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BACKGROUND Immunosuppression is essential after organ transplantation to prevent severe graft injury due to rejection, but in long-term, transplanted organs are generally accepted with minimal dose of immunosuppression, and adverse effects of it such as renal dysfunction, diabetes and development of malignancies might become to exceed over the benefits in majority of the cases. Accordingly, to achieve the immunologic tolerance has been the ultimate goal in organ transplantation, and the liver has been well recognized as the tolerogenic organ compared to other organs. METHODS We referred the reported studies showing the actual protocol to achieve the immunologic tolerance after clinical liver transplantation. RESULTS Actually, two main procedures as "elective weaning of immunosuppression" and/or "cell therapy" using various immune-related cells have been introduced to induce the immunologic tolerance in clinical liver transplantation. The cell therapy, especially using regulatory T-cell has been reported to achieve definitive immunologic tolerance in living donor liver transplantation. CONCLUSION Although it is still developing, the induction of immunologic tolerance in clinical liver transplantation is realistic. Herein, the current topics of immunologic tolerance in liver transplantation is described.

This historical retrospective explores the study of the freemartin condition and its impact on the discovery of immunologic tolerance and the field of transplant surgery-from the ancient Romans, to early modern anatomists Valsalva, Scarpa, and Hunter, to contemporary immunologists Owen, Medawar, and Billingham, and to legendary transplant surgeon Joseph Murray. The legacy of freemartin cattle in the understanding of acquired tolerance and transplant immunology represents generations of scientific inquiry guided by careful observation and occasional serendipity, and the present-day immunologists and surgeons exploring immune transplant tolerance owe much to the history of the freemartin, several millennia in the making.

Induction of longstanding immunologic tolerance is essential for survival of transplanted organs and tissues. Despite recent advances in immunosuppression protocols, allograft damage inflicted by antibody specific for donor organs continues to represent a major obstacle to graft survival. Here we report that activation of regulatory CD8 T cells (CD8 Treg) that recognize the Qa-1 class Ib major histocompatibility complex (MHC), a mouse homolog of human leukocyte antigen-E (HLA-E), inhibits antibody-mediated immune rejection of heart allografts. We analyzed this response using a mouse model that harbors a point mutation in the class Ib MHC molecule Qa-1, which disrupts Qa-1 binding to the T cell receptor (TCR)-CD8 complex and impairs the CD8 Treg response. Despite administration of cytotoxic T lymphocyte antigen 4 (CTLA-4) immunoglobulin (Ig), Qa-1 mutant mice developed robust donor-specific antibody responses and accelerated heart graft rejection. We show that these allo-antibody responses reflect diminished Qa-1-restricted CD8 Treg-mediated suppression of host follicular helper T cell-dependent antibody production. These findings underscore the critical contribution of this Qa-1/HLA-E-dependent regulatory pathway to maintenance of transplanted organs and suggest therapeutic approaches to ameliorate allograft rejection.

Maternal-fetal immune-tolerance occurs throughout the whole gestational trimester, thus a mother can accept a genetically distinct fetus without immunological aggressive behavior. HLA-G, one of the non-classical HLA class I molecules, is restricted-expression at extravillous trophoblast. It can concordantly interact with various kinds of receptors mounted on maternally immune cells residing in the uterus (e.g. CD4+ T cells, CD8+ T cells, natural killer cells, macrophages, and dendritic cells) for maintaining immune homeostasis of the maternal-fetus interface. HLA-G is widely regarded as the pivotal protective factor for successful pregnancies. In the past 20 years, researches associated with HLA-G have been continually published. Indeed, HLA-G plays a mysterious role in the mechanism of maternal-fetal immune-tolerance. It can also be ectopically expressed on tumor cells, infected sites and other pathologic microenvironments to confer a significant local tolerance. Understanding the characteristics of HLA-G in immunologic tolerance is not only beneficial for pathological pregnancy, but also helpful to the therapy of other immune-related diseases, such as organ transplant rejection, tumor migration, and autoimmune disease. In this review, we describe the biological properties of HLA-G, then summarize our understanding of the mechanisms of fetomaternal immunologic tolerance and the difference from transplant tolerance. Furthermore, we will discuss how HLA-G contributes to the tolerogenic microenvironment during pregnancy. Finally, we hope to find some new aspects of HLA-G in fundamental research or clinical application for the future.

Superspreader hosts carry out most pathogen transmission events and are often disease tolerant since they remain asymptomatic despite high pathogen burdens. Here we describe the superspreader immune state that allows for disease tolerance. In a model ofSalmonellainfection, superspreader mice develop colitis with robust CD4+and CD8+T-cell responses, however, they remain asymptomatic. We found that superspreaders have significantly more regulatory T cells (Tregs) in the distal gut compared to non-superspreader infected hosts. Surprisingly, the depletion of Tregs did not induce pathogen clearance but rather exacerbated weight loss, increased gut inflammation, and compromised epithelial intestinal barrier. This loss of tolerance correlated with dramatic increases in cytotoxic CD4+and CD8+T cells. Interestingly, CD4 neutralization in Tregs-depleted superspreaders was sufficient to rescue tolerance. Our results indicate that Tregs play a crucial role in maintaining immunologic tolerance in the guts of superspreader mice by suppressing cytotoxic CD4+and CD8+T-cell activities.AUTHOR SUMMARYSuperspreader hosts are the main cause of disease transmission and a very important public health concern. Here, we evaluated the immunological tolerance of theSalmonellainfected superspreaders in a mouse model. By manipulating Tregs, we demonstrated the immunological mechanism from the host to maintain health status and high pathogen burden. Tregs depletion in the superspreaders led to severe disease, with damage of the intestinal epithelia, and high morbidity without having any effect on shedding and systemicSalmonellaburden. Furthermore, we demonstrated that the damage of the intestinal epithelia was related to cytotoxic activity of T cells. When Tregs were depleted, CD8+T cells produced high levels of granzyme B and perforin. CD8+T cells neutralization in Tregs depleted mice led to increased cytotoxic CD4+T cells. Interestingly, neutralization of CD4+T cells in the Tregs depleted mice led to a reduction in the CD8+T cells producing granzyme B and it was sufficient to rescue host tolerance in this model. We demonstrate for the first time that cytotoxic CD4+T cells damage the epithelial intestinal barrier and contribute to loss of tolerance in the context of a superspreader host. These findings open new perspectives to understand mechanisms of tolerance in the intestine of a superspreader host.

Summary: Although CD4+ FOXP3+ T regulatory (Treg) cells are well-known mediators of immunologic tolerance, their influences in the tumor microenviroment are incompletely understood. Writing in this issue of Cancer Discovery, Zhang and colleagues demonstrate that in pancreatic cancer, Treg cells promote the differentiation of tumor-restraining myofibroblastic cancer-associated fibroblasts, challenging the existing notion that Treg cells enable tumor progression. See related article by Zhang et al., p. 422.

PURPOSE OF REVIEW We evaluated the time-course of clinical and immunologic changes that occur during and after cessation of sublingual and subcutaneous allergen immunotherapy for inhalant allergies. RECENT FINDINGS Increases in production of inhibitory cytokines, such as IL-10 and allergen-specific IgE and IgG4 antibodies are induced within weeks of starting immunotherapy for both seasonal and perennial allergens. In general, 2-4 months' immunotherapy is needed for onset of efficacy whereas maximal clinical effect is achieved within 1-2 years of treatment. Therefore, assuming optimal patient selection, good compliance and at least moderate allergen exposure, if immunotherapy is ineffective at 2 years, it is reasonable to discontinue the treatment. For long-term clinical efficacy, at least 3 years of either subcutaneous or sublingual immunotherapy is required and this results in clinical and immunologic tolerance -- persistence of clinical benefits and suppression of type 2 immunity for years after discontinuation of treatment. SUMMARY Both sublingual and subcutaneous immunotherapy are effective and well tolerated for respiratory allergy. Clinical and immunological changes occur at early stages of treatment. Long-term evaluations support recommendations in international guidelines that both routes of administration should be continued for a minimum of 3 years to achieve disease modification and long-term tolerance.

The objective of this article is to provide a brief and concise review about the history, indications, surgical technical challenges, post-transplant complications, and overall outcomes of pediatric abdominal organ transplantation (kidney transplant (KT), liver transplant (LT), and intestinal transplant (IT)). Pediatric abdominal organ transplantation (KT, LT, IT) has evolved over the last 50 years to emerge as a successful option for children suffering from end-stage renal disease, end-stage liver disease, liver malignancy, disabling metabolic disease, acute liver failure, and life-threatening intestinal failure. However, pediatric abdominal organ transplantation requires a fundamentally different approach from adult abdominal organ transplantation due to differences in underlying indications for transplant, smaller pediatric recipient size, and various growth stages of childhood. Excellent short-term and good long-term outcomes have been achieved in pediatric KT, LT, and IT recipient when compared with adult counterparts. Further research to develop strategies to induce immunologic tolerance of allografts and diagnose/treat chronic allograft rejection is required in order to continue to improve overall survival of pediatric abdominal organ transplant recipients.

The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin1, a rod-like protein2 that protects striated myocytes from contraction-induced injury3,4. Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin5. Importantly, normal thymic expression in DMD patients6 should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic transgene encoding a miniaturized utrophin (µUtro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that µUtro is a highly functional, non-immunogenic substitute for dystrophin, preventing the most deleterious histological and physiological aspects of muscular dystrophy in small and large animal models. Following systemic administration of an AAV-µUtro to neonatal dystrophin-deficient mdx mice, histological and biochemical markers of myonecrosis and regeneration are completely suppressed throughout growth to adult weight. In the dystrophin-deficient golden retriever model, µUtro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of µUtro in the deletional-null German shorthaired pointer model produced no evidence of cell-mediated immunity, in contrast to the robust T cell response against similarly constructed µDystrophin (µDystro). These findings support a model in which utrophin-derived therapies might be used to treat clinical dystrophin deficiency, with a favorable immunologic profile and preserved function in the face of extreme miniaturization.

Gastrointestinal (GI) allergic disease is an umbrella term used to describe a variety of adverse, food antigen-driven, immune-mediated diseases. Although these diseases vary mechanistically, common elements include a breakdown of immunologic tolerance, a biased type 2 immune response, and an impaired mucosal barrier. These pathways are influenced by diverse factors such as diet, infections, exposure to antibiotics and chemicals, GI microbiome composition, and genetic and epigenetic elements. Early childhood has emerged as a critical period when these factors have a dramatic impact on shaping the immune system and therefore triggering or protecting against the onset of GI allergic diseases. In this Review, we will discuss the latest findings on the molecular and cellular mechanisms that govern GI allergic diseases and how these findings have set the stage for emerging preventative and treatment strategies.

Immunologic tolerance refers to a state of immune nonreactivity specific to particular antigens as an important issue in the field of transplantation and the management of autoimmune diseases. Tolerance conceptually originated from Owen’s observation of blood cell sharing in twin calves. Owen’s conceptual framework subsequently constituted the backbone of Medawar’s “actively acquired tolerance” as the major tenet of modern immunology. Based upon this knowledge, the delivery of genetically distinct hematopoietic stem cells into pre-immune fetuses represented a novel and unique approach to their engraftment without the requirement of myeloablation or immunosuppression. It might also make fetal recipients commit donor alloantigens to memory of their patterns as “self” so as to create a state of donor-specific tolerance. Over the years, the effort made experimentally or clinically toward in utero marrow transplantation could not reliably yield sufficient hematopoietic chimerism for curing candidate diseases as anticipated, nor did allogeneic graft tolerance universally develop as envisaged by Medawar following in utero exposure to various forms of alloantigens from exosomes, lymphocytes or marrow cells. Enduring graft tolerance was only conditional on a state of significant hematopoietic chimerism conferred by marrow inocula. Notably, fetal exposure to ovalbumin, oncoprotein and microbial antigens did not elicit immune tolerance, but instead triggered an event of sensitization to the antigens inoculated. These fetal immunogenic events might be clinically relevant to prenatal imprinting of atopy, immune surveillance against developmental tumorigenesis, and prenatal immunization against infectious diseases. Briefly, the immunological consequences of fetal exposure to foreign antigens could be tolerogenic or immunogenic, relying upon the type or nature of antigens introduced. Thus, the classical school of “actively acquired tolerance” might oversimplify the interactions between developing fetal immune system and antigens. Such interactions might rely upon fetal macrophages, which showed up earlier than lymphocytes and were competent to phagocytose foreign antigens so as to bridge toward antigen-specific adaptive immunity later on in life. Thus, innate fetal macrophages may be the potential basis for exploring how the immunological outcome of fetal exposure to foreign antigens is determined to improve the likelihood and reliability of manipulating fetal immune system toward tolerization or immunization to antigens.

Adeno-associated viral (AAV) vector gene therapy has shown promise as a possible cure for hemophilia. However, immune responses directed against AAV vectors remain a hurdle to the broader use of this gene transfer platform. Both innate and adaptive immune responses can affect the safety and efficacy of AAV vector–mediated gene transfer in humans. These immune responses may be triggered by the viral capsid, the vector’s nucleic acid payload, or other vector contaminants or excipients, or by the transgene product encoded by the vector itself. Various preclinical and clinical strategies have been explored to overcome the issues of AAV vector immunogenicity and transgene-related immune responses. Although results of these strategies are encouraging, more efficient approaches are needed to deliver safe, predictable, and durable outcomes for people with hemophilia. In addition to durability, long-term follow-up of gene therapy trial participants will allow us to address potential safety concerns related to vector integration. Herein, we describe the challenges with current methodologies to deliver optimal outcomes for people with hemophilia who choose to undergo AAV vector gene therapy and the potential opportunities to improve on the results.

In recent years, consumption of ultra-processed food around the world has been increasing. The nutritional profile of an ultra-processed diet is associated with the development of cellular alterations that lead to oxidative stress. The chronic prooxidative state leads to an environment that influences the proliferation, apoptosis, and signaling pathways of immune cells. Likewise, the decrease in the transcription factor NRF2, owing to exacerbated production of reactive oxygen species, leads to changes in immune function and response to infections. This review aims to analyze the connection between an ultra-processed diet, systemic oxidative stress, and immune tolerance, as a contribution to the scientific evidence on the impact of oxidative stress on health and the possible risk of infections-an important consideration in the association of eating pattern and the immune response.

Hepatocytes compose up to 80% of the total liver and have been indicated as important players in the induction of immunologic tolerance in this organ. We show that hepatocytes possess the molecular machinery required for the cross-presentation of extracellular antigens. Using a derivative of the model antigen ovalbumin (OVA) covalently modified with a polymer containing multiple N-acetylgalactosamine residues (pGal-OVA) that enhance extracellular antigen uptake by mimicking the glycome of apoptotic debris, we show efficient hepatocyte-dependent induction of cross-tolerance of both adoptively transferred OT-I cells and endogenous OVA-specific CD8+ T lymphocytes, for example inducing tolerance to OVA-expressing skin transplants. Our study confirms that hepatocytes are capable of inducing peripheral tolerogenesis and provides proof of concept that they may be a valuable candidate for in vivo targeted tolerogenic treatments.

Dendritic cells (DC) are antigen-presenting cells that can communicate with T cells both directly and indirectly, regulating our adaptive immune responses against environmental and self-antigens. Under some microenvironmental conditions DC develop into anti-inflammatory cells which can induce immunologic tolerance. A substantial body of literature has confirmed that in such settings regulatory DC (DCreg) induce T cell tolerance by suppression of effector T cells as well as by induction of regulatory T cells (Treg). Many in vitro studies have been undertaken with human DCreg which, as a surrogate marker of antigen-specific tolerogenic potential, only poorly activate allogeneic T cell responses. Fewer studies have addressed the abilities of, or mechanisms by which these human DCreg suppress autologous effector T cell responses and induce infectious tolerance-promoting Treg responses. Moreover, the agents and properties that render DC as tolerogenic are many and varied, as are the cells’ relative regulatory activities and mechanisms of action. Herein we review the most current human and, where gaps exist, murine DCreg literature that addresses the cellular and molecular biology of these cells. We also address the clinical relevance of human DCreg, highlighting the outcomes of pre-clinical mouse and non-human primate studies and early phase clinical trials that have been undertaken, as well as the impact of innate immune receptors and symbiotic microbial signaling on the immunobiology of DCreg.

Successful pregnancy relies on maternal immunologic tolerance mechanisms limit maladaptive immune responses against the semi-allogeneic fetus and placenta and support fetal growth. Preeclampsia is a common disorder of pregnancy that affects 4-10% of pregnancies and is a leading cause of maternal and neonatal morbidity and mortality. Preeclampsia clinically manifests as maternal hypertension, proteinuria, and progressive multi-organ injury likely triggered by hypoxic injury to the placenta, resulting in local and systemic anti-angiogenic and inflammatory factor production. Despite the steady rising rates of preeclampsia in the United States, effective treatment options are limited to delivery, which improves maternal status often at the cost of prematurity in the newborn. Preeclampsia also increases the lifelong risk of cardiovascular disease for both mother and infant. Thus, identifying new therapeutic targets is a high priority area to improve maternal, fetal, and infant health outcomes. Immune abnormalities in the placenta and in the maternal circulation have been reported to precede the clinical onset of disease. In particular, excessive systemic and placental complement activation and impaired adaptive T cell tolerance with Th1/Th2/Th17/Treg imbalance has been reported in humans and in animal models of preeclampsia. In this review, we focus on the evidence for the immune origins of preeclampsia, discuss the promise of immune modulating therapy for prevention or treatment, and highlight key areas for future research.

Acute graft-versus-host disease (aGvHD) is induced by immunocompetent alloreactive T lymphocytes in the donor graft responding to polymorphic and non-polymorphic host antigens and causing inflammation in primarily the skin, gastrointestinal tract and liver. aGvHD remains an important toxicity of allogeneic transplantation, and the search for better prophylactic and therapeutic strategies is critical to improve transplant outcomes. In this review, we discuss the significant translational and clinical advances in the field which have evolved based on a better understanding of transplant immunology. Prophylactic advances have been primarily focused on the depletion of T lymphocytes and modulation of T-cell activation, proliferation, effector and regulatory functions. Therapeutic strategies beyond corticosteroids have focused on inhibiting key cytokine pathways, lymphocyte trafficking, and immunologic tolerance. We also briefly discuss important future trends in the field, the role of the intestinal microbiome and dysbiosis, as well as prognostic biomarkers for aGvHD which may improve stratification-based application of preventive and therapeutic strategies.

LncRNAs can act crucial roles in multiple tumors including cholangiocarcinoma (CCA). M2 polarization of macrophages is crucial for their biological roles in immunologic tolerance, which is able to induce tumorigenesis. Given that increasing evidence have suggested that lncRNAs could participate in modulating immune cell differentiation and function. Our current study was aimed to identify the underlying mechanism of lncRNA prostate cancer-associated transcript 6 (PCAT6) in CCA progression via regulating M2 macrophage polarization. PCAT6 has been reported as an oncogene in many cancers. In our work, we observed increased expression of PCAT6 in CCA patients. PCAT6 expression in various types of immune cells derived from CCA patients was tested by quantitative real-time PCR (qRT-PCR). It was revealed that PCAT6 was highly expressed in macrophages, which indicated that PCAT6 might regulate the function of macrophages to promote CCA progression. Then, via establishing CCA xenograft mouse model, we found loss of PCAT6 obviously triggered the immune response and reduced the in vivo tumor growth. In addition, overexpression of PCAT6 led to the M2 polarization of THP-1-differentiated macrophages. Moreover, miR-326 was predicted and proved as a target for PCAT6. In addition, down-regulation of PCAT6 repressed M2 polarization of macrophages, which was reversed by miR-326 inhibitors. The increase of PCAT6 induced the accumulation of ROS, mitochondrial and metabolic dysfunction in macrophages and mimics of miR-326 exhibited an opposite process. RohA has been recognized as a significant regulator of immune cell function. In our current work, we observed that RohA function as a downstream target for miR-326. In conclusion, our study highlighted a significant role of PCAT6/miR-326/RohA in immune response of macrophages in CCA and indicated PCAT6 as a potential target of immunotherapy in CCA.

Brazilian-born British biologist Dr. Peter Medawar played an integral role in developing the concepts of immunologic rejection and tolerance, which led to him receiving the Nobel Prize “for the discovery of acquired immunologic tolerance” and eventually made organ transplantation a reality. However, at the time of his early work in tolerance, a paradox to his theories was brought to his attention; how was pregnancy possible? Pregnancy resembles organ transplantation in that the fetus, possessing paternal antigens, is a semi-allogeneic graft that can survive without immunosuppression for 9 months. To answer this question, Medawar proposed three hypotheses of how a mother supports her fetus in utero, now known as “Medawar’s Paradox.” The mechanisms that govern fetomaternal tolerance are still incompletely understood but may provide critical insight into how to achieve immune tolerance in organ transplantation. Here, we review current understanding of the immune factors responsible for fetomaternal tolerance during pregnancy and discuss the potential implications for advances in transplantation science., Graphical Abstract

Background and Purpose: Describe clinical course and outcomes of two cases of autoimmune DM who experienced remission and have remained insulin-free or on significantly reduced doses following pregnancy. Case Description: Case 1: 41 year old female G1P0 at 27w1d presented with diabetic ketoacidosis and was found to have new onset autoimmune diabetes with positive anti-GAD antibodies. She was treated with insulin therapy through the remainder of her pregnancy, and at post-partum follow-up found to be having hypoglycemic episodes. Insulin therapy was titrated down and eventually stopped. She has remained insulin-free with A1C Outcome: Two cases of autoimmune DM with prolonged remission following pregnancy requiring little to no insulin therapy. Discussion: During pregnancy, multiple biological adaptations lead to increased insulin resistance and clearance, and following deliver many of these alterations revert and allow return to pre-pregnancy insulin dosing. These two cases demonstrate prolonged honeymoon phase. In addition to the cases, a literature review of the physiology of honeymoon phase including development of immunologic tolerance and possible mechanisms of resolution of autoimmune DM including suppression of autoimmunity and development of endogenous insulin production is included. Disclosure M.M. Kristan: None. Y. Kim: None. S.E. Thomas: None. K.M. Munir: None.

Objective Four autoantigens have been described recently in IgG4-related disease (IgG4-RD): prohibitin, annexin A11, laminin 511-E8, and galectin-3. However, no external validation has been performed, and the possibility that some individuals break tolerance to more than 1 autoantigen has not been explored. We undertook this study to evaluate the relative frequencies of antibody responses against these autoantigens in order to explore the role of adaptive immune response in IgG4-RD. Methods Autoantibody responses against prohibitin, annexin A11, and laminin 511-E8 were measured among a clinically diverse cohort of IgG4-RD patients (n = 100) using enzyme-linked immunosorbent assays. Autoantibody responses were correlated with disease severity and organ distribution. Results The frequencies of IgG4 autoantibody responses against prohibitin (10%), annexin A11 (12%), and laminin 511-E8 (7%) were not significantly different from those of controls. A portion of the cohort (n = 86) had been analyzed previously at our center for anti-galectin-3 antibody responses, with 25 patients (29%) having IgG4 anti-galectin-3 antibodies. Of these 86 patients, 32 (37%) had IgG4 antibodies to ≥1 of the 4 autoantigens and 12 (14%) showed reactivity with ≥2 of the tested antigens. The subset of patients with ≥2 autoantibodies had higher total levels of IgG1, IgG2, IgG4, and C-reactive protein, were more commonly hypocomplementemic, and were more likely to have visceral organ involvement. Conclusion Antibodies against prohibitin, annexin A11, and laminin 511-E8 were found in only a small portion of patients with IgG4-RD. A subset of IgG4-RD patients, however, had IgG4 antibodies against ≥2 autoantigens. These patients presented with robust IgG subclass elevations, complement consumption, and visceral organ involvement. This broader break in immunologic tolerance in IgG4-RD was associated with more severe disease.

Islet transplantation has potential to dramatically alter the treatment strategy for both type 1 and type 2 diabetes mellitus. In contrast to exogenous insulin administration, islet transplantation offers a curative therapy through the islets’ natural ability to monitor blood glucose levels and deliver the appropriate amount of insulin. However, several challenges hinder the widespread adoption of islet transplantation as a primary treatment for diabetes. Aside from the challenges of islet hypoxia and a lack of readily available donor islets, immune-mediated rejection of the transplanted islets represents a significant challenge, preventing widespread adoption of islet transplantation as a mainstay of diabetes treatment. As with any allogeneic transplantation, the decision to perform isle transplants must carefully weigh the benefits of the new, healthy tissue (i.e., superior glucose control) against the risks of life-long systemic immunosuppression. Because of the life-saving advances in exogenous insulin production and delivery over the last 100 years, islet transplantation and whole pancreas transplant are currently reserved for individuals who have exhibited life threatening, severe hypoglycemic episodes or are already immunosuppressed for an additional, concurrent organ transplant, most commonly kidney transplant recipients. Additionally, several of the most common immunosuppressants are diabetogenic and toxic to pancreatic beta cells. For these reasons, the risks of the immunosuppressive regimen typically outweigh the benefit for the average diabetic patient. However, induction of immunologic tolerance to the transplanted islet grafts has become a very attractive alternative to pharmacologic immunosuppression because it holds the promise of the benefit of the transplant without the risks of the immunosuppression. Islet transplant tolerance has, thus, become a very active area of research. Speaking generally, transplant tolerance is an immunological state in which the recipient immune system ignores the nonself-tissue, while the immune system maintains reactivity to other agents, such as bacterial or viruses. Immunologic tolerance would, therefore, establish the long-term survival of the transplanted islets without the sequalae of systemic immunosuppression. This chapter provides an overview of current clinical approaches to tolerance induction as well as preclinical strategies being studied for islet tolerance. Because islets are transplanted as an organized cluster of cells, they lend themselves to additional immunoprotective strategies that large organ transplants do not, such as encapsulation and stem-cell-derived production. The potential immunological impact of these technologies and how they work into tolerance strategies will also be discussed.

Salivary glands (SGs) represent a permissive site for several sialotropic viruses whose persistence is linked to the development of autoimmunity. Natural Killer (NK) cells play a key role in viral clearance but their involvement in viral infection control and in tertiary lymphoid structures (TLS) development within SGs is unknown. By using an inducible model of TLS in the SGs of wild-type C57BL/6 mice, induced by the local delivery of a replication-defective adenovirus (AdV), we demonstrated that circulating NK cells are rapidly recruited to SGs and highly enrich the early inflammatory infiltrate prior to TLS development. NK cells migrating to SGs in response to AdV infection up-regulate NKp46, undergo proliferation, acquire cytotoxic potential, produce Granzyme-B and IFN-γ, and reduce viral load in the acute phase of the infection. Nonetheless, the selective depletion of both circulating and infiltrating NK cells in AdV-infected mice neither affect the development and frequency of TLS nor the onset of autoimmunity. These data demonstrate that, upon local viral delivery of AdV, peripheral NK cells homing to SGs can exert an early control of the viral infection but are dispensable for the formation of TLS and breach of immunologic tolerance.

Environmental factors play an important role in the pathogenesis of Crohn's Disease (CD). In particular, by virtue of the instability of the microbiome and development of immunologic tolerance, early life factors may exert the strongest influence on disease risk and phenotype.We used data from 1119 CD subjects recruited from RISK inception cohort to examine the impact of early life environment on disease progression. Our primary exposures of interest were breastfeeding in infancy and exposure to maternal, active, or passive smoke. Our primary outcomes were development of complicated (stricturing or penetrating) disease, and need for CD-related hospitalization, and surgery. Multivariable logistic regression models were used to define independent associations, adjusting for relevant covariates.Our study cohort included 1119 patients with CD among whom 15% had stricturing (B2) or penetrating disease (B3) by 3 years. 331 patients (35%) and 95 patients (10.6%) required CD-related hospitalizations and surgery respectively. 74.5% were breastfed in infancy and 31% were exposed to smoking among whom 7% were exposed to maternal smoke. On multivariable analysis, a history of breastfeeding was inversely associated with complicated (B2/B3 disease) 0.65, CI 95% 0.44-96; P = 0.03) in pediatric CD. Maternal smoking during pregnancy was associated with increased risk of hospitalization during the 3-year follow-up period (OR 1.75, CI 95% 1.05-2.89; P = 0.03).Early life environmental factors influence the eventual phenotypes and disease course in CD.

Background The mixed chimerism approach for intentional induction of donor-specific tolerance was shown to be successful in various models from mice to humans. For transplant patients, the approach would obviate the need for long-term immunosuppression and associated side effects; moreover, it would preclude the risk of late graft loss due to chronic rejection. Widespread clinical application is hindered by toxicities related to recipient pre-conditioning. Herein we aimed to investigate a clinically relevant protocol for tolerance induction to cardiac allografts, sparing CD40 blockade or T-cell depletion. Methods B6 mice were conditioned with non-myeloablative total body irradiation, fully mismatched BALB/c bone marrow cells, and short-term therapy, based on either anti– lymphocyte function–associated antigen-1 (anti–LFA-1) or anti-CD40L. Multilineage chimerism was followed by flow-cytometric analysis, tolerance was assessed with skin and heart allografts from fully or major histocompatibility complex–mismatched donors. Mechanisms of tolerance were investigated by analysis of donor-specific antibodies (DSAs), mixed lymphocyte reaction (MLR) assays, and deletion of donor-reactive T cells. Results We found that the combination of cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4Ig) and rapamycin with LFA-1 blockade enhanced bone marrow engraftment and led to more efficient T-cell engraftment and subsequent tolerization. Although fully mismatched skin grafts were chronically rejected, primarily vascularized heart allografts survived indefinitely and without signs of chronic rejection, independent of minor antigen mismatches. Conclusions We have demonstarted a robust protocol for the induction of tolerance for cardiac allografts in the absence of CD40 blockade. Our findings demonstrate the potential of a clinically relevant minimal conditioning protocol designed to induce lifelong immunologic tolerance toward cardiac allografts.

The purpose of this review is to discuss immunologic tolerance as it applies to solid organ transplantation and to identify barriers that hinder the achievement of this long-term goal. First, the definition of tolerance and an introduction of mechanisms by which tolerance exists or can be achieved will be discussed. Next, a review of contemporary attempts at achieving transplant tolerance will be described. Finally, a discussion of the humoral barriers to transplantation tolerance and potential ways to overcome these barriers will be presented., In this review regarding tolerance induction in organ transplantation, the authors highlight the current attempts of induction with their mechanisms, the contemporary barriers and the specific role of humoral immunity

Xenotransplantation is an attractive solution to the problem of allograft shortage. However, transplants across discordant species barriers are subject to vigorous immunologic and pathobiologic hurdles, some of which might be overcome with the induction of immunologic tolerance. Several strategies have been designed to induce tolerance to a xenograft at both the central (including induction of mixed chimerism and thymic transplantation) and peripheral (including adoptive transfer of regulatory cells and blocking T cell costimulation) levels. Currently, xenograft tolerance has been well-established in rodent models, but these protocols have not yet achieved similar success in nonhuman primates. This review will discuss the major barriers that impede the establishment of immunological tolerance across xenogeneic barriers and the potential solution to these challenges, and provide a perspective on the future of the development of novel tolerance-inducing strategies.

Limited availability of donor organs and risk of ischemia‐reperfusion injury (IRI) seriously restrict organ transplantation. Therapeutics that can prevent or reduce IRI could potentially increase the number of transplants by increasing use of borderline organs and decreasing discards. Alpha‐1 antitrypsin (AAT) is an acute phase reactant and serine protease inhibitor that limits inflammatory tissue damage. Purified plasma–derived AAT has been well tolerated in more than 30 years of use to prevent emphysema in AAT‐deficient individuals. Accumulating evidence suggests that AAT has additional anti‐inflammatory and tissue‐protective effects including improving mitochondrial membrane stability, inhibiting apoptosis, inhibiting nuclear factor kappa B activation, modulating pro‐ vs anti‐inflammatory cytokine balance, and promoting immunologic tolerance. Cell culture and animal studies have shown that AAT limits tissue injury and promotes cell and tissue survival. AAT can promote tolerance in animal models by downregulating early inflammation and favoring induction and stabilization of regulatory T cells. The diverse intracellular and immune‐modulatory effects of AAT and its well‐established tolerability in patients suggest that it might be useful in transplantation. Clinical trials, planned and/or in progress, should help determine whether the promise of the animal and cellular studies will be fulfilled by improving outcomes in human organ transplantation., Although traditionally considered an extracellular inhibitor of serine proteases, alpha‐1‐antitrypsin also has intracellular effects that may be beneficial in transplantation, including inhibiting apoptosis and NF‐kB activation, modulating proversus anti‐inflammatory cytokine balance, and promoting tolerance.

Background Dendritic cells (DCs) are bone marrow-derived, professional antigen-presenting cells with tolerogenic function. The ability of DCs to regulate alloantigen-specific T cell responses and to promote tolerance has aligned them ideally for a role in vascularized composite allotransplantation (VCA). In this study, we summarize the current evidence for DC therapies for tolerance induction to alleviate the requirement for chronic immunosuppression. Method A comprehensive and structured review of manuscripts published on VCA was performed using the MEDLINE and PubMed databases. All eligible studies published from the year 2000 to 2017 were included in the final results. Result Nineteen original preclinical and clinical studies that employed cell therapy for VCA were included in this review. In vivo DC therapy was found to direct the alloimmune response toward either transplant rejection or tolerance in VCA models. While injection of mature DCs rapidly increases T-cell activity in humans and promotes transplant rejection, the injection of immature DCs acts as an immunosuppressant and inhibits T-cell activity. In addition to immature DCs, mesenchymal stem cells were also found to have a positive effect on allotransplantation of solid organs and bone marrow via cytokine expression which decreases the alloreactive effector lymphocytes and increases CD4+/CD25+/FoxP3 Tregs. Despite the promising findings, the efficacy of cell-based therapies varies greatly across studies, partly due to different methods of cell isolation and purification techniques, source, route and timing of administration, and combination immunosuppressive therapy. Conclusion Additional research is needed to evaluate the efficacy and safety of DC and other cell-based therapeutic measures in human allotransplant recipients. Future direction will focus on the development of novel methods to reduce immunosuppression and develop more individualized management, as well as the clinical application of basic research in the mechanisms of immunologic tolerance.

Dendritic cells (DCs) are professional antigen-presenting cells (APC) that facilitate the development and progression of atherosclerosis. However, DCs also function as novel “switches” between immune activation and immune tolerance and represent a heterogeneous hematopoietic lineage, with cell subsets in different tissues that show a differential morphology, phenotype, and function. Regulatory DCs, depending on their immature state, can be induced by immunosuppressive modulation, which plays an important part in the maintenance of immunologic tolerance via suppression of the immune response. In this review, we describe the current understanding of the generation of regulatory DCs. The novel role of selectins in the modification of DCs in atherosclerosis is also discussed. Keywords: Dendritic cells, Selectins, Atherosclerosis, Immune tolerance

Objective To explore the effect of umbilical cord mesenchymal stem cells with positive human leukocyte antigen (HLA)-G on inducing the production of regulatory T cells (Treg) in vitro. Methods Umbilical cord mesenchymal stem cells were isolated from umbilical cord of neonates. PEGFP-N1-HLA-G plasmid was transfected into the human umbilical cord mesenchymal stem cells by liposome transfection, as PEGFP-N1-HLA-G group. PEGFP-N1 empty vector plasmid was transfected into the human umbilical cord mesenchymal stem cells, as PEGFP-N1 group. The human umbilical cord mesenchymal stem cells without empty vector under the same conditions were set as blank control group. Markers of the umbilical cord mesenchymal stem cells were detected using flow cytometry. The expression of HLA-G protein in each group of cells was identified by Western Blot. After mixed-culturing with CD4+T cells in peripheral blood of healthy subjects for 24 h and 48 h, the proportion of CD4+ CD25+ Foxp3+Treg in total T cells of each group was detected by flow cytometry. Results CD45, CD34 and HLA-DR presented negative expression on umbilical cord mesenchymal stem cells, while CD29, CD44 and CD105 presented positive expression. HLA-G protein could be expressed in the PEGFP-N1-HLA-G group, which had statistically significant difference compared with the blank control group and PEGFP-N1 group (both P < 0.01). After PEGFP-N1-HLA-G group and CD4+T cells were mixed-cultured for 24 h and 48 h, CD4+ CD25+ Foxp3+Treg accounted for (15.3±1.9)% and (14.3±2.1)% of the total T cells respectively, both of which presented statistically significant difference compared with the blank control group and PEGFP-N1 group (all P < 0.05). Conclusions Umbilical cord mesenchymal stem cells with HLA-G gene modified can effectively induce the production of CD4+ CD25+ Foxp3+Treg in vitro.

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) catalyze the first rate-limiting step in the oxidative metabolism of compounds containing indole rings, including the transformation of the essential amino acid L-tryptophan to N-formyl-L-kynurenine. Through direct and indirect means, IDO exerts both tolerogenic and pro-inflammatory effects and has a profound immunoregulatory role in the tumor microenvironment. Although the role of IDO in mediating peripheral acquired immunologic tolerance has been known for some time, its role in tumorigenesis and the subversion of anti-tumor immunity have only recently been appreciated. Small-molecule inhibitors of IDO1 and TDO are being evaluated as single agents and in combination with immune checkpoint blockade in a host of advanced cancers. In this review, we delineate the tolerogenic and pro-inflammatory effects of IDO as it relates to immune escape and discuss current clinical progress in this area.