ transplantation. This therapeutic strategy designed to treat organ failure and organ dysfunction allows to prolong the survival of many patients that are faced with no other treatment option. Today, organ transplantation between genetically dissimilar individuals (allogeneic grafting) is a procedure widely used as a therapeutic alternative in cases of organ failure, hematological disease treatment, and some malignancies. Despite the potential of organ transplantation, the administration of immunosuppressive drugs required for allograft acceptance induces severe immunosuppression in transplanted patients, which leads to serious side effects such as infection with opportunistic pathogens and the occurrence of neoplasias, in addition to the known intrinsic toxicity of these drugs. To solve this setback in allotransplantation, researchers have focused on manipulating the immune response in order to create a state of tolerance rather than unspecific immunosuppression. Here, we describe the different treatments and some of the novel immunotherapeutic strategies undertaken to induce transplantation tolerance. 1. History of Organ Transplantation Earl C. Padgett first described the phenomenon of allograft rejection in 1932. He used nonrelated skin allografts to cover severely burned patients and reported that none of the skin allografts survived permanently. However, he observed that skin grafts from relatives seemed to survive longer than those from unrelated donors [1]. In 1943, Gibson and Medawar developed the first scientific explanation of the phenomenon of allorejection. They observed that patients who received autografts (tissue from the same individual transplanted to a different part of the body) accepted the tissue with no complications unlike patients that had received a sibling’s skin allograft (tissue from a different individual belonging to the same species) who eventually rejected the allograft. In addition, they observed that a second skin transplant with skin from the same donor resulted in more rapid rejection compared with the first skin transplantation. The observation of the accelerated rejection of the second graft from the same donor was convincing evidence that supported the involvement of an immunological process during allograft rejection [2, 3]. In 1948, Medawar and colleagues excluded an important role of antibodies in allograft rejection [4, 5] and designed an experiment to assess whether cellular components of the immune system are responsible for transplant rejection. They injected cells from the allograft-draining lymph node from transplanted mice into mice recently transplanted with skin from the same donor. They observed that mice rejected the allograft as similar to mice transplanted for a second time, 2 indicating that cellular components of the immune system are responsible for the generation of the immune response against the allograft [3, 6]. Advances achieved in surgical techniques in parallel with improvements in knowledge of the immune mechanisms mediating allograft rejection allowed the first kidney transplant in 1963 [7–10]. Joseph E. Murray and his colleagues at Peter Bent Brigham Hospital in Boston performed the first successful kidney transplant from one twin to another [11]. It was a great advance in medicine, demonstrating that it was possible to perform successful organ transplants in humans, but it was still necessary to solve the problem of rejection between unrelated donors [12]. Since then, different pharmacological treatments have been developed in order to induce an immunosuppressive state that allows the acceptance of an allograft transplant between unrelated donors [1, 13–16]. The first successful cadaveric unrelated kidney transplant was performed in 1962 by Joseph Murray and his group [17]. Murray used azathioprine, an immunosuppressive drug previously tested in dogs [18], which allowed the transplant recipient to survive one year after receiving the kidney transplant [17, 19]. The immunosuppressive effects of cyclosporine A (CsA) were discovered in Switzerland in 1972. Some trials to compare CsA versus azathioprine and steroids were developed and the promising results led to clinical approval for the use of CsA in human transplants in 1980 [20, 21]. The introduction of CsA contributed substantially towards the improvement of allograft and patient survival [22]. The massive development of immunosuppressive drugs opened the door to organ transplantation, extending to other organs such as the liver, lungs, and heart. In parallel with the increased number of organ transplants, several investigators are currently working on developing new immunosuppressive drug protocols that will further improve the outcome and reduce tissue toxicity in transplanted patients [23–26]. However, despite these efforts, currently all immunosuppressive drugs have serious side effects including nephrotoxicity, development of malignancies, and susceptibility to infections by opportunistic pathogens. For this reason, immunologists face a new challenge in developing strategies to reduce or eliminate the use of immunosuppressive drugs in organ transplants. These efforts are being focused on reeducating the immune system or inducing allograft-specific tolerance mechanisms. 2. Immune Tolerance One of the hallmarks of the adaptive immune system is its ability to recognize a vast number of different antigens. This ability is a consequence of the large lymphocyte repertoire, in which each cell has a different antigen receptor generated by the process of somatic recombination. This process is able to produce an estimate of 1015 different lymphocyte clones, each with a different antigen receptor tha (...truncated)