Improving outcome of allogeneic stem cell transplantation by immunomodulation of the early post-transplant environment

There has been great progress in understanding the alloresponse and the process of immune recovery after stem cell transplantation. Here, we highlight ways in which transplant outcome is determined by unique immunological features of the early post-transplant period that modulate the growth and function of the grafted donor T cells and stem cells. Better understanding of these early events and more detailed knowledge of the phenotype and function of transplanted donor cells facilitate strategies to optimize immune recovery, prevent graft-versus-host disease (GVHD) and boost immunity to viruses and leukemia. Approaches that optimize CD34 cell dose, techniques to remove GVHD-reacting T cells by T cell subset selection, suicide gene insertion or selective allodepletion, and the adoptive transfer of antigen-specific T cells have reached the stage of clinical trials. Furthermore, murine transplant experiments indicate ways to prevent GVHD while preserving immune function by depletion of na?ve cells, T cytotoxic 1 and T helper 1 cells, or by enrichment of regulatory T cells. Many of these approaches appear feasible in clinical transplantation and have yielded promising initial results, but proof that the goal of controlled selective immune reconstitution can be achieved is still awaited.     

The importance of 'Mechnikov's thorn' for an improved understanding of 21st century medicine and immunology: a view from the eye

In 1908, Ehrlich and Mechnikov shared the Nobel Prize in Medicine for their independent studies that set the scene for the modern understanding of innate and adaptive immunity. However, 20th century immunology thinking was dominated by aberrant adaptive immunity but this never adequately explained the full spectrum of inflammatory disease. This article draws on medical observations, from where immunology originated, and uses the example of the eye to illustrate how the integration of medicine and immunology leads to an improved understanding of inflammation against self. The spectrum of ocular inflammation can be viewed as either predominantly adaptive immune mediated (mostly the realm of immunology), or predominantly due to ocular tissues factors that lead to regional innate immune activation (the realm of medicine), or a variable interaction between the two. Just as the thorns that Mechnikov inserted into molluscs lead to localized innate immune activation; ocular inflammation can likewise be driven by non-immune factors that include tissue degeneration or microdamage. The present article emphasizes the importance of such factors in the initiation or phenotypic expression of ocular immunopathology allowing different immunological dogmas including self–non-self discrimination, immunological tolerance and immunoprivilege to be viewed in a different light. This scheme also leads to an appreciation of how the innate immune system may be the sole perpetuator of some ocular immunopathologies. We propose that this integrated view of medicine and immunology is crucial for understanding immunology from a translational angle and has implications far beyond ocular disease.     

Anamnestic responses of mice following Mycobacterium tuberculosis infection

The anamnestic response is the property of the immune system that makes vaccine development possible. Although the development of a vaccine against Mycobacterium tuberculosis is an important global priority, there are many gaps in our understanding of how immunological memory develops following M. tuberculosis infection or after BCG vaccination. In experiments designed to compare the anamnestic response of susceptible and resistant mouse strains, major histocompatibility complex-matched memory-immune C3.SW-H2(b)/SnJ and C57BL/6 mice both demonstrated better control of bacterial replication following reinfection with M. tuberculosis than control mice. Nevertheless, this memory response did not appear to have any long-term protective effect for either mouse strain. A greater understanding of the immunological factors that govern the maintenance of immunological memory following exposure to M. tuberculosis will be required to develop an effective vaccine.     

Antimicrobial responses of teleost phagocytes and innate immune evasion strategies of intracellular bacteria

During infection, macrophage lineage cells eliminate infiltrating pathogens through a battery of antimicrobial responses, where the efficacy of these innate immune responses is pivotal to immunological outcomes. Not surprisingly, many intracellular pathogens have evolved mechanisms to overcome macrophage defenses, using these immune cells as residences and dissemination strategies. With pathogenic infections causing increasing detriments to both aquacultural and wild fish populations, it is imperative to garner greater understanding of fish phagocyte antimicrobial responses and the mechanisms by which aquatic pathogens are able to overcome these teleost macrophage barriers. Insights into the regulation of macrophage immunity of bony fish species will lend to the development of more effective aquacultural prophylaxis as well as broadening our understanding of the evolution of these immune processes. Accordingly, this review focuses on recent advances in the understanding of teleost macrophage antimicrobial responses and the strategies by which intracellular fish pathogens are able to avoid being killed by phagocytes, with a focus on Mycobacterium marinum.     

Human self‐protein CD8+ T‐cell epitopes are both positively and negatively selected

The cellular immune system recognizes self‐epitopes in the context of MHC‐I molecules. The immunological general view presumes that these self‐epitopes are just a background, both positively and negatively selecting T cells. We here estimate the number of epitopes in each human protein for many frequent HLA alleles, and a score representing over or under presentation of epitopes on these proteins. We further show that there is a clear selection for the presentation of specific self‐protein types. Proteins presenting many epitopes include, for example, autoimmune regulator (AIRE) upregulated tissue‐specific antigens, immune system receptors and proteins with a high expression level. On the other hand, proteins that may be considered less “useful” for the immune system, such as low expression level proteins, are under‐presented. We combine our epitope estimate with single nucleotide polymorphism (SNP) measures to show that this selection can be directly observed through the fraction of non‐synonymous SNP (replacement fraction), which is significantly higher inside epitopes than outside.     

Tumor immune therapy: Lessons from infection and implications for cancer – Can IL‐7 help overcome immune inhibitory networks?

The complexity that the immune system faces in distinguishing pathogens from self is manifested by the intricate immunological networks involved in initiation, promotion and abrogation of immunity. A substantially more complex algorithm is required to distinguish normal from aberrant self (e.g. in the form of cancers), and this is reflected by the apparent inefficiency of our immune system to eradicate tumors; however, with our expanding insights into the molecular networks that govern immunity, we can now consider therapies that transiently promote immunity and/or antagonize immune inhibitory networks. Cytokines that normally function to regulate immune responses hold much therapeutic promise in this regard. Translating this promise to tangible outcomes will require a thorough analysis of how, when and in what way these cytokines should be used to take advantage of synergistic and complementary effects of current cancer therapeutics. In this review, we focus on IL‐7, as much data are emerging on the ability of this unique homeostatic cytokine to augment various anti‐tumor immunotherapeutic modalities.     

Translational mini-review series on Toll-like receptors: networks regulated by Toll-like receptors mediate innate and adaptive immunity

The Toll-like receptor (TLR) family provide key components of mammalian immunity and are part of the earliest surveillance mechanisms responding to infection. Their activation triggers the innate immune response, and is crucial to the successful induction of Th1/Th2-phenotyped adaptive immunity. Innate immunity was long considered to be non-specific and somewhat simple compared to adaptive immunity, mediated via the engulfment and lysis of microbial pathogens by phagocytic cells such as macrophages and neutrophils, and involving no complex protein-protein interactions. The emergence of the TLR field has contributed to a revision of our understanding, and innate immunity is now viewed as a highly complex process, in line with adaptive immunity. This review will give a brief overview of our current knowledge of TLR biology, and will focus on TLRs as key components in complex networks that activate, integrate and select the appropriate innate and adaptive immune responses in the face of immunological danger.     

Testicular defense systems： immune privilege and innate immunity

The mammalian testis possesses a special immunological environment because of its properties of remarkable immune privilege and effective local innate immunity. Testicular immune privilege protects immunogenic germ cells from systemic immune attack, and local innate immunity is important in preventing testicular microbial infections. The breakdown of local testicular immune homeostasis may lead to orchitis, an etiological factor of male infertility. The mechanisms underlying testicular immune privilege have been investigated for a long time. Increasing evidence shows that both a local immunosuppressive milieu and systemic immune tolerance are involved in maintaining testicular immune privilege status. The mechanisms underlying testicular innate immunity are emerging based on the investigation of the pattern recognition receptor-mediated innate immune response in testicular cells. This review summarizes our current understanding of testicular defense mechanisms and identifies topics that merit further investigation.     

Understanding the Complexity of the Immune System during Pregnancy

Progress in our understanding of the role of the maternal immune system during healthy pregnancy will help us better understand the role of the immune system in adverse pregnancy outcomes. In this review, we discuss our present understanding of the ‘immunity of pregnancy’ in the context of the response to cervical and placental infections and how these responses affect both the mother and the fetus. We discuss novel and challenging concepts that help explain the immunological aspects of pregnancy and how the mother and fetus respond to infection.     

Unravelling the nature of non-specific effects of vaccines—A challenge for innate immunologists

Epidemiological observations have shown that vaccines can influence morbidity and mortality more than can be ascribed to target-disease immunity. A growing number of immunological studies have helped identify possible biological mechanisms to explain these so-called nonspecific effects (NSE) of vaccines, including heterologous T-cell reactivity and innate immune memory or ‘trained innate immunity’, which involves epigenetic reprogramming of innate immune cells. Here, we review the epidemiological evidence for NSE as well as human, animal and in vitro immunological data that could explain these NSE, and discuss priorities for future epidemiologic and immunologic studies to further unravel the biology and optimize the benefits of current and new vaccines.     

CD4+CD25+调节性T细胞的胸腺发育机制

天然产生的CD4^＋CD25^＋调节性T细胞（Treg）细胞不仅是机体维持自身耐受的重要组成部分，而且在肿瘤免疫、抗感染免疫、免疫病理、移植物耐受、阻止自身免疫反应和维持机体免疫平衡等方面都具有重要意义。近年来关于发育机制的研究初露端倪，对这些细胞产生的组织定位、相互作用的细胞、参与发育的信号分子等都有较迅速的进展。对上述问题的了解，不仅有利于对Treg细胞本身的研究，同时，对于Treg细胞相关疾病的发病机制和防治研究也具有重要的理论意义和应用前景。     

Tacrolimus treatment for infertility related to maternal‐fetal immune interactions

Many approaches have been used to achieve successful pregnancies in patients with infertility, though existing treatments remain unsatisfactory in patients with infertility caused by abnormal maternal‐fetal immunity. However, our understanding of the immunological aspects of infertility has steadily progressed, aided by recent research into organ transplantation and cancer. The results of these recent analyses have led to the development and evaluation of several candidate immunological treatments, but the use of immunological treatments remains a novel approach. The current paper presents the hypothesis that tacrolimus may have potential as a candidate agent for the treatment of maternal‐fetal immunity‐related infertility.     

Intestinal stromal cells in mucosal immunity and homeostasis

A growing body of evidence suggests that non-hematopoietic stromal cells of the intestine have multiple roles in immune responses and inflammation at this mucosal site. Despite this, many still consider gut stromal cells as passive structural entities, with past research focused heavily on their roles in fibrosis, tumor progression, and wound healing, rather than their contributions to immune function. In this review, we discuss our current knowledge of stromal cells in intestinal immunity, highlighting the many immunological axes in which stromal cells have a functional role. We also consider emerging data that broaden the potential scope of their contribution to immunity in the gut and argue that these so-called “non-immune” cells are reclassified in light of their diverse contributions to intestinal innate immunity and the maintenance of mucosal homeostasis.     

Effects of helminths on the human immune response and the microbiome

Helminths have evolved sophisticated immune regulating mechanisms to prevent rejection by their mammalian host. Our understanding of how the human immune system responds to these parasites remains poor compared to mouse models of infection and this limits our ability to develop vaccines as well as harness their unique properties as therapeutic strategies against inflammatory disorders. Here, we review how recent studies on human challenge infections, self-infected individuals, travelers, and endemic populations have improved our understanding of human type 2 immunity and its effects on the microbiome. The heterogeneity of responses between individuals and the limited access to tissue samples beyond the peripheral blood are challenges that limit human studies on helminths, but also provide opportunities to transform our understanding of human immunology. Organoids and single-cell sequencing are exciting new tools for immunological analysis that may aid this pursuit. Learning about the genetic and immunological basis of resistance, tolerance, and pathogenesis to helminth infections may thus uncover mechanisms that can be utilized for therapeutic purposes.     

OPINION: Some Severe Maternal Diseases Might be Caused by Fetal‐Versus‐Maternal Disease (FVMD)

Citation Yan L, Zuo C, Wei D, Zhao X. Some severe maternal diseases might be caused by fetal‐versus‐maternal disease (FVMD). Am J Reprod Immunol 2010; 63: 189–192 Pregnancy‐related disease is a common challenging clinical problem. From our review and clinical experience, we hypothesize that many severe pregnancy‐related complications might be caused by a fetal‐versus‐maternal disease (FVMD), based on the fact that maternal disease is related to immunity and that fetal cells are present in maternal blood. Fetus is a semi‐antigen and can be considered as a tumor or graft. The pathophysiology of FVMD must be complex. We speculate it to be a three‐step process: impaired maternal immunological function, fetal T‐cell activation and injury of target organs. More experiments and research will be needed to prove our hypothesis.     

Immunologic characteristics of repeated spontaneous abortions

In 28 couples with spontaneous abortions, data of immunological investigations revealed an elevated frequency of HLA DR compatibility and immunological characteristics defining distinct patterns of immune responsiveness. In the half of women with recurrent spontaneous abortion (RSA) we observed a failure to develop a recognition response to paternal inherited fetal antigens expressed by the lack of classical evidence of in vivo allo-immunization such as antipaternal antibodies, and the absence of the inhibitors of cell-mediated immunity found in maternal blood during pregnancy. In few cases, the paternal cells are inefficient to elicit in vitro maternal cell-mediated lympholysis. In most women with a normal pregnancy occurring after spontaneous abortions or prior to RSA, an immune recognition response was evidenced by the presence of antipaternal antibodies and/or blocking factor acting on in vitro cell-mediated lympholysis. These observations support the hypothesis that immunological process could be the cause of some fetal losses of unknown etiology, through a defective or unsuitable maternal immune response.     

A model of development of acquired immunity to malaria in humans living under endemic conditions.

Malaria remains a significant global health problem. Most morbidity and mortality in an endemic setting is in children less than 5 years old, and increasing resistance to infection and disease with age is thought to reflect a slow, gradual acquisition of protective immunity. It is not clear if the semi-immune status of adults, in which parasites are present at below clinical threshold, is the result of cumulative exposure to Plasmodium falciparum or reflects an underlying difference between adult and infant immunity. Immuno-epidemiological studies of people living in malaria-endemic areas have not produced consistent examples of surrogate markers of protection. This gulf in our understanding of immunity to malaria may be addressed by novel application of an established murine model of immune regulation of blood stage infection. This exploits two examples of loss of immunity, selective immunosuppression in pregnancy, and waning of maternally transferred protection in neonates, to distinguish the immunological determinants involved in the radical transition between susceptible and resistant immune status. It is suggested that application of this unique model should significantly advance knowledge of how acquired immunity to malaria develops and is highly relevant to the pathogenesis of malaria in human pregnancy and the design of antimalarial vaccines for use in children.     

Schizophrenia, autoimmunity and immune system dysregulation: a comprehensive model updated and revisited

Recent investigation suggests a strong relationship between immunological effects and the pathophysiology of schizophrenia. Two prevalent approaches exist to this association. First, is more empirical a-priori research investigating immunological changes prevalent in schizophrenia and the second approach is more hypothesis-driven with analysis of immunological changes in schizophrenia based on known irregularities of the illness. The former approach is based upon three predominant lines of investigation including observations of a diffuse non-specific overactivation of the immunological response system, of a T-helper cell type 1 immune activation and of a T-helper cell type 2 immune activation in subgroups of schizophrenia patients. These last two theories suggest that a subgroup of patients with schizophrenia may demonstrate features of an autoimmune process, a theory supported by a growing database of investigation. The latter approach notes that many observations of immune dysregulation in schizophrenia overlap with central etiopathophysiological mechanisms as well as with clinical manifestations of the illness. Immunotherapy offers the opportunity to modify or re-balance the immune system and may become useful in management of the illness. Given that autoimmune mechanisms could interrupt neurotransmission, any process interfering with this disruption including therapeutic antibodies to involved cytokines, or with various other natural autoantibodies or immune system regulators, may become useful in the augmentative management of the illness.     

Immunological memory: What's in a name?

Immunological memory is one of the core topics of contemporary immunology. Yet there are many discussions about what this concept precisely means, which components of the immune system display it, and in which phyla it exists. Recent years have seen the multiplication of claims that immunological memory can be found in “innate” immune cells and in many phyla beyond vertebrates (including invertebrates, plants, but also bacteria and archaea), as well as the multiplication of concepts to account for these phenomena, such as “innate immune memory” or “trained immunity”. The aim of this critical review is to analyze these recent claims and concepts, and to distinguish ideas that have often been misleadingly associated, such as memory, adaptive immunity, and specificity. We argue that immunological memory is a gradual and multidimensional phenomenon, irreducible to any simple dichotomy, and we show why adopting this new view matters from an experimental and therapeutic point of view.     

白细胞介素2与调节性T细胞介导的免疫耐受

调节性T细胞(Tregs)可以诱导机体对自身抗原和过敏原产生免疫耐受,从而维持机体免疫稳态.白细胞介素(IL)-2是一种具有双向免疫调节作用的糖蛋白,其不仅可以增强免疫反应,更重要的是可以维持Tregs的稳定及其介导的免疫耐受.研究IL-2与Tregs功能活性及其介导的免疫耐受的关系对更好地了解免疫相关性疾病的发病机制和指导临床正确使用IL-2或IL-2拮抗剂具有重要意义.