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Graft-versus-host disease (GVHD) is characterized by an impairment of mechanisms that underlie the development of immunologic tolerance. Although the cytokine storm associated with GVHD leads to expression of cell surface markers on both effector and regulatory T cells, regulatory CD4+ T cells that play an instrumental role in the maintenance of tolerance appear to uniquely express the Foxp3 transcriptional repressor. Foxp3 mRNA expression was significantly decreased in peripheral blood mononuclear cells from patients with either allogeneic GVHD or autologous GVHD compared with patients without GVHD. Expression of Foxp3 negatively correlated with the severity of GVHD but positively correlated with recent thymic emigrants. The results suggest that defective thymic function contributes to the impaired reconstitution of immune regulatory mechanisms following transplantation. The decrease in regulatory mechanisms after transplantation appears to provide an environment permissive to the development of GVHD. (Blood. 2004;104:2187-2193)

The outcome of an immune response is dependent on the interplay and complex interactions of positive (stimulatory) and negative (inhibitory) pathways and a major goal of modern immunology is to dissect these physiologic interactions in order to apply these physiologic mechanisms therapeutically. The balance of stimulatory and inhibitory signals is critical for maximizing the ability of the adoptive immune response to defend the host while maintaining immunologic tolerance and preventing autoimmunity. Cellular quiescence is a state characterized by decreased cell size and metabolic activity. The quiescent state of unstimulated T lymphocytes is thought to be due to the lack of activation signals. However, recent studies have shown that quiescence in lymphocytes is not a default state, but an actively maintained gene program. This program regulates intrinsic expression of quiescence factors in T lymphocytes. In addition to intrinsic mechanisms regulating T cell quiescence, CD4 + CD25 + regulatory T cells (Treg) naturally arising in the thymus, engage in the maintenance of immunological self-tolerance by preventing autoimmunity in vivo in a non cell-autonomous manner. Although there is still only a rudimentary knowledge of the molecular mechanisms that govern the activity of the intrinsic quiescence factors and the development of Treg, it is now clear that immune quiescence is regulated by constitutively ongoing active mechanisms.

Purpose of review Recent clinical successes in pancreatic islet transplantation have spurred a resurgent interest in this approach to treating insulin-dependent diabetes. There is an ongoing need to develop therapies that will induce immunologic tolerance to islet transplants. The purpose of this review is to evaluate recent progress in promoting long-term allograft survival and tolerance in animal models of islet transplantation. Recent findings An increasing variety of cell surface molecules involved in costimulation, adhesion, and cytokine responses have proved useful as therapeutic targets for inducing indefinite islet allograft survival in non–autoimmune-prone rodent models. In some cases, treatment regimens can result in the generation of active, donor-specific regulatory tolerance. However, the primary application of islet transplantation is for the restoration of euglycemia in recipients with autoimmune (Type Ia) diabetes. Spontaneously autoimmune nonobese diabetic mice represent a formidable barrier to allograft tolerance relative to non–autoimmune-prone strains. Importantly, nonobese diabetic mice harbor inherent genetic resistance to allograft tolerance that can be dissociated from the autoimmune phenotype. Thus, the autoimmune-prone recipient represents a particularly stringent model for islet allograft tolerance. Summary Although several approaches can induce tolerance induction to islet allografts in autoimmune-resistant strains of mice, relatively few therapies permit long-term islet allograft survival in nonobese diabetic or nonobese diabetic–related mouse strains. A primary future goal will be solving the inherent tolerance resistance in autoimmune-prone allograft recipients.

Infusion of donor bone marrow (DBM)-derived cells continue to be tested in clinical protocols intended to induce specific immunologic tolerance. Central clonal deletion of donor-specific alloreactive cells associated with mixed chimerism reliably produced long-term graft tolerance. In this setting, depletion of recipient T cells by antilymphocyte antibodies and subsequent repopulation by donor hematopoietic cells after donor bone marrow infusion (DBMI) are prerequisites for tolerance induction. Major advances have been made in animal models and in pilot clinical trials and the key questions with the future perspectives are presented in this article.

Clinical trials in transplantation have focused on improving outcomes and minimizing side effects associated with renal transplantation. Although immunologic tolerance, which means complete freedom from immunosuppressive drugs and maintenance of excellent long-term graft function, has seldom been achieved, in rare cases, this has been accomplished. Most current clinical trials focus on minimization of steroid use and calcineurin inhibitor use as a step toward tolerance, sometimes termed prope tolerance. Alternatively, new immunosuppressive agents are studied to assess their efficacy in preventing graft rejection with the anticipation of lesser toxicity. This review is organized in a case presentation style with actual cases from the University of Wisconsin kidney transplant experience presented as illustrations of actual scenarios in clinical trials. Lessons learned from these particular patients are then summarized with reference to the literature associated with the case. Using this format, some of the important lessons learned from clinical trials are outlined and directions for future study are noted. Clinical trials have permitted a dramatic improvement in graft survival and lowering of infectious and malignant side effects over the past 30-40 years. Nevertheless, we remain far from achieving true tolerance in patients for a variety of reasons.

Although many factors contribute to the clinical presentation and subsequent course of individuals with lupus nephritis, the formation of glomerular immune deposits is typically one of the initial events. In general, breakdown in immunologic tolerance leads to the production of autoreactive B and T cells that, either through direct infiltration and/or their secretory products, initiate inflammation. Immune deposition within glomeruli results in complement activation and recruitment of inflammatory cells, along with activation of endogenous renal cells. This inflammatory cascade leads to secretion of cytokines and chemokines, which in turn attract more infiltrating cells. Up-regulation of lymphoid-derived chemokines further enhance the cellular influx, augmenting inflammation and resulting in further tissue damage. The degree of inflammation is determined by the extent of this invasion along with both the systemic and local responses to the assault. This review focuses mainly on the contributions of pathogenic autoantibodies, autoreactive B cells to lupus nephritis, and potential immunologic therapies for lupus nephritis. Manipulation of both the cells and soluble mediators that initiate and perpetuate the disease are essential to suppressing autoreactivity and inflammation and preventing disease progression.

Aspergilli are saprophytic fungi widely distributed in nature, and because of their universal presence, all individuals are exposed to these organisms. Among the various members of this genus, Aspergillus fumigatus is associated with over 80% of all human syndromes caused by aspergilli. Saprophytic presence to extensive invasion with this organism has been reported with various intermediary conditions depending on susceptibility and immunocompetence of the host. 55 Other species that have been associated with aspergillosis include A. flavus, A. nidulans, A. niger, A. terreus, A. oryzae, and A. ochraceus. 55,57,72,88 The predominance of A. fumigatus over other aspergilli in human diseases may be due to its ability to grow at human body temperature, its small spore size, and its comparative resistance to oxidative killing. 7,8 Three main processes are involved in the interaction between aspergilli and the lung: colonization, hypersensitivity, and invasion. Colonization is usually a passive process but may lead to immunologic tolerance and local production of potentially toxic fungal metabolites. Allergy or hypersensitivity to Aspergillus antigens depends on the mode and frequency of exposures to the organism as well as on the host immune responses. Aspergillomas (fungus ball) develop in pulmonary cavities secondary to other lung diseases, such as histoplasmosis, tuberculosis, and so forth, whereas invasive aspergillosis is usually associated with underlying defects in host–defense mechanism. 7,8 In this article, we review the recent advances in the field of molecular biology and immunology of Aspergillus allergens and how this new information will lead to enhance the knowledge for better diagnosis and management of allergic aspergillosis.

Graft-versus-host disease (GVHD) is an underappreciated complication of autologous hematopoietic stem cell transplantation (AHSCT) that can affect the skin, gastrointestinal tract, and liver. The development of this rare condition is probably due to an impairment of immunologic tolerance that can occur spontaneously through T-cell dysregulation, possibly from intensive conditioning chemotherapy regimens, or intentionally through administration of cyclosporine in the hopes of promoting an antitumor response. We present the case of a 2-year-old boy with metastatic neuroblastoma who spontaneously developed autologous GVHD after AHSCT. Severe pruritus and an inability to taper his oral steroids without a disease flare marked his disease. Eventually partial relief was achieved with initiation of cyclosporine and a strict soak and smear protocol using topical triamcinolone 0.1% ointment.

Autoimmune neuropathies occur when immunologic tolerance to myelin or axonal antigens is lost Even though the triggering factors and the underling immunopathology have not been fully elucidated in all neuropathy subsets, immunological studies on the patients’ nerves, transfer experiments with the patients’ serum or intraneural injections, and molecular fingerprinting on circulating autoantibodies or autoreactive T cells, indicate that cellular and humoral factors, either independently or in concert with each other, play a fundamental role in their cause. The review is focused on the main subtypes of autoimmune neuropathies, mainly the Guillain-Barre syndrome(s), the Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), the Multifocal Motor Neuropathy (MMN), and the IgM anti-MAC-antibody mediated neuropathy. It addresses the factors associated with breaking tolerance, examines the T cell activation process including co-stimulatory molecules and key cytoldnes, and discusses the role of antibodies against peripheral nerve glycolipids or glycoproteins. Special attention is given to the newly identified proteins in the nodal, paranodal and juxtaparanodal regions as potential antigenic targets that could best explain conduction failure and rapid recovery. New biological agents against T cells, cytokines, B cells, transmigration and transduction molecules involved in their immunopathologic network, are discussed as future therapeutic options in difficult cases. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. (C) 2014 Elsevier B.V. All rights reserved.

Whereas a neonate is born is sterile, immediate exposure to its mother's mucosal surfaces allows it to acquire microflora, which plays an important role in defense against potential pathogens. This initial stimulus helps the immature immune system of the newborn to develop the capacity to respond with specific immunologic tolerance while avoiding the development of allergic and autoimmune disease. Breast-feeding provides nutritional and developmental, along with anti-infectious, advantages to the infant. The significant protection conferred by breast-feeding against varied infections such as acute and prolonged diarrhea, neonatal septicemia, respiratory tract infections, acute and recurrent otitis media, and urinary tract infections is observed worldwide. Human breast milk contains numerous components, including antibodies, cytokines, hormones, enzymes, and major proteins with multiple activities (microbicidal, tumoricidal, anti-inflammatory, autoimmune, etc.). Breast-feeding can strikingly reduce infant mortality, as well as the fertility of the breast-feeding mother. In this manner, breast-feeding provides significant benefits for lactating mothers and their offspring, in addition to society as a whole. © 2015 Elsevier Inc. All rights reserved.

Background and Purpose— Inflammatory and immune mechanisms can precipitate cerebrovascular thrombosis and hemorrhage. Immunologic tolerance can be induced to a specific antigen by intranasal instillation of that antigen. Lymphocytes tolerized in this way provide local immunosuppression on restimulation with the same antigen. This study tests whether tolerization of lymphocytes to E-selectin can suppress local vessel activation and prevent stroke. Methods— Spontaneously hypertensive genetically stroke-prone rats (n=113) were distributed among the following studies: comparison of ischemic infarcts/intraparenchymal hemorrhages after single or repetitive tolerization schedules with ovalbumin, E-selectin, or PBS; comparison of E-selectin tolerization– and PBS tolerization–induced suppression of delayed-type hypersensitivity in animals subsequently sensitized to E-selectin; and comparison of PBS–, ovalbumin–, and E-selectin–tolerized groups (after intravenous lipopolysaccharide to activate vessels) regarding transforming growth factor-β1–positive splenocyte counts, plasma interferon-γ levels, anti-human E-selectin antibodies, endothelial intercellular adhesion molecule-1, and anti–endothelial cell antibodies. Results— Nasal instillation of E-selectin, which is specifically expressed on activated endothelium, potently inhibited the development of ischemic and hemorrhagic strokes in spontaneously hypertensive stroke-prone rats with untreated hypertension. Repeated schedules of tolerization were required to maintain the resistance to stroke. Suppression of delayed-type hypersensitivity to E-selectin and increased numbers of transforming growth factor-β1–positive splenocytes showed that intranasal exposure to E-selectin induced immunologic tolerance. E-selectin tolerization also reduced endothelial activation and immune responses after intravenous lipopolysaccharide, as shown by marked suppression of intercellular adhesion molecule-1 expression, anti–endothelial cell antibodies on luminal endothelium, and plasma interferon-γ levels compared with the control condition. Conclusions— The novel findings in this study support further investigation of immunologic tolerance as applied to the prevention of stroke.

Oral administration of antigen induces antigen-specific immunologic tolerance, which is known to be dose-dependent. We studied the influence of continuous oral administration of nanogram and microgram doses of antigen on oral tolerance induction. Mice were continuously exposed to varying doses (1 ng−1 mg/day) of ovomucoid (OM) for a minimum of 30 days and a maximum of 100 days. It was possible to induce oral tolerance measured as reduced proliferation and antibody production (immunoglobulin (Ig)G1, IgG2a and total Igs) when mice were fed 1 mg of OM/day for 40 or 50 days. It was not possible to induce oral tolerance with daily doses of antigen of 10 µg or less. Feeding of 100 µg OM/day for 40 and 50 days and 1 mg OM/day for 30 days generated tolerization of Th2-dependent responses, but retained an intact response of Th1-dependent antibodies, whereas feeding of 1 mg OM/day for 40 and 50 days resulted in tolerization of both Th1- and Th2-antibody responses. The results presented here suggest that there is a threshold of microgram-doses below which oral tolerance cannot be induced, and that selective suppression of Th2 responses can be achieved by continuous microdose feeding, while an extension of the feeding dose or feeding period tolerizes both Th1- and Th2-dependent responses.

Apoptotic cell death contributes to the regulation of immunologic tolerance at a number of levels, beginning with negative and positive selection of T and B cells to establish an appropriately self-tolerant lymphocyte repertoire and extending to inducible immune privilege and peripheral tolerance. Apoptotic cells provide crucial signals for engulfment by professional phagocytes, inducing release of immunoregulatory cytokines, a function that cannot be performed by necrotic cells. Failure to induce apoptosis in immune cells can lead to hyperlymphoproliferation and an inability to moderate the immune response. Significant advances have been made in understanding of intracellular mechanisms of apoptosis and, perhaps more importantly, of the difference in effects of apoptotic cells and necrotic cells in inducing and maintaining immune homeostasis and tolerance.

A number of genetic alterations are required for malignant transformation. However, these mutations provide the source for tumor-associated antigens which can be recognized by cellular effectors of the immune system. Recent advances in tumor immunology - such as the improved understanding of antigen presentation as well as T cell activation - have opened new perspectives for cancer immunotherapy. The advantage of using tumor cell based vaccines is that these comprise the complete antigen pool of an individual tumor for activating polyclonal immune responses. However, the induction of antigen-specific immune responses is impaired by the fact that T cell activation is depending on additional nonspecific costimulatory signals provided by the antigen-presenting cell. The majority of solid human tumors does not express costimulatory molecules and is unable to deliver all signals required for T cell activation. In contrast, tumors often induce immunologic tolerance. Therefore, the introduction of genes encoding costimulatory molecules such as CD80 or cytokines is aimed at conferring the immunostimulatory potential of tumor cells. We have undertaken efforts at endowing a breast carcinoma cell line expressing at least seven known tumor associated antigens with immunostimulatory competence by CD80 gene transfer. In preclinical studies this cell line was demonstrated to induce specific immune responses. We designed a phase I/II trial to administer the CD80-modified cell line to patients with metastatic breast cancer to determine the toxicities of the vaccination protocol and nature of the vaccine-induced immune response.

The induction of immunologic tolerance to solid organ allografts is a subject of intense investigation because of the morbidity and mortality associated with standard immunosuppressive therapy. One method that is currently in clinical and preclinical testing involves the transient ablation of recipient T cells using polyclonal antithymocyte sera or monoclonal anti-CD4/CD8 antibody treatment, followed by the posttransplant administration of donor bone marrow cells or of donor peripheral lymphoid populations. Recent studies in our laboratory have shown that the molecular and cellular basis of the prolongation of graft survival by donor cell administration depends on the cellular compartment from which the donor cells were derived. We provide here a brief review of these data followed by new data suggesting that the mode of peripheral and central selection is also dependent on the source from which the donor cells were derived.

Pre- and post-transplant infusions of donor splenocytes treated with 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (ECDI-SPs) induce donor-specific tolerance and prolong rat renal allograft survival. However, proinflammatory cytokine production during peritransplantation negates the effects of ECDI-SPs. Therefore, we reasoned that blocking proinflammatory cytokines would promote long-term ECDI-SP-induced allograft survival. We therefore examined the effects of infusing ECDI-SPs alone or in combination with a short course of α1-Antitrypsin (AAT) on the long-term outcomes of a rat kidney allograft model. The data showed that ECDI-SPs + AAT promote renal allograft survival compared with ECDI-SPs alone. This effect was accompanied by expansion of Foxp3 + Tregs, enhanced alloantigen-specific Treg function, and modulation of expression levels of proinflammatory cytokines IL-1β, IL-6, TNF-α, and the anti-inflammatory cytokine IL-10. In conclusion, our strategy of combining ECDI-SPs and AAT provides a promising approach for inducing specific transplant tolerance.

In utero hematopoietic cell transplantation (IUHCT) is a non-myeloablative non-immunosuppressive transplant approach that allows for donor cell engraftment across immunologic barriers. Successful engraftment is associated with donor-specific tolerance. IUHCT has the potential to treat a large number of congenital hematologic, immunologic, and genetic diseases either by achieving high enough engraftment levels following a single IUHCT or by inducing donor specific tolerance to allow for non-toxic same-donor postnatal transplants. This review evaluates donor specific tolerance induction achieved by IUHCT. Specifically it addresses the need to achieve threshold levels of donor cell engraftment following IUHCT to consistently obtain immunologic tolerance. The mechanisms of tolerance induction including partial deletion of donor reactive host T cells by direct and indirect antigen presentation and the role of regulatory T cells in maintaining tolerance are reviewed. Finally, this review highlights the promising clinical potential of in utero tolerance induction to provide a platform on which postnatal cellular and organ transplants can be performed without myeloablative or immunosuppressive conditioning.

Induced pluripotent stem cells (iPSCs) hold the potential for future development of genetically identical tissues from almost any mature cell lineage. For clinical applications in cell therapy and transplantation, it may provide a means to one-day restore dysfunctional or damaged tissue without the need for immunosuppression. A recent study by de Almeida et al. published in the journal Nature Communications indicates that iPSCs may indeed elicit an immune response that evolves as cells differentiate toward maturity to induce a state of tolerance within a recipient animal. If these early findings hold true, it suggests a possible explanation for self-recognition of mature cells derived from iPSCs for use in future therapeutic interventions in transplantation such as cellular therapy or tissue engineering.

Chimerism is a state in which bone marrow hematopoietic stem cells from two genetically different animals coexist. To date, the approach has been used successfully to induce the state of immunologic tolerance in the animal models and is now being evaluated in clinical trials of both HLA-identical and HLA-mismatched living-donor kidney transplant recipients in some transplant centers with varying degrees of success. Although the results are promising, the current conditioning regimens are not optimal and longer-term follow up and multicenter studies are needed to ensure the efficacy and safety of the procedures.

Over the last few years a variety of conditioning regimens have been developed that allow allogeneic hematopoietic stem cell engraftment with significantly decreased transplant related-toxicity. While these reduced-intensity regimens have offered hope for patients with malignancies formerly not eligible for myeloablative transplantation due to excessive morbidity (older patients and patients with significant organ toxicity), the role of nonmyeloablative hematopoietic cell transplantation (NM-HCT) in children is unclear. A review of the available literature for pediatric and adult studies shows several malignancies in which approaches designed to limit long-term complications in children may be appropriate. In addition, NM-HCT may offer a safer approach for children with inherited disorders curable by marrow transplantation, such as immunodeficiencies, hemoglobinopathies, or storage diseases. Finally, use of this approach to establish partial donor chimerism may provide an immunologic platform that will allow specific cellular therapies, targeted gene therapy, or immunologic tolerance in solid organ transplantation.

Transfusions of UV-B--irradiated peripheral blood mononuclear cells (UV-B--PBMCs) from BALB/c (H-2(d)) mice into CBA (H-2(k)) mice can induce humoral immune tolerance to H-2(d) antigens, and the induced tolerance is partially mediated by negative regulatory PBMCs. To further identify which subset of spleen mononuclear leukocytes (MNLs) in the tolerant CBA mice is responsible for the negative regulatory activity, adoptive transfer experiments were conducted using spleen MNLs from the tolerant CBA mice. Results showed that only CD4(+) T cells could transfer the negative regulatory activity in a dose-dependent manner. This negative regulatory activity was significantly reduced when CD25(+) helper T cells were removed. Further study suggested that inhibition of IL-12 production by UV-B--irradiated PBMCs played a role in the induction of immune tolerance. In vitro study of the cytokine production profile by CBA CD4(+) T cells, after stimulation with gamma-irradiated BALB/c spleen cells, revealed an enhanced production of the type 2 T-cell cytokines after tolerance induction. Induction of tolerance also prevented the development of cytotoxic T cells in CBA mice against BALB/c MNLs. Adoptive transfer study suggested that the cellular immune tolerance was also mediated by CD4(+) negative regulatory T cells. The induced immune tolerance was nullified after 400 cGy sublethal gamma irradiation. These results suggest that the ex vivo study of cytokine production by T cells may be used to monitor tolerance induction and the selection of gamma radiation dose is critical for potential clinical application of the tolerance induced by UV-B--PBMCs. (Blood. 2001;98:1239-1245)

Opportunities for the treatment of melanoma with high-dose chemotherapy have been inadequately explored because of the failure of early studies to demonstrate an advantage for high doses of those agents with disease activity that could also be safely dose-escalated without excessive extramedullary toxicities. However, emerging concepts of tumor and transplantation immunology have recently coincided, providing the rationale for new strategies that exploit principles of allogeneic transplant to overcome immunologic tolerance and escape mechanisms in the tumor-bearing individual. It is hoped that this setting will provide an improved milieu for donor-derived immunotherapeutic intervention that takes advantage of shared tumor antigens with therapeutic potential shown in a variety of tumor vaccination studies.

Although short- and long-term results after organ transplantation have improved considerably in recent years, morbidity and mortality rates in graft recipients remain high. The induction of lifelong donor-specific tolerance would dramatically improve outcome after organ transplantation. Although many tolerance protocols have been successful in rodent studies, most of these approaches have failed when attempted in large animals or humans. Robust tolerance, in contrast, has been demonstrated with mixed chimerism regimens not only in rodents but also in large animal models, including non-human primates. Furthermore, mixed chimerism protocols have been developed that would be feasible in cadaveric, and thus in thoracic, transplantation. The induction of mixed hematopoietic chimerism is therefore an attractive experimental approach for development of clinical tolerance protocols. One of the obstacles to widespread clinical application of this concept is the remaining toxicity of the host conditioning. Recent advances, however, have led to substantially milder protocols that could become clinically acceptable in the foreseeable future. This article provides a short overview of the basic mechanisms by which immunologic tolerance may be induced, describes the concept of mixed chimerism as a promising approach for clinical tolerance induction, and reviews recent progress in developing clinically feasible mixed chimerism protocols.

This paper will serve as a contribution to the current reassessment of the relative roles of clonal selection and regulation in specific immunologic tolerance. We review basic studies in the Waksman laboratory that first established the importance of the thymus in tolerance and the possible contribution of regulatory cells generated in the thymus to self-tolerance. Experimental evidence is presented to suggest that there exists a wide range of immunoregulatory mechanisms, many of which deserve more intensive investigation in relation to the tolerance question. These include regulation based on idiotype-specific recognition, multiple forms of immune deviation, two well-described and quite distinct forms of T-cell receptor alphabeta "suppressor cell", and several regulatory systems involving multiple cells acting in concert. We do not comment on more recently described regulatory cells, such as certain gammadelta T-cell subsets, natural killer T cells, CD4-CD8- T cells, and others. Basic studies in our laboratory and in other laboratories pointed to antigen-presenting cells (APC) generated in the thymus as possible mediators of tolerance. Certain cytokines, first described in our laboratory, including lymphotoxin and the "inhibitor of DNA synthesis" produced by T cells and interleukin-1 produced by macrophages, also may act as significant components of regulatory systems. The rapid entry of exogenous and self-antigens into the thymus and the free migration of specific regulatory T cells and of APC in both directions between thymus and periphery are also stressed.

BACKGROUND Intravenous injection of soluble antigen has been reported to induce immunologic tolerance through a variety of mechanisms including T-cell deletion, anergy, and suppression. To clarify the reported discrepancies, we studied mechanisms of intravenous tolerance to a defined transgenic minor transplantation antigen in mice. METHODS Wild-type C57BL/6 (B6) mice or congenic B6 B-cell knockout mice were made tolerant to beta-galactosidase (beta-gal). Clinical tolerance was assessed by placement of B6 beta-gal transgenic (tg) and third-party skin grafts. In vitro analysis of T- and B-cell immunity and in vivo treatment with anti-TGFbeta antibodies were used to define mechanisms of induced tolerance. RESULTS Intravenous injection of beta-gal induced true immunologic tolerance to beta-gal tg skin in wild-type but not in B-cell-deficient recipients, suggesting that antigen presentation by B cells was required for the effect. The tolerogenic manipulation primed a population of CD4+, beta-gal-specific, TGFbeta-producing T cells. Although evidence for both anergy and suppression were observed, subsequent data demonstrated that TGFbeta was a critical immunoregulatory mediator of the tolerant state: neutralizing anti-TGFbeta antibodies fully prevented the induction of tolerance to B6 beta-gal tg skin grafts. Second male beta-gal tg grafts placed onto female recipients that were previously made tolerant to female beta-gal tg skin were rapidly rejected, however, suggesting that this TGFbeta-induced tolerance could not be linked to additional antigenic determinants. CONCLUSIONS The studies demonstrate a critical role for TGFbeta in mediating tolerance after intravenous injection of antigen but additionally raise concerns about the stability of this tolerant state.

There is accumulating evidence that T-cell-mediated dominant control of self-reactive T-cells contributes to the maintenance of immunologic self-tolerance and its alteration can cause autoimmune disease. Efforts to delineate such a regulatory T-cell population have revealed that CD25+ cells in the CD4+ population in normal naive animals bear the ability to prevent autoimmune disease in vivo and, upon antigenic stimulation, suppress the activation/proliferation of other T cells in vitro. The CD25+ CD4+ regulatory T cells, which are naturally anergic and suppressive, appear to be produced by the normal thymus as a functionally distinct subpopulation of T cells. They play critical roles not only in preventing autoimmunity but also in controlling tumor immunity and transplantation tolerance.

Background Although transplantation of musculoskeletal allografts in humans is technically feasible, the adverse effects of long-term immunosuppression subject the patient to high risks for correcting a non-life-threatening condition. Achieving immunologic tolerance to musculoskeletal allografts, without the need for chronic immunosuppression, could expand the clinical application of limb tissue allografting. Tolerance to musculoskeletal allografts has been accomplished previously in miniature swine in our laboratory. Although stable, mixed chimerism has been suggested as the mechanism underlying long-term tolerance in a rat limb model, the mechanism of this tolerance induction has not been established. This report explores the possible relationship between hematopoietic chimerism and tolerance to musculoskeletal allografts in swine. Methods Twelve miniature swine underwent vascularized musculoskeletal allograft transplantation from histocompatibility complex (MHC) matched, minor antigen-mismatched donors. Eight animals received a 12-day coprse of cyclosporine, one of which was excluded due to subtherapeutic levels. Four recipients were not immunosuppressed. Serial biopsies to assess graft viability and flow cytometry to assess chimerism were performed. Donor and third-party skin grafts were placed on recipients with surviving allografts greater than 100 days to validate tolerance. Results Both groups developed early peripheral chimerism, but this chimerism became undetectable by postoperative day 19 in the cyclosporine group and by day 13 in the control group. Animals receiving cyclosporine developed permanent tolerance to their allografts, whereas those not receiving cyclosporine rejected their allografts in 6-9 weeks. Animals demonstrating tolerance to their bone allografts also demonstrated prolonged donor skin graft survival. Conclusions Induction of tolerance to musculoskeletal allografts can be achieved in the MHC matched swine. Although hematopoietic chimerism is present in the immediate postoperative period, persistent, long-term chimerism does not seem to be necessary for maintenance of such tolerance.

Recently, an association between hepatitis B virus (HBV) genotype and clinical characteristics has been identified. Of special interest is the recent increase of acute hepatitis B (AHB) genotype A observed in urban areas of Japan. To determine the clinical characteristics associated with AHB genotype A, we compared admission serum levels of alanine aminotransferase, total bilirubin, and HBV markers for patients infected with AHB genotype A (A group) and AHB genotypes B or C (non-A group). Serum level of total bilirubin was significantly higher in the A group than in the non-A group. Serum titers of HBV-DNA and HBe antigen were also significantly higher in the A group, and these may be related to the production of certain types of HBe antigen in genotype A HBV while the other genotypes produce only a single variant of the antigen. Although patients in the non-A group did not develop to chronic hepatitis, 3 of 11 patients in the A group progressed to chronic hepatitis, suggesting that serum HBe antigen promotes immunologic tolerance to persistent viral infection.

Summary Though it has not been described by the HIV1-AIDS consensual thinkers, we propose the thesis according to which some immunocyte populations or their interactions can achieve tolerance or split immunologic tolerance in patients suffering from this disease. The proposed concept is based on data registered: 1) after Langerhans cell local injury by UV irradiation in their physiologic localisations, the skin and mucosae; and 2) after systemic infections of dendritic cells by immunosuppressive viruses, including some animal retroviruses, measles, lymphocytic choriomeningitis viruses, and HIV1. We can describe both types or manifestations concerning local UV injury and systemic viral infection combined in an AIDS patient, who received a PUVA irradiation before and at the beginning of his virostatic treatment, which he has now successfully received for eight years. The conditions of this patient differ from those of non-UV victim patients of the cohort to which he belongs, for two reasons: 1 ) the numbers of both his CD4+ and his suppressor T cells have been reduced to near 0 after UV irradiation; and b) his viral load, which has been exponentially reduced, has not reached, after eight years, the asymptotic part of the VL curve, characterized by PCR non-assessable viral load, which the non-UV victims of the cohort have reached. We wonder if, in this patient, there do not coexist two sorts of immunologic phenomena: 1) one bound to CTL, the numbers of which are increased, whose cytotoxicity is added to the virostatic action; and 2) one bound to the virus attack restriction by an immunologic tolerance. Contrary to the cohort controls, in whom an allogenic skin graft was only accepted for 20 days, the graft of the same donor has been tolerated in the UV victim patient for 70 days. This patient will be discussed in the second part of this editorial: the first part is devoted to the description of several conditions in which Langerhans cell injury by UV, or dendritic cell infections by measles, lymphocytic choriomeningitis viruses or animal retroviruses are followed, not only by immunodepression manifestations, but by immunologic tolerance.

The phenomena of T cell–mediated suppression in immunologic tolerance have been controversial and remain an exciting area of active research. An approach from the analysis of autoimmune-preventive activity of normal T cells is now revealing a unique regulatory T cell population dominantly engaged in the maintenance of immunologic self-tolerance. Production of such regulatory T cells can be another key function of the thymus in mediating self-tolerance. Recent research has also revealed that a part of the suppressive phenomena can be attributed to immunosuppressive cytokines secreted by particular types of effector T cells. Therefore, more than one population of regulatory T cells seem to be engaged in the maintenance of self-tolerance and these populations function in different ways—some are locally induced as a result of immune responses, while others are naturally produced. Further characterization of the function and development of these regulatory T cells will contribute to our understanding of immunologic self-tolerance as an acquired process and of the cause and mechanism of autoimmune disease. Manipulation of regulatory T cells will lead to new strategies for the treatment or prevention of autoimmune disease, transplant rejection, and cancer.*E-mail: shimon@frontier.kyoto-u.ac.jp

Transplants of hematopoietic stem cells from unrelated donors have become feasible for a growing population of patients with hematologic malignancy. More than 2,000 patients with acute and chronic leukemia, lymphoma, myeloma, and myelodysplasia are transplanted each year worldwide using marrow or blood stem cells from unrelated volunteers. Many patients have achieved complete immunologic tolerance and have become long-term survivors. The probability of finding a suitable donor has increased, because of the expansion of the network of registries containing more than 5 million HLA-typed donors worldwide. The selection of compatible donors has become more effective, thanks to the discovery of new HLA alleles and the development of precise and efficient HLA typing methods using DNA technology. Prophylaxis of viral and fungal infections has decreased morbidity and improved survival. The availability of more selective immunosuppressive agents provides the opportunity to decrease treatment-related toxicity and graft-versus-host disease.

The evolution of clinical transplantation has hinged on 2 seminal turning points. The first was the demonstration in 1953 by Billingham, Brent, and Medawar that chimerism-associated tolerance could be induced deliberately in neonatal mice by infusing adult donor hematolymphopoietic cells. This discovery escalated in a straight line over the next 15 years to successful bone marrow transplantation in humans. The second turning point was the demonstration that organ allografts could self-induce tolerance under an umbrella of immunosuppression, or in some species without immunosuppression. Unfortunately, it was incorrectly concluded by most immunologists and surgeons that bone marrow and organ engraftment involved different immune mechanisms. In a derivative error, it became widely believed that the tolerogenicity of the liver differed fundamentally not only from that of bone marrow but also from that of other whole organs. These errors became dogma and were not corrected until low level donor leukocyte chimerism was found in humans and animals bearing long surviving liver, kidney, heart, and other kinds of allografts. With successful bone marrow transplantation, the trace population consisted of recipient rather than donor leukocytes. Thus, the consequences of organ and bone marrow engraftment were mirror images. From these observations, it was proposed that the engraftment of all kinds of organs as well as bone marrow cells (BMC) involved host versus graft (HVG) and graft versus host (GVH) reactions with reciprocal induction of variable degrees of specific non-reactivity (tolerance). The maintenance of the tolerance was an active and ongoing process requiring the persistence of the transplanted fragment of the donor immune system. The immune responsiveness and unresponsiveness to both organ and bone marrow allografts are thought to be governed by the migration and localization of leukocytes. The clarifying principles of transplantation immunology that have emerged from the chimerism studies are relevant to the adaptive immune response to microbial, tumor, allogeneic, and self antigens. These principles should be used to guide efforts to systematically induce tolerance to human tissues and organs, and perhaps ultimately to xenografts.

Immune-mediated mechanisms are involved in the pathogenesis of cardiomyopathies. In this study, we investigate which pattern of immune response (Th1 or Th2) lies behind these diseases by analysing the basic cytokines secreted from PHA-cultured T lymphocytes and determining what differences, if any, exist between dilated cardiomyopathy (DMC) and hypertrophic cardiomyopathy (HCM). Two groups of patients were studied: 10 patients with DCM and 10 patients with HCM. Age- and sex-matched healthy individuals were used as controls. PHA-cultured T lymphocytes in the presence or absence of different myocardial antigen (MA) concentrations were measured. Interleukine-2 (IL-2), Interleukine-6 (IL-6) and Interferon-gamma (IFN-gamma) levels were measured in culture supernatants by an ELISA method. At the same time, delayed-type hyperactivity (DTH) against the same antigenic preparation was measured by the leukocyte migration inhibitory index technique. Patients were subdivided into DTH-positive and DTH-negative and re-examined for IL-2 cytokine expression. IL-6 levels were found to increase both in the presence and in the absence of MA in the patient groups compared to the controls. IL-2 levels were decreased in both groups, in an antigen dose-related manner. Anergic patients showed a further reduction in IL-2 levels for both groups of patients. IFN-gamma remained unaffected in the patient groups. Almost half of the patients exhibited anergy to the DTH reaction against MA. We conclude that, upon antigenic stimulation, the initially mounted immune response (increased IL-6) is somehow blocked/switched off in patients, resulting in an immunologic tolerance/unresponsiveness to MA (IL-2 decreased, IFN-gamma unchanged). Finally, increased IL-6 could lead to a perpetuation of immunologic injury through the release of oxygen-free radicals with a cytotoxic effect on the myocardium. We hypothesize an antigen-related, defective macrophage-Th1 cell reaction, which accounts for the differences in the IL-2 profile between the DCM and HCM groups, that might cause local immune responses to lead to immunosuppression (immune tolerance effect), thus contributing to the pathogenesis of cardiomyopathies.

An understanding of the immunologic basis of atopy helps one to devise strategies for allergy prevention. A duality of T-helper cells (i.e., Th1 and Th2) exists in rodents and probably also in humans. 69 Th1-like cells are linked to a lymphokine profile that stimulates cell-mediated immunity while suppressing IgE antibody formation, whereas Th2-type cells are linked with IgE antibody formation, the appearance of mast cells and eosinophils, and atopic diatheses. A hypothesis of IgE immunoregulation suggests that the magnitude of the IgE reponse to antigen-specific immune responses to persistent allergens depends upon the relative balance between antigen-specific Th1 and Th2 cells represented in relevant T-memory populations. 36 Repeated allergen exposure by immunologically naive rat pups from low IgE responder strains usually results in transient and low-level IgE antibody responses. Low IgE responders are typically Th1-dominant, whereas high IgE responders are Th2-phenotype dominant. This form of genetically determined immunologic tolerance induction and Th profiles are markedly influenced by a range of environmental factors, including chemical air pollutants and also infection. Exposure to infections and microbial adjuvants simultaneously with allergen or large doses of antigen suppresses the Th2 response in high responder rat pups. In contrast, a switch towards a Th2 response occurs in low responder pups with simultaneous exposure to allergen and air pollutants (e.g., tobacco smoke). Cytokine regulation of IgE synthesis in humans is consistent with this animal model. The human immune system appears to begin responding to ubiquitous food and inhalant allergens in the early perinatal period. High-atopic risk infants (infants from allergic families or with elevated cord blood IgE levels) have less capacity to produce interferon gamma (IFN-γ), and thereby a less efficient induction of Th1-type responses. 80 Furthermore, infants developing allergic disease by 18 months of life have elevated levels of interleukin (IL)-4, the major cytokine from Th2-type cells. 2 In addition, epidemiologic studies indicate that certain recurrent infections (varicella and tuberculosis) in infancy protect against sensitization to inhalant allergens by switching the Th balance to Th1-type cells. The kinetics of humoral antibody responses to food and inhalant antigens/allergens in infants and young children support the previous animal model. IgG antibodies to ubiquitous environmental antigens appear very early in life and remain detectable in serum from the majority of both atopic and normals throughout life. In contrast, the humoral IgE antibody response to environmental allergens is markedly different. Serum IgE levels to foods are commonly detected in atopic and nonatopic infants during the first year of life, although the magnitude of the response is higher and of longer duration in the atopic. 30 In most children, however, these initial IgE responses to foods are terminated spontaneously by 2 to 4 years of age, leaving intact IgG responses to the same food antigens that persist into adulthood. Immunologic intervention that switches high-risk newborns to a Th1 from a Th2 bias may be a fruitful avenue for allergy prevention (Fig. 1). This issue is discussed later. Clinical Aspects of Allergy Prevention Food allergy occurs in about 4% to 6% of children, is increasing in prevalence over the past decade, and represents a major burden to our young. The natural history of food allergy documents that allergies to cow's milk (CM), egg, and soy frequently remit, whereas allergies to peanut, nuts, and fish typically persist into adulthood, although exceptions exist. Food allergen avoidance subsequent to sensitization and manifestation of symptoms appears to hasten tolerance; however, the immunologic mechanism responsible for tolerance to one food group and not another is poorly understood. Identification and characterization of allergens and determination of B- and T-cell epitopes has provided an opportunity to better define these mechanisms. Identifying and developing effective strategies to prevent food allergy and other atopic diseases represents a high priority for medicine at this time because of the unbridled increase in their prevalence and morbidity. Immunologic engineering holds the greatest promise for allergy prevention in the not-too distant future, but environmental strategies that promote food and aero-allergen avoidance provide an avenue for prevention at the present time. Such efforts rely actively on reducing the allergenic load and exposure of atopic-prone infants and children to allergens. Systematically, allergy prevention may be directed at three potential stages: (1) primary prevention that inhibits IgE and other immunologic sensitization, (2) secondary prevention that abrogates disease expression subsequent to immunologic sensitization, and (3) tertiary prevention that suppresses symptoms after and despite disease expression (Fig. 2). 86 Strategies to promote allergen avoidance have met with great difficulty at all of these stages because of limitations in knowledge, societal compliance, and resources. Whereas primary prevention of allergy is optimal, secondary prevention may be a necessary adjunct to the former or serve as a fall-back option to families disinterested in allergy prevention until real markers or indicators of atopic risk are identified in their offspring. Tertiary prevention, the realm most familiar to practicing allergists and pediatricians, is generally instituted after manifestations of allergy are recognized, often, long after clinical disease has been expressed and suffering experienced (see Fig. 2). These stages must be integrated into any program that attempts to prevent the consequences of atopic disease. The success of allergy prevention strategies must be judged by the degree to which they satisfy specific criteria, including the ability to (1) predict the high-risk infant and child, (2) demonstrate effectiveness of the intervention strategy, (3) utilize acceptable interventions, (4) minimize adverse effects, and (5) generate cost-effective outcomes. To date, no allergen avoidance intervention study has met all of these prerequisites. A critical period exists early postnatally and possibly prenatally in which the genetically programmed atopic-prone infant may be at an increased risk to become sensitized to exposed or encountered allergens. As such, prompt perinatal identification of such at-risk neonates is important to institute preventive efforts early. Many genetic linkage markers and immunologic factors or markers (e.g., elevated cord blood and infancy IgE levels, egg-specific IgE, lower IFN-γ or IL-4 ratio) have been determined to be significantly associated with the subsequent development of allergic disease. Presently, none of these markers possess greater predictive value than atopic family history for the practical screening of at-risk neonates for allergy prevention. 3 The extent to which atopic risk factors are amenable to preventive modulation depends upon the factor. Factors such as atopic heredity, male gender, and nonwhite ethnicity cannot be modulated, whereas factors such as birth month, low socioeconomic status, and urban residence require great effort to modulate. Other risk factors conducive to and fruitful for modulation include (1) low atopic health consciousness; (2) early introduction of allergenic foods during infancy; (3) high household dust-mite, cockroach, and dander levels; and (4) environmental pollution and environmental tobacco exposure (ETS). A strategy that identifies high-risk newborns and infants and directs preventive measures at all three stages of allergy prevention is depicted in Figure 2.

Oral administration of antigen induces an antigen-specific immunologic tolerance and many studies are being carried out to apply this phenomenon to the treatment of autoimmune diseases. In this study, we investigated long-term Th1 and Th2 tolerance in mice given a high dose of orally administered Ovalbumin (OVA). Feeding OVA to BALB/c mice suppressed OVAspecific IgG response and the degree of inhibition was dose-dependent in the range of 2.5∼250 mg. Moreover, the state of tolerance established by prior feeding of high dose of OVA was present after 26 weeks. Interestingly, even though both Th subsets were tolerized significantly for a short period, the tolerizing effect was more pronounced and persistent in Th2-mediated immune responses. Thus we speculate that oral administration of a single high dose of OVA induces Th1- and Th2-tolerance by different mechanisms. Our findings could be important in the development of therapeutics for the treatment of autoimmune disease and allergy.

A growing body of experimental evidence demonstrates that synthetic peptides corresponding to linear sequences of MHC (HLA in humans) proteins have immunomodulatory effects in vitro and in vivo in animal models and in humans. Although the original concept was that these peptides inhibited antigen recognition at the MHC-T cell receptor interface via physical blockade, it is now clear that the mechanisms responsible for the myriad of functional effects are more complex. Recent findings show that some peptides affect signal transduction and cell cycle progression. Fragments of MHC molecules can dampen or downregulate immune responses via a variety of mechanisms. Some soluble MHC molecules or synthetic peptides are capable of inducing and maintaining immunologic tolerance in animals. This information suggests that synthetic peptides themselves or drugs mimicking their effects may represent a new class of immunotherapeutics.

Induction of long-term, antigen-specific immunologic unresponsiveness holds great promise for the treatment of many immune system-mediated diseases, including asthma, allergies, autoimmune diseases, and transplant rejection. Unlike current immunosuppressive treatments, immunologic tolerance therapies would affect only the undesired immune responses, leaving protective immunity intact. A variety of approaches to immunologic tolerance induction are being taken, reflecting the molecular and cellular complexity of immune system activation and regulation. The presentations summarized in this report represent promising strategies, some of which are being evaluated in advanced animal models and human clinical trials. Approaches presented include the following: interference with costimulatory signals in T-cell induction, T-cell receptor antagonism by altered peptides, exploitation of antigen-induced apoptosis to eliminate undesired T cells, opposition of inflammation by the induction of regulatory cytokines, induction of transplant tolerance by mixed chimerism, and deviation from deleterious allergic antibody responses by use of immunostimulatory DNA sequences. These multifaceted approaches are strongly supported by knowledge of basic immune mechanisms, which should facilitate the rational development of these therapies for controlling immune-mediated diseases.

Animal models have shown that oral administration of an antigen induces a specific immunologic tolerance to this antigen. Induction of such an oral tolerance has been well documented with intact proteins. The purpose of our study was to determine whether oral tolerance to cow's milk proteins (CMP) can be induced also with protein peptides contained in either partially hydrolysed or extensively hydrolysed cow's milk formulas. Five-week-old Sprague-Dawley rats were fed cow's milk formulas ad libitum before they were parenterally challenged with CMP. The modulation of specific IgE anti-CMP antibodies and intestinal mast cell stimulation were measured. Results showed that preventive feeding of rats with a partially hydrolysed cow's milk formula suppresses specific IgE anti-CMP antibodies as well as IgE mediated mediator release (rat mast cell protease RMCPII) from intestinal mast cells. An extensively hydrolysed cow's milk formula was unable to achieve the induction of such an oral tolerance. Our experiments show that selected peptides of CMP may induce a specific oral tolerance to CMP.

Complement component 3 (C3), a critical regulator of innate immunity, may also play a role in the regulation of cognate immunity, such as contact sensitivity responses. Because ultraviolet (UV) radiation also activates C3 in the skin, we determined whether the immunosuppressed state that results when a contact sensitizer is applied through UVB-exposed skin requires the presence and activation of C3. This question was addressed through the use of C3-deficient mice, blockade of C3 cleavage to C3b, and accelerated degradation of iC3b by soluble complement receptor 1 (sCR1). Both C3-modulated systems totally reversed the failure to induce a contact sensitivity response to dinitrofluorobenzene (DNFB) upon primary sensitization at the UV-exposed site, as well as immunologic tolerance to a second DNFB immunization through normal skin. Treatment with sCR1 reduced the infiltration of CD11b+ leukocytes into the epidermis and dermis of UV-irradiated skin but did not reverse the UV-induced depletion of epidermal class II MHC+CD11blo Langerhans cells. These data, taken together with previous results showing abrogation of locally induced UV immunosuppression by in vivo anti-CD11b treatment, suggest a novel mechanism by which ligation of the leukocyte β2 integrin, CD11b, by iC3b molecules formed from C3 activation in UV-exposed skin, modifies cutaneous CD11b+ cells such that skin antigen-presenting cells are unable to sensitize in a primary immune response, but actively induce antigenic tolerance.

The function of the secretory core gene product (HBeAg) of the human hepatitis B virus is unclear. It has been discussed that this protein may be passed from the mother to the fetus, where it might induce immunologic tolerance. Here we have examined this possibility with transgenic mice expressing high levels of HBeAg. Analysis of serum samples obtained from nontrangenic fetuses which developed in HBeAg-positive mothers showed no evidence that the HBeAg can pass the placenta. Moreover, direct examination of the HBeAg- and HBcAg-specific cytotoxic T-cell immune response of H-2 b mice which developed in either transgenic or nontransgenic mothers revealed no indication that mice which could have been exposed to the HBeAg in utero become tolerant to HBV core gene products. From these data we conclude that the placenta represents an efficient barrier for HBeAg transfer and that the HBeAg does not tolerize cytotoxic T cells, at least in mice of the H-2 b haplotype.

Major advances in the understanding of the immunologic process responsible for organ or cellular transplant rejection, a dramatic improvement in available immunosuppressive drugs, development of more sophisticated surgical techniques, and important progress in posttransplant intensive care over the last 30 years have led to a remarkable improvement in success following organ transplantation. Whereas excellent short-term survival of most transplanted organs is readily achieved, graft loss because of chronic rejection and the worsening problem of organ donor shortage remain major concerns in the field of transplantation. Recent advances in immunosuppressive drugs, induction of immunologic tolerance, and gene therapy strategies may help to prolong organ allograft survival in the future. Revised criteria for organ donation and xenotransplantation may one day solve the problem of organ supply. Today, as we approach the next millennium, we are optimistic that the elusive goal of immunologic tolerance will be achieved and perhaps applied to animal tissue. Such will certainly be the challenge for the next century.

The presence of microchimerism in the peripheral blood of solid organ graft recipients has been associated with long-term solid organ acceptance, immunologic tolerance, and less aggressive immunosuppressive therapy. Molecular biology assays are among the most sensitive methods to detect microchimerism, primarily to evaluate Y chromosome sequences in females as indirect evidence of circulating male nucleated donor cells. We screened for the presence of the SRY sequence region in peripheral blood of 13 female recipients of male kidney grafts: 5 living-related and 8 deceased grafts. 2 Only patients who received grafts from related living donors exhibited microchimerism. Five of 13 patients studied exhibited better graft outcomes, including the 4 who were positive for the SRY sequences.

Immunologic tolerance is a state of immune paralysis specific to a given antigen (the tolerogen) coexisting with the maintenance of normal immunocompetence towards other antigens. Anti-T cell monoclonal antibodies allow its induction in organ transplantation and autoimmune disease essentially through the stimulation of regulatory T cells. Very promising results obtained in animals have been recently confirmed in the human in recent-onset insulin-dependent diabetes mellitus with an anti-CD3 antibody (with long-term remission of the disease following a treatment of only six days). To cite this article: J.-F. Bach, C. R. Biologies 329 (2006).

To the Editor: Rosalyn Yalow, the inventor of radioimmunoassay, found that insulin treatments led to the production of antibodies against insulin.1 Initially, this phenomenon was thought to be due ...

Organ transplantation is useful for treating the end stage of organ failure. The induction of tolerance to the transplanted organ is essential for its long-term survival. Immunologic tolerance can be induced by immunosuppressive agents and mixed chimerism. Mixed chimerism is a state in which both recipient-and donor-derived blood cells remain in the hematopoietic system after allogeneic hematopoietic stem cells have been transplanted. Mesenchymal stem cells (MSCs), and immune cells such as dendritic cells and T-reg cells play an important role in the induction of tolerance. MSCs secrete cytokines, which modulate the immune response. In particular, they upregulate T-reg cell function and thereby induce tolerance. Intra-bone marrow-bone marrow transplantation recruits both donor-derived HSCs and MSCs, inducing persistent donor-specific tolerance without the use of immunosuppressants. In this review, we summarize the use of MSCs to induce tolerance in organ transplantation.

Objective The objective of this study was to determine if tobacco smoke (TS), a risk factor for cancers of the aerodigestive tract, may contribute to oral carcinogenesis, in part, by suppressing local immunity. Methods Mice were placed in Plexiglas holders in which they breathed TS through the nose and mouth for 1 hour daily for 21 days. Control mice breathed room air in the same manner. One day after the last exposure, mice were immunized by application of oxazolone to each buccal mucosa. Control mice were mock immunized by application of vehicle alone. Five days later, all mice were challenged on the ears with oxazolone, and 24-hour ear swelling assessed as contact hypersensitivity. Results Mice exposed to TS had a significantly smaller contact hypersensitivity response compared with controls. When subsequently reimmunized on the glabrous skin, mice originally primed through TS-exposed mucosa could not be fully immunized, indicating induction of immunologic tolerance by exposure to hapten through TS-perturbed mucosa. Immunocompetent mice exposed to TS in this manner and challenged by submucosal placement of a syngeneic malignant tumor had significantly increased tumor growth over time compared with controls. No difference in growth rate was observed when the experiment was performed with natural killer cell–deficient, SCID (severe combined immunodeficiency) mice. In addition, exposure of epidermal Langerhans cells in vitro to an aqueous extract of TS impaired their ability to undergo maturation and to present antigen to responsive T cells. Conclusions Immunologic changes induced in the oral cavity by exposure to TS may play a role in the development of oral cancers.

Vascularized composite allograft (VCA) transplantation can restore form and function following severe craniofacial injuries, extremity amputations or massive tissue loss. The induction of transplant tolerance would eliminate the need for long-term immunosuppression, realigning the risk–benefit ratio for these life-enhancing procedures. Skin, a critical component of VCA, has consistently presented the most stringent challenge to transplant tolerance. Here, we demonstrate, in a clinically relevant miniature swine model, induction of immunologic tolerance of VCAs across MHC barriers by induction of stable hematopoietic mixed chimerism. Recipient conditioning consisted of T cell depletion with CD3-immunotoxin, and 100 cGy total body irradiation prior to hematopoietic cell transplantation (HCT) and a 45-day course of cyclosporine A. VCA transplantation was performed either simultaneously to induction of mixed chimerism or into established mixed chimeras 85–150 days later. Following withdrawal of immunosuppression both VCAs transplanted into stable chimeras (n =4), and those transplanted at the time of HCT (n =2) accepted all components, including skin, without evidence of rejection to the experimental end point 115–504 days posttransplant. These data demonstrate that tolerance across MHC mismatches can be induced in a clinically relevant VCA model, providing proof of concept for long-term immunosuppression-free survival.