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The term allorecognition refers to the series of mechanisms used by an individual’s immune system to distinguish its own cells and tissues from those of another individual belonging to the same species. During evolution, different cells and molecules of both innate and adaptive immune systems have been selected to recognize and respond to antigens expressed by allogeneic cells, but not autologous cells (alloantigens). This research topic focuses on allorecognition by lymphocytes of the adaptive immune system and its involvement in rejection or tolerance of allogeneic transplants. T and B cells recognizing alloantigens via specific receptors become activated and undergo proliferation and differentiation into different types of effector and memory cells. Allorecognition by lymphocytes occurs regularly during pregnancy upon trafficking of both maternal and fetal cells. In this setting, allorecognition triggers an alloresponse that is protective towards the fetus thus preventing abortion. Protective alloimmunity is mediated through cooperation between different lymphocytes and antigen presenting cells (APCs), as well as regulatory mediators and receptors. Likewise, certain transplants placed in organs and tissues called immune-privileged sites such as the eye, the central nervous system and the testis elicit protective rather than destructive adaptive immune responses. Therefore, under certain circumstances, allorecognition by regulatory lymphocytes (Tregs and Bregs) can lead to tolerance of alloantigens. In contrast, allorecognition by T cells in non-immune privileged sites and under inflammatory conditions leads to a destructive immune response. Indeed, after transplantation of most allogeneic organs and tissues, activation of pro-inflammatory T cells (TH1 and TH17), which recognize donor MHC proteins (direct pathway) or peptides derived from donor MHC and minor antigens (indirect pathway), leads to graft rejection. This inflammatory response leads to the differentiation of allospecific cytotoxic T cells as well as production of donor specific antibodies by B cells, both of which contribute to the destruction of the transplant. In this Research Topic, we describe the different pathways of allorecognition by T cells involved in allograft rejection, as well as the role of different antigen presenting cells and graft-derived microvesicles (exosomes) involved in this process. Another aspect of this Research Topic addresses the essential role of alloreactive memory T cells in allograft rejection and resistance to transplant tolerance induction in laboratory rodents, as well as non-human primates and patients. Indeed, it has become evident that laboratory mice display very few memory alloreactive T cells pre-transplantation, essentially due to the fact that they are raised in pathogen-free facilities. In contrast, primates display high frequencies of alloreactive memory T cells, either generated through prior exposure to allogeneic MHC molecules or via cross-reactivity with microbial antigens. We and others have provided ample evidence showing that this feature accounts for differences in terms of tolerance susceptibility between laboratory rodents and patients. This implies that further investigation of tolerance protocols in laboratory mice should be performed using “dirty mice” i.e., mice raised in non-sterile conditions. In summary, this Research Topic addresses key aspects of allorecognition by lymphocytes and alloantigen presentation by dendritic cells, and specifically how these processes shape our immune system and govern the rejection or tolerance of allogeneic tissues and organs.

lymphocytes --- dendritic cells --- transplantation --- Allorecognition --- antibodies --- transplant rejection --- transplant tolerance --- immune privilege --- alloantigens

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Organ transplantation is a life-saving surgical procedure through which the functionality of a failing organ system can be restored. However, without the life-long administration of immunosuppressive drugs, the recipient’s immune system will launch a massive immune attack that will ultimately destroy the graft. Although successful at protecting the graft from an immune attack, long-term use of immunosuppressive drugs leads to serious complications (e.g., increased risk of infection, diabetes, hypertension, cardiovascular disease, and cancer). Moreover, recipients suffer from limited long-term graft survival rates due to the inability of current treatments to establish tolerance to the transplanted tissues. Thus, there is a great medical need to understand the complex network of immune system interactions that lead to transplant rejection so that new strategies of intervention can be determined that will redirect the system toward transplant acceptance while preserving immune competence against offending agents. In the past 20 years, the discovery and growing understanding of the positive and negative regulators of the activation of the immune system have fostered new interventional procedures targeting one or the other. While pre-clinical results proved the validity of these strategies, their clinical implementation has been troublesome. These results underscore the need for additional methods to determine the most effective interventions to prevent long-term transplant rejection. New tools of genomics, proteomics and metabolomics are being implemented in powerful analyses that promise the development of better, safer personalized treatments. In parallel, theoretical modeling has emerged as a tool that transcends investigations of individual mechanistic processes and instead unravels the relevant mechanisms of complex systems such as the immune response triggered by a transplant. In this way, theoretical models can be used to identify important behavior that arises from complex systems and thereby delineate emergent properties of biological systems that could not be identified studying single components. Employing this approach, interdisciplinary collaborations among immunologists, mathematicians, and system biologists will yield novel perspectives in the development of more effective strategies of intervention. The aim of this Research Topic is to demonstrate how new insight and methods from theoretical and experimental studies of the immune response can aid in identifying new research directions in transplant immunology. First, techniques from various theoretical and experimental studies with applications to the immune response will be reviewed to determine how they can be adapted to explore the complexity of transplant rejection. Second, recent advances in the acquisition and mining of large data sets related to transplant genomics, proteomics, and metabolomics will be discussed in the context of their predictive power and potential for optimizing and personalizing patient treatment. Last, new perspectives will be offered on the integration of computational immune modeling with transplant and omics data to establish more effective strategies of intervention that promote transplant tolerance.

systems biology --- theoretical modeling --- transplant immunology --- biomarkers --- big data and bioinformatics --- transplant rejection --- transplant tolerance --- mechanistic models --- systems biology --- theoretical modeling --- transplant immunology --- biomarkers --- big data and bioinformatics --- transplant rejection --- transplant tolerance --- mechanistic models

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Organ transplantation is a life-saving surgical procedure through which the functionality of a failing organ system can be restored. However, without the life-long administration of immunosuppressive drugs, the recipient’s immune system will launch a massive immune attack that will ultimately destroy the graft. Although successful at protecting the graft from an immune attack, long-term use of immunosuppressive drugs leads to serious complications (e.g., increased risk of infection, diabetes, hypertension, cardiovascular disease, and cancer). Moreover, recipients suffer from limited long-term graft survival rates due to the inability of current treatments to establish tolerance to the transplanted tissues. Thus, there is a great medical need to understand the complex network of immune system interactions that lead to transplant rejection so that new strategies of intervention can be determined that will redirect the system toward transplant acceptance while preserving immune competence against offending agents. In the past 20 years, the discovery and growing understanding of the positive and negative regulators of the activation of the immune system have fostered new interventional procedures targeting one or the other. While pre-clinical results proved the validity of these strategies, their clinical implementation has been troublesome. These results underscore the need for additional methods to determine the most effective interventions to prevent long-term transplant rejection. New tools of genomics, proteomics and metabolomics are being implemented in powerful analyses that promise the development of better, safer personalized treatments. In parallel, theoretical modeling has emerged as a tool that transcends investigations of individual mechanistic processes and instead unravels the relevant mechanisms of complex systems such as the immune response triggered by a transplant. In this way, theoretical models can be used to identify important behavior that arises from complex systems and thereby delineate emergent properties of biological systems that could not be identified studying single components. Employing this approach, interdisciplinary collaborations among immunologists, mathematicians, and system biologists will yield novel perspectives in the development of more effective strategies of intervention. The aim of this Research Topic is to demonstrate how new insight and methods from theoretical and experimental studies of the immune response can aid in identifying new research directions in transplant immunology. First, techniques from various theoretical and experimental studies with applications to the immune response will be reviewed to determine how they can be adapted to explore the complexity of transplant rejection. Second, recent advances in the acquisition and mining of large data sets related to transplant genomics, proteomics, and metabolomics will be discussed in the context of their predictive power and potential for optimizing and personalizing patient treatment. Last, new perspectives will be offered on the integration of computational immune modeling with transplant and omics data to establish more effective strategies of intervention that promote transplant tolerance.

systems biology --- theoretical modeling --- transplant immunology --- biomarkers --- big data and bioinformatics --- transplant rejection --- transplant tolerance --- mechanistic models

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Graft Rejection. --- Kidney Transplantation --- Graft Survival --- Rejection, Transplant --- Transplantation Rejection --- Transplant Rejection --- Graft Rejections --- Rejection, Graft --- Rejection, Transplantation --- Rejections, Graft --- Rejections, Transplant --- Rejections, Transplantation --- Transplant Rejections --- Transplantation Rejections --- Delayed Graft Function --- immunology. --- physiology. --- Theses --- Graft Rejection --- immunology --- physiology --- Grafting, Kidney --- Renal Transplantation --- Transplantation, Kidney --- Transplantation, Renal --- Kidney Grafting --- Kidney Transplantations --- Renal Transplantations --- Transplantations, Kidney --- Transplantations, Renal --- Kidney --- transplantation

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Transplantation of organs, tissues, etc. --- Cell transplantation --- Transplantation immunology --- Graft rejection --- Bone marrow --- Organ Transplantation. --- Bone Marrow Transplantation. --- Cell Transplantation. --- Graft Rejection. --- Transplantation Immunology. --- Greffe (Chirurgie) --- Cellules --- Rejet (Biologie) --- Moelle osseuse --- Cell transplantation. --- Graft rejection. --- Transplantation immunology. --- Transplantation --- Greffe --- Immunologie --- Transplantation. --- Rejection, Transplant --- Transplantation Rejection --- Transplant Rejection --- Graft Rejections --- Rejection, Graft --- Rejection, Transplantation --- Rejections, Graft --- Rejections, Transplant --- Rejections, Transplantation --- Transplant Rejections --- Transplantation Rejections --- Transplantation, Cell --- Cells --- Bone Marrow Cell Transplantation --- Grafting, Bone Marrow --- Transplantation, Bone Marrow --- Transplantation, Bone Marrow Cell --- Bone Marrow Grafting --- Bone Marrow --- Bone Marrow Cells --- Grafting, Organ --- Transplantation, Organ --- Graftings, Organ --- Organ Grafting --- Organ Graftings --- Organ Transplantations --- Transplantations, Organ --- Medical transplantation --- Organ transplantation --- Organ transplants --- Organs (Anatomy) --- Surgical transplantation --- Tissue transplantation --- Tissues --- Transplants, Organ --- Rejection of grafts --- Rejection of transplants --- Transplant rejection --- Cellular transplantation --- Marrow --- Medulla ossium --- Immunology, Transplantation --- transplantation --- Immunological aspects --- Organ Transplantation --- Bone Marrow Transplantation --- Cell Transplantation --- Graft Rejection --- Transplantation Immunology --- Transplantation of organs, tissues, etc --- Surgery --- Preservation of organs, tissues, etc. --- Procurement of organs, tissues, etc. --- Cellular immunity --- Immunology --- Histocompatibility --- Immunological tolerance --- Cellular therapy --- Hematopoietic system --- Immune system --- Tissue Transplantation --- Delayed Graft Function --- Bone Marrow Purging --- Hematopoietic Stem Cell Transplantation --- Transplant surgery --- Transplantation surgery --- Greffe. --- Immunologie.