Mechanisms Of Immunological Tolerance Research Articles

Multi-Layered Mechanisms of Immunological Tolerance at the Maternal-Fetal Interface.

Pregnancy represents an immunological paradox where the maternal immune system must tolerate the semi-allogeneic fetus expressing paternally-derived Ags. Accumulating evidence over decades has revealed that successful pregnancy requires the active development of robust immune tolerance mechanisms. This review outlines the multi-layered processes that establish fetomaternal tolerance, including the physical barrier of the placenta, restricted chemokine-mediated leukocyte trafficking, lack of sufficient alloantigen presentation, the presence of immunosuppressive regulatory T cells and tolerogenic decidual natural killer cells, expression of immune checkpoint molecules, specific glycosylation patterns conferring immune evasion, and unique metabolic/hormonal modulations. Interestingly, many of the strategies that enable fetal tolerance parallel those employed by cancer cells to promote angiogenesis, invasion, and immune escape. As such, further elucidating the mechanistic underpinnings of fetal-maternal tolerance may reciprocally provide insights into developing novel cancer immunotherapies as well as understanding the pathogenesis of gestational complications linked to dysregulated tolerance processes.

The cutaneous virome: from virology to personalized medicine

The virome of the skin, defined as all viruses detected in the skin, represents a significant part of the microbiota. A much more recent discovery than the bacterial flora, the existence of the cutaneous virome has been revealed by recent metagenomic studies. The normal human skin virome is dominated by bacteriophages, Papillomaviridae, whose genomic diversity has proved extraordinary, and Polyomaviridae. Many yet unknown viral genomes within this virome await identification. The composition of the virome of the skin has been shown to be strictly individual and relatively stable over time, resulting from adaptation to everyone's genetics, lifestyle and mechanisms of immunological tolerance finely selected over the course of evolution. Yet little studied, the virome of the skin and all its interactions with other microbiota and the host are attracting growing interest. Indeed, constitutional or acquired alterations in the homeostasis between the commensal virome and the skin, ranging from sub-clinical viral dysbiosis to severe transformation of keratinocytes or adnexal cells, have been observed. These recent observations are stimulating the search for innovative solutions aimed at measuring or even modulating its pathological expression, with a view to personalized medicine.

ANCA vasculitis expands the spectrum of autoimmune manifestations of activated PI3 kinase δ syndrome.

Activated phosphoinositide 3-kinase δ syndrome (APDS) is a combined immunodeficiency with a broad clinical phenotype, including not only an increased propensity for sinopulmonary and herpesviruses infections but also immune dysregulation, such as benign lymphoproliferation, autoimmunity, and malignancy. Autoimmune complications are increasingly recognized as initial presenting features of immune dysregulation in inborn errors of immunity (IEIs), including APDS, so awareness of the spectrum of autoimmune features inherit within these disorders is critical. We present here a patient vignette to highlight cutaneous antineutrophil cytoplasmic antibody (ANCA) vasculitis as an underrecognized autoimmune manifestation of APDS. The genetic defects underlying APDS result in increased PI3Kδ signaling with aberrant downstream signaling pathways and loss of B- and/or T-cell immunologic tolerance mechanisms, which promote the development of autoimmunity. An understanding of the molecular pathways and mechanisms that lead to immune dysregulation in APDS has allowed for significant advancements in the development of precision-medicine therapeutics, such as leniolisib, to reduce the morbidity and mortality for these patients. Overall, this case and review highlight the need to maintain a high index of suspicion for IEIs, such as APDS, in those presenting with autoimmunity in combination with a dysregulated immune phenotype for prompt diagnosis and targeted intervention.

Mechanisms of immunological tolerance and their dysregulation in rheumatic diseases

The major tasks of the immune system are protection against infectious agents, maintaining homeostasis by recognizing and neutralizing noxious substances from the environment, and monitoring pathological, e.g. neoplastic tissue changes. It accomplishes these tasks through complex interactions of cellular and humoral components of the innate and adaptive immune system. This review article focuses on acentral problem of self versus non-self discrimination in the development of B and Tlymphocytes as carriers of adaptive immunity. During maturation of the lymphocytes in the bone marrow, large repertoires of lymphocyte receptors are randomly generated by somatic recombination, which as awhole have the capability of recognizing any foreign antigen. In order to reduce the implicit risk of autoaggressive immunity that might arise from evolutionary conserved structural motifs in self and foreign antigens, the adaptive immune system must provide redundant mechanisms (clonal deletion, anergy, quiescence and suppression) to eliminate or inactivate lymphocytes expressing highly avid receptors for autoantigens. Thus, the provision of costimulatory signals resulting in areduced activation threshold of potentially autoreactive anergic Tcells through infection, molecular mimicry, disrupted apoptosis regulation, altered "self" by post-translational modification, genetic changes in transcription factors with critical importance for thymic tolerance induction or signaling components of apoptosis can lead to adisruption of self-tolerance and the induction of pathogenic autoimmunity.

Helicobacter Pylori and Gastric Cancer Progression.

Gastric cancer (GC) remains the fifth most common malignant tumor and the third leading cause of cancer death, despite the decline in incidence and mortality worldwide over the past five decades. Currently, the roles of Helicobacter pylori (H. pylori) in the development of GC have been established. The effects of H. pylori are mediated through interactions of H. pylori pathogen-associated molecular patterns (PAMPs) with pattern-recognition receptors (PRRs) located on immune and epithelial cells. It is known that this interaction leads to the generation of reactive oxygen species (ROS), activation of the mechanisms of angiogenesis, epithelial-mesenchymal transformation (EMT), and immunological tolerance. Not all this excludes the possibility that H. pylori may have an effect not only on the induction, but also on the mechanisms of GC progression. In this review, we will consider the main structural elements of the innate immune system and the mechanisms of their interaction with H. pylori; the possible role of H. pylori in GC progression; relationship of H. pylori with clinical and pathological characteristics and prognosis of GC, as well as data on the effect of eradication therapy on long-term results of GC patient treatment.

Immunological Tolerance in Liver Transplant Recipients: Putative Involvement of Neuroendocrine-Immune Interactions.

The transplantation world changed significantly following the introduction of immunosuppressants, with millions of people saved. Several physicians have noted that liver recipients that do not take their medication for different reasons became tolerant regarding kidney, heart, and lung transplantations at higher frequencies. Most studies have attempted to explain this phenomenon through unique immunological mechanisms and the fact that the hepatic environment is continuously exposed to high levels of pathogen-associated molecular patterns (PAMPs) or non-pathogenic microorganism-associated molecular patterns (MAMPs) from commensal flora. These components are highly inflammatory in the periphery but tolerated in the liver as part of the normal components that arrive via the hepatic portal vein. These immunological mechanisms are discussed herein based on current evidence, although we hypothesize the participation of neuroendocrine-immune pathways, which have played a relevant role in autoimmune diseases. Cells found in the liver present receptors for several cytokines, hormones, peptides, and neurotransmitters that would allow for system crosstalk. Furthermore, the liver is innervated by the autonomic system and may, thus, be influenced by the parasympathetic and sympathetic systems. This review therefore seeks to discuss classical immunological hepatic tolerance mechanisms and hypothesizes the possible participation of the neuroendocrine-immune system based on the current literature.

The trend for transplant medicine development: induction of immune tolerance or regulation of immune response?

One of the greatest medical advances of the last century has been the introduction of organ transplantation. However, despite the considerable potential of transplantation as often the only therapy for severe diseases, the toxicity of immunosuppressive drugs supporting the transplant remains a serious problem for its further development. Modification of immune response in order to form tolerance to the transplanted organ can play an important role on the way to minimize immunosuppression. Successful cases of withdrawal of immunosuppressive drugs for medical reasons in kidney and liver transplantation recorded in the literature, as well as the results obtained in the process of modeling such a situation in the experiment, prove that achieving tolerance in organ transplantation is fundamentally possible.The aim of this review is to investigate the ways of immunologic suppression and fundamental mechanisms of immunologic tolerance in the field of transplantation and to review the latest clinical achievements in this respect.The review describes various approaches to the induction of central tolerance in solid organ transplantation implemented in the framework of the original clinical protocols. Special attention is given to a new direction in transplantation medicine – cell technologies providing tolerogenic effect by means of peripheral mechanisms activation, in particular due to activation of suppressor function of regulatory T cells.We draw the attention to the advantages and disadvantages of these two trends. Which of them is preferable? In which direction will scientific thought be developed for realization of the long-term goal of transplantologists: to avoid allograft rejection without affecting the physiological homeostasis of the body? Possible answers to these questions are discussed in this review.

Efficacy of the immune checkpoint inhibitor nivolumab in the treatment of advanced hepatocellular carcinoma with the exhausted possibilities of therapy with tyrosine kinase inhibitors

Hepatocellular carcinoma is one of the most formidable and deadly cancers. The limited possibilities of surgical methods of treatment as well as the formation of multiple drug resistance caused by the biological characteristics of both the liver tissue itself and tumor cells with their microenvironment determine the unsatisfactory indicators of relapse free survival and overall survival of patients. In addition, therapy with tyrosine kinase inhibitors, which has become the “gold” standard, has limited possibilities: a large number of side effects significantly reduce the quality of life and adherence to treatment in patients with hepatocellular cancer. The search for molecular biological targets, as well as new therapeutic agents that block these targets, does not always lead to positive results. Immunotherapy in this sense is a priority, having good tolerance, a low number of side effects, no need for additional testing of the patient’s biological material before starting treatment, high efficiency and a long response time. However, there are many unresolved questions about the duration of therapy, predicting its efficacy, the optimal combination of drugs or the use of monotherapy, the formation of priority subgroups of patients. Understanding the mechanisms of immune evasion, an ability that hepatocellular carcinoma possesses, – is the key to successful use of immunotherapeutic agents alone, in combination with tyrosine kinase inhibitors, antiangiogenic drugs or among themselves. This article provides an overview of data from clinical studies of modern drugs for the treatment of hepatocellular carcinoma and describes the mechanism of liver immunological tolerance as a possible predictive marker of sensitivity to immunotherapy. It seems promising to study the role of cells in the microenvironment of hepatocellular carcinoma for predicting the effectiveness of immunotherapy. The clinical example is used to demonstrate the successful experience of using the immunotherapeutic drug nivolumab in the treatment of hepatocellular carcinoma resistance to tyrosine kinase inhibitors. This is a classic example of duration of response to therapy, lack of reactivation of chronic viral hepatitis and controlled toxicity. All these indicators enable the clinician to consider immunotherapy as a priority option for the treatment of inoperable hepatocellular carcinoma.

HLA-G: An Important Mediator of Maternal-Fetal Immune-Tolerance.

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.

Sertoli cells: immunomodulatory properties, methods of isolation and culture

Due to complications caused by the inevitable use of immunosuppressive drugs in organ and cell transplantation, the use of natural mechanisms of immunological tolerance identified in animal and human organisms arouses interest. It has long been known that there are certain areas in them, including the testis, where immune reactions are virtually impossible. Our review focuses on the role of Sertoli cells that provide testicular immune privilege. Methods of isolation and cultivation of Sertoli cells are described and their potentials in biology and medicine are discussed.

Peptide-based immunotherapy against oxidized elastin ameliorates pathology in mouse model of smoke-induced ocular injury

PurposeAge-related macular degeneration (AMD), the leading cause of blindness in western populations, is associated with an overactive complement system, and an increase in circulating antibodies against certain epitopes, including elastin. As loss of the elastin layer of Bruch's membrane (BrM) has been reported in aging and AMD, we previously showed that immunization with elastin peptide oxidatively modified by cigarette smoke (ox-elastin), exacerbated ocular pathology in the smoke-induced ocular pathology (SIOP) model. Here we asked whether ox-elastin peptide-based immunotherapy (PIT) ameliorates damage. MethodsC57BL/6J mice were injected with ox-elastin peptide at two doses via weekly subcutaneous administration, while exposed to cigarette smoke for 6 months. FcγR−/− and uninjected C57BL/6J mice served as controls. Retinal morphology was assessed by electron microscopy, and complement activation, antibody deposition and mechanisms of immunological tolerance were assessed by Western blotting and ELISA. ResultsElimination of Fcγ receptors, preventing antigen/antibody-dependent cytotoxicity, protected against SIOP. Mice receiving PIT with low dose ox-elastin (LD-PIT) exhibited reduced humoral immunity, reduced complement activation and IgG/IgM deposition in the RPE/choroid, and largely a preserved BrM. While there is no direct evidence of ox-elastin pathogenicity, LD-PIT reduced IFNγ and increased IL-4 within RPE/choroid. High dose PIT was not protective. ConclusionsThese data further support ox-elastin role in ocular damage in part via elastin-specific antibodies, and support the corollary that PIT with ox-elastin attenuates ocular pathology. Overall, damage is associated with complement activation, antibody-dependent cell-mediated cytotoxicity, and altered cytokine signature.

Review of the immune mechanisms of preeclampsia and the potential of immune modulating therapy

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.

The diagnostic and prognostic value of serological markers of inflammatory bowel diseases (a literature review)

The diagnosis of inflammatory bowel disease (IBD) is based on a combination of clinical, endoscopic, histological, radiological and laboratory methods. However, conventional diagnostic methods are not always sufficiently informative in IBD, especially in the case of unclassified colitis, which necessitates the extension of standard diagnostic approaches. Currently, there is an actively search for non-invasive serological markers for early and differential diagnosis of IBD and for the assessment of activity and prognosis of Crohn's disease (CD) and ulcerative colitis (UC). Among the most interesting serological markers are anti-Saccharomyces cerevisiae antibodies (ASCA), anti-neutrophil cytoplasmic antibodies (ANCA), goblet cells antibodies (GAB) and pancreatic autoantibodies (PAB). The aim of this review is to assess the diagnostic and prognostic significance of ASCA, ANCA, GAB, PAB in CD and UC. The paper presents the summary of the data on the role of ASCA, ANCA, GAB and PAB in abnormalities of the immunological tolerance mechanisms to intestinal microflora and intestinal permeability in IBD. We discuss the results of the studies on the associations of ASCA with a complicated CD phenotype, its response to genetically engineered biological therapies, and the need for surgical intervention. The article describes the data on the association of ANCA to the risk of progression of left-sided UC to widespread (total) colon lesions resistant to hormonal therapy, and that of antibodies to DNA-lactoferrin complexes and proteinase 3 to primary sclerosing cholangitis. It has been noted that PAB may be a prognostic marker for ileocolitis, perianal lesions, extraintestinal manifestations and complicated CD, and GAB a predictor of total UC with chronic persistent course. It should be emphasized that combined determination of ASCA, ANCA, GAB and PAB is highly informative, compared to the isolated detection of autoantibodies, for the differential diagnosis and prognosis of CD and UC.

Targeting Dendritic Cells with Antigen-Delivering Antibodies for Amelioration of Autoimmunity in Animal Models of Multiple Sclerosis and Other Autoimmune Diseases.

The specific targeting of dendritic cells (DCs) using antigen-delivering antibodies has been established to be a highly efficient protocol for the induction of tolerance and protection from autoimmune processes in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), as well as in some other animal disease models. As the specific mechanisms of such induced tolerance are being investigated, the newly gained insights may also possibly help to design effective treatments for patients. Here we review approaches applied for the amelioration of autoimmunity in animal models based on antibody-mediated targeting of self-antigens to DCs. Further, we discuss relevant mechanisms of immunological tolerance that underlie such approaches, and we also offer some future perspectives for the application of similar methods in certain related disease settings such as transplantation.

173-LB: Two Cases of Autoimmune Type 1 Diabetes Mellitus (DM) with Prolonged Honeymoon Phase Leading to Partial and Complete Remission following Pregnancy

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 <6% for two and a half years. Case 2: 28 year old female G2P2002 with history of DM 1 since age 8 at 33w6d presented with preeclampsia requiring early induction. Her hospital course was complicated by severe hypoglycemia. She was discharged on 14% of her pre-pregnancy insulin dose and was still hypoglycemic while on only 3 units of glargine. 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.

Allergen immunotherapy and asthma.

Allergen immunotherapy (AIT) represents at present the unique disease-modifying treatment strategy for IgE-mediated allergic diseases. AIT can induce clinical improvement of allergic asthma, including reduced symptoms, medication use, and improvement of quality of life, with a long-lasting effect after cessation of treatment. Notably, the current asthma guidelines are now recommending sublingual immunotherapy as an add-on therapy for asthma in adults and adolescents with house dust mite allergy. Clinical indications of AIT, with particular reference to pediatric asthma, mechanisms of clinical and immunological tolerance to allergens, and the potential biomarkers predicting clinical response are discussed.

The JAK-STAT Signaling Pathway: A Novel Therapeutic Target for Unexplained Recurrent Implantation Failures

Unexplained recurrent implantation failure has become a public health problem especially in the context of a high cost, demand for assisted reproductive therapy and multiple therapy failures. It is attributed to the failure of immunological tolerance between the transferred embryo and the endometrium during assisted reproductive therapy cycles. Cytokines are surrogate mediators of immunological tolerance mechanisms. Since the synergistic interaction between individual cytokines is dynamic, perturbations in the cytokine crosstalk during embryo implantation is considered a major etiology for unexplained recurrent implantation failures. Genome Wide Association Studies suggests that most cytokines initiate their actions through receptor interactions that activate the JAK-STAT signaling pathways. Aberrations in the JAK-STAT signaling pathways have as well been shown to cause perturbations in cytokine crosstalk that result in diseases. We therefore propose the JAK-STAT signaling pathway a potential therapeutic target for unexplained recurrent implantation failures. Currently, many studies have recorded potential therapies in IL-6/JAK/STAT 3 pathway to treat many diseases but limited attention has been paid to unexplained recurrent implantation failures.

A Brief Review about the Role of Nanomaterials, Mineral-Organic Nanoparticles, and Extra-Bone Calcification in Promoting Carcinogenesis and Tumor Progression.

People come in contact with a huge number of nanoparticles (NPs) throughout their lives, which can be of both natural and anthropogenic origin and are capable of entering the body through swallowing, skin penetration, or inhalation. In connection with the expanding use of nanomaterials in various industrial processes, the question of whether there is a need to study the potentially adverse effects of NPs on human health becomes increasingly important. Despite the fact that the nature and the extent of damage caused depends on the chemical and the physical characteristics of individual NPs, there are also general mechanisms related to their toxicity. These mechanisms include the ability of NPs to translocate to various organs through endocytosis, as well as their ability to stimulate the production of reactive oxygen species (ROS), leading to oxidative stress, inflammation, genotoxicity, metabolic changes, and potentially carcinogenesis. In this review, we discuss the main characteristics of NPs and the effects they cause at both cellular and tissue levels. We also focus on possible mechanisms that underlie the relationship of NPs with carcinogenesis. We briefly summarize the main concepts related to the role of endogenous mineral organic NPs in the development of various human diseases and their participation in extra-bone calcification. Considering data from both our studies and those published in scientific literature, we propose the revision of some ideas concerning extra-bone calcification, since it may be one of the factors associated with the initiation of the mechanisms of immunological tolerance.

PF755 PD‐1 PATHWAY IS A KEY IMMUNOSUPPRESSIVE MECHANISM IN PATIENTS AFTER HAPLOIDENTICAL STEM CELL TRANSPLANTATION WITH TCR AB–DEPLETION

Background:Programmed cell death protein 1 (PD‐1) is a surface receptor expressed normally on distinct immune cells. It's well known PD‐1 pathway blockade is a negative immune regulatory mechanism that has detrimental effects on anti‐tumor immunity. Currently some studies have revealed different immune cells overexpressed PD‐1 as a predictable marker of leukemia relapse. On the other hand its assay after allo‐HSCT could be controversial due to alternative GVHD prophylaxis regimens that might affect PD‐1 expression, such as post‐transplant high dose Cyclophosphamide (PT‐Cy) or graft‐manipulated TCR αβ‐depletion are taken place if mismatched or haploidentical donors are used.Aims:To evaluate PD‐1 expression on bone marrow (BM) resident CD8+ memory T‐cell subsets in leukemia patients after allo‐HSCT and its input on immunosuppressive mechanisms of different GVHD prophylaxis regimens after allo‐HSCT.Methods:BM samples were collected from 56 leukemia patients with a median age of 33 years on day +30, +60 and +90 after allo‐HSCT. Detailed patients characteristics are presented in Table 1. Flow cytometry analysis was performed on BD FACS Canto II (Becton Dickinson, USA) to define CD8+ T‐memory subsets with PD‐1 expression: T‐naive and T‐stem cell memory (Tnv+Tscm) –CD45R0‐CCR7+CD28+; T‐central memory (Tcm) ‐ CD45R0+CCR7+CD28+; T‐transitional memory (Ttm) ‐ CD45R0+CCR7‐CD28+; T‐effector memory (Tem) ‐ CD45R0+CCR7‐CD28‐; T‐terminal effector (Tte) ‐ CD45R0‐CCR7‐CD28‐. Sysmex XE‐2100 was used to calculate absolute count of different CD8+ T‐ memory cell subsets with PD‐1. Mann–Whitney U test was used for nonparametric data analysis. A p‐value less than 0.05 was considered as significant.Table 1. Patients characteristics.Results:During all follow‐up period PD‐1 expression remains increased on all CD8+ T‐memory cell subsets after TCR αβ‐depletion compared to PT‐Cy–based and classical immunosuppressive regimen based on Cyclosporine+MMF. On day +30 we observe significantly higher expression of PD‐1 on Tnv+scm, Tcm, Ttm after TCR αβ‐depletion compared to PT‐Cy or classical regimen (p < 0.05). On day +60 PD‐1 is still overexpressed on Tnv+scm after TCR αβ‐depletion compared to PT‐Cy or classical regimen (p = 0.008). Moreover on day +60 and +90 PD‐1 expression is elevated on terminally differentiated CD8+ T cells (Ttm, Tem) after TCR αβ‐depletion comparing PT‐Cy or classical regimen (р<0.05). (Figure 1).imageSummary/Conclusion:According to our data PD‐1 is overexpressed on distinct subsets of BM resident CD8+ T‐memory cells after TCR αβ‐depletion during follow‐up period in first 3 months after allo‐HSCT. Since other immune signaling pathways are inhibited due to the other immunosupressive agents had been used, PD‐1 pathway seems to be a key mechanism of immunological tolerance after haploidentacal allo‐HSCT with TCR αβ‐depletion.image

Immunotherapy and Asthma in Children.

Allergen immunotherapy (AIT) is still the only disease-modifying treatment strategy for IgE-mediated allergic diseases, with consolidated evidence both in adults and children. AIT is effective in determining clinical improvement of allergic rhinitis and asthma, such as reduced symptoms, medication use, and improvement of quality of life, with a long-lasting effect after cessation of treatment. Results from recent clinical studies have implemented the evidence of effectiveness and safety of allergen immunotherapy for the treatment of allergic asthma, so that the current asthma guidelines now recommend sublingual immunotherapy as an add-on therapy for asthma in adults and adolescents with house dust mite allergy, allergic rhinitis, and exacerbations despite low-to-moderate dose ICS, with forced expiratory volume in 1 second more than 70% predicted. AIT may also reduce the risk of progression from allergic rhinitis to asthma in children and prevent the onset of new sensitizations, thus representing a potentially preventive method of treatment. The aim of this review is to present an updated overview of the clinical indications of AIT, with particular reference to pediatric asthma, of the mechanisms of clinical and immunological tolerance to allergens, and of the potential biomarkers predicting clinical response.