Intestinal epithelial barrier and mucosal immunity

Intestinal mucosa integrates primary digestive functions with immune functions such as pathogen surveillance, antigen transport and induction of mucosal immunity and tolerance. Intestinal adaptive immunity is elicited in organized mucosa-associated lymphoid tissue (O-MALT) that is composed of antigen-presenting cells and lymphocytes and achieved by effector cells widely distributed in mucosa (diffuse MALT or D-MALT). Interaction between the intestinal epithelium, the O-MALT and the diffuse MALT plays a critical role in establishing an adequate immune response. In regions associated to O-MALT, lympho-epithelial cross-talks lead to acquisition of a specific epithelial phenotype that contributes to O-MALT organization and functionality. Beyond the expression of several innate immune functions, the intestinal epithelium may directly take up and present antigens due to the expression of major histocompatibility complex (MHC) and MHC-related molecules. A complex genetic program that will be outlined in the present review controls the development of immune functions of the intestinal epithelium. The effect of environmental signals on the modulation of this ontogenetic program during development and neonatal life, from bioactive components of amniotic fluid to lactation and bacterial colonization, will be discussed.     

Central role of dendritic cells in the regulation and deregulation of immune responses

Dendritic cells (DCs) play a critical role in orchestrating the innate and adaptive components of the immune system so that appropriate, coordinated responses are mounted against infectious agents. Tissue-resident DCs interact with microbes through germline-encoded pattern-recognition receptors (PRRs), which recognize molecular patterns expressed by various microorganisms. Antigens use PRR activation to instruct DCs for the appropriate priming of natural killer (NK) cells, followed by specific T-cell responses. Due to the central role of DCs in regulating the activation and progression of immune responses, minor imbalances in the feedback control of Toll-like receptor (TLR)-activated cells have been associated with autoimmunity in genetically prone individuals. We review here recent findings on the role of DCs in the priming of innate and adaptive immune responses and the possible involvement of DCs in inducing and maintaining autoimmune reactions.     

Intestinal epithelial barrier and mucosal immunity

The mucosal immune system acts as a first line of defense against bacterial and viral infections while also playing a crucial role in the establishment and maintenance of mucosal homeostasis between the host and the outside environment. In addition to epithelial cells and antigen-presenting cells (dendritic cells and macrophages), B and T lymphocytes form a dynamic mucosal network for the induction and regulation of secretory IgA (S-IgA) and cytotoxic T lymphocyte (CTL) responses. This review seeks to shed light on the pathways of induction and regulation of these responses and to elucidate the role they simultaneously play in fending off pathogen invasion and maintaining mucosal homeostasis.     

Natural killer cell activation by dendritic cells: balancing inhibitory and activating signals

Natural killer (NK) cells have originally been identified by their spontaneous cytolytic potential against tumor cells, which, however, might result from pre-activation due to prior pathogen exposure. Resting NK cells, on the contrary, require activation by bystander antigen-presenting cells to reach their full functional competence. In this review, we will summarize studies on how dendritic cells (DCs), the most potent type of antigen-presenting cell, communicate with human NK cells to activate them in secondary lymphoid organs and to integrate signals from activated NK cells at sites of inflammation for their own maturation. Furthermore, we will review aspects of the immunological synapse, which mediates this cross-talk. These studies provide the mechanistic understanding of how mature DCs can activate NK cells and survive to go on for the activation of adaptive immunity. This feature of DCs, to activate different waves of immune responses, could be harnessed for immunotherapies, including vaccinations.     

How plants recognize pathogens and defend themselves

Plants have an innate immunity system to defend themselves against pathogens. With the primary immune system, plants recognize microbe-associated molecular patterns (MAMPs) of potential pathogens through pattern recognition receptors (PRRs) that mediate a basal defense response. Plant pathogens suppress this basal defense response by means of effectors that enable them to cause disease. With the secondary immune system, plants have gained the ability to recognize effector-induced perturbations of host targets through resistance proteins (RPs) that mediate a strong local defense response that stops pathogen growth. Both primary and secondary immune responses in plants depend on germ line-encoded PRRs and RPs. During induction of local immune responses, systemic immune responses also become activated, which predispose plants to become more resistant to subsequent pathogen attacks. This review gives an update on recent findings that have enhanced our understanding of plant innate immunity and the arms race between plants and their pathogens. Received 24 June 2007; received after revision 18 July 2007; accepted 15 August 2007     

Generation of improved mucosal vaccines by induction of innate immunity

Vaccination is a highly effective means of disease prevention and has saved countless lives worldwide over the past 200 years. Traditional vaccines based on killed and attenuated organisms and inactivated toxins have constituted the majority of clinically used vaccines to date, but novel vaccines based on subunits of these organisms will be increasingly represented in future. In contrast to attenuated and whole cell vaccines, subunit vaccines do not generally contain immune-stimulatory components and are poorly immunogenic. As a result, new, potent and safe adjuvants and delivery systems are needed to enhance the immunogenicity of these vaccines. Furthermore, there is a drive to replace injected vaccines with those that can be administered by mucosal routes. Since the induction of innate immunity is crucial for vaccines to elicit potent antigen specific immune responses, a greater understanding of innate immunity at mucosal surfaces and the mechanism of action of adjuvants and delivery systems is required. Received 28 June 2005; received after revision 2 August 2005; accepted 30 August 2005     

Molecular mechanisms involved in dendritic cell dysfunction in cancer

Dendritic cells (DC) play a pivotal role in the tumor microenvironment (TME). As the primary antigen-presenting cells in the tumor, DCs modulate anti-tumor responses by regulating the magnitude and duration of infiltrating cytotoxic T lymphocyte responses. Unfortunately, due to the immunosuppressive nature of the TME, as well as the inherent plasticity of DCs, tumor DCs are often dysfunctional, a phenomenon that contributes to immune evasion. Recent progresses in our understanding of tumor DC biology have revealed potential molecular targets that allow us to improve tumor DC immunogenicity and cancer immunotherapy. Here, we review the molecular mechanisms that drive tumor DC dysfunction. We discuss recent advances in our understanding of tumor DC ontogeny, tumor DC subset heterogeneity, and factors in the tumor microenvironment that affect DC recruitment, differentiation, and function. Finally, we describe potential strategies to optimize tumor DC function in the context of cancer therapy.     

Mechanistic insights into the efficacy of cell penetrating peptide-based cancer vaccines

Immunotherapies are increasingly used to treat cancer, with some outstanding results. Immunotherapy modalities include therapeutic vaccination to eliminate cancer cells through the activation of patient’s immune system against tumor-derived antigens. Nevertheless, the full potential of therapeutic vaccination has yet to be demonstrated clinically because many early generation vaccines elicited low-level immune responses targeting only few tumor antigens. Cell penetrating peptides (CPPs) are highly promising tools to advance the field towards clinical success. CPPs efficiently penetrate cell membranes, even when linked to antigenic cargos, which can induce both CD8 and CD4 T-cell responses. Pre-clinical studies demonstrated that targeting multiple tumor antigens, even those considered to be poorly immunogenic, led to tumor regression. Therefore, CPP-based cancer vaccines represent a flexible and powerful means to extend therapeutic vaccination to many cancer indications. Here, we review recent findings in CPP development and discuss their use in next generation immunotherapies.     

Immunogenicity of necrotic cell death

The mode of tumor cell death has significant effects on anti-tumor immunity. Although, previously it was thought that cell death is an inert effect, different investigators have clearly shown that dying tumors can attract, activate and mature professional antigen presenting cells and dendritic cells. In addition, others and we have shown that the type of tumor cell death not only controls the presence or absence of specific tumor antigens, but also can result in immunological responses ranging from immunosuppression to anti-tumor immunity. More importantly, it is possible to enhance anti-tumor immunity both in vitro and in vivo by targeting specific molecular mechanisms such as oligopeptidases and the proteasome. These studies not only extend our knowledge on basic immunological questions and the induction of anti-tumor immunity, but also have implications for all types of cancer treatments, in which rapid tumor cell death is induced. This review is a comprehensive summary of cell death and particularly necrosis and the pivotal role it plays in anti-tumor immunity.     

Genetic dissection of dendritic cell homeostasis and function: lessons from cell type-specific gene ablation

Dendritic cells (DCs) are a heterogeneous cell population of great importance in the immune system. The emergence of new genetic technology utilizing the CD11c promoter and Cre recombinase has facilitated the dissection of functional significance and molecular regulation of DCs in immune responses and homeostasis in vivo. For the first time, this strategy allows observation of the effects of DC-specific gene deletion on immune system function in an intact organism. In this review, we present the latest findings from studies using the Cre recombinase system for cell type-specific deletion of key molecules that mediate DC homeostasis and function. Our focus is on the molecular pathways that orchestrate DC life span, migration, antigen presentation, pattern recognition, and cytokine production and signaling.     

Schistosome vaccines.

Schistosomiasis control currently relies primarily on chemotherapy which is both expensive and temporary. There is an urgent need for an effective vaccine. Studies in animal models and man have demonstrated the existence of protective immunity. Antibody-dependent cell-mediated cytotoxicity mechanisms involving eosinophils and macrophages have been implemented in destruction of the parasites. Antigens expressed on the surface of the schistosomulum are among the targets of protective immune responses. Vaccines comprising recombinant antigens are now being tested in vivo for their capacity to evoke protective responses. Live oral vaccines based on attenuated Salmonella expressing schistosomular surface antigens are being developed.     

Heat shock proteins in autoimmune disease. From causative antigen to specific therapy?

Heat shock proteins (hsp) are highly conserved from bacteria to man. Bacterial hsp, with approximate molecular weights of 60 kDa (hsp60), are immunodominant antigens that are immunologically cross-reactive with their mammalian counterparts. Hsp molecules are therefore useful in studies of fundamental questions concerning immune responses to foreign as opposed to self antigens. The finding that immune responses to hsp are associated with both experimentally-induced and spontaneous autoimmune diseases in animals has prompted intensive research to assess the role of bacterial hsp as the etiological agents involved in the development of autoimmune diseases. Recent evidence from animal models of autoimmune disease has clearly demonstrated the involvement of hsp in both the pathogenesis and the immunoregulation of autoimmune diseases. Studies with arthritogenic and diabetogenic T cell clones have identified immunogenic epitopes of hsp. These have been shown to ameliorate adjuvant arthritis in Lewis rats, and insulin-dependent diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice. Such studies may have important therapeutic implications for the future treatment of human autoimmune disease.     

Schistosome vaccines

Summary Schistosomiasis control currently relies primarily on chemotherapy which is both expensive and temporary. There is an urgent need for an effective vaccine. Studies in animal models and man have demonstrated the existence of protective immunity. Antibody-dependent cell-mediated cytotoxicity mechanisms involving eosinophils and macrophages have been implemented in destruction of the parasites. Antigens expressed on the surface of the schistosomulum are among the targets of protective immune responses. Vaccines comprising recombinant antigens are now being tested in vivo for their capacity to evoke protective responses. Live oral vaccines based on attenuatedSalmonella expressing schistosomular surface antigens are being developed.     

Monocytes and their pathophysiological role in Crohn’s disease

Our immune system shows a stringent dichotomy, on the one hand displaying tolerance towards commensal bacteria, but on the other hand vigorously combating pathogens. Under normal conditions the balance between flora tolerance and active immunity is maintained via a plethora of dynamic feedback mechanisms. If, however, the balancing act goes faulty, an inappropriate immune reaction towards an otherwise harmless intestinal flora causes disease, Crohn’s disease for example. Recent developments in the immunology and genetics of mucosal diseases suggest that monocytes and their derivative cells play an important role in the pathophysiology of Crohn’s disease. In our review, we summarize the recent studies to discuss the dual function of monocytes - on the one hand the impaired monocyte function initiating Crohn’s disease, and on the other hand the overactivation of monocytes and adaptive immunity maintaining the disease. With a view to developing new therapies, both aspects of monocyte functions need to be taken into account. Received 1 June 2008; received after revision 24 July 2008; accepted 13 August 2008     

Heat shock proteins in autoimmune disease. From causative antigen to specific therapy?

Heat shock proteins (hsp) are highly conserved from bacteria to man. Bacterial hsp, with approximate molecular weights of 60 kDa (hsp60), are immunodominant antigens that are immunologically cross-reactive with their mammalian counterparts. Hsp molecules are therefore useful in studies of fundamental questions concerning immune responses to foreign as opposed to self antigens. The finding that immune responses to hsp are associated with both experimentally-induced and spontaneous autoimmune diseases in animals has prompted intensive research to assess the role of bacterial hsp as the etiological agents involved in the development of autoimmune diseases. Recent evidence from animal models of autoimmune disease has clearly demonstrated the involvement of hsp in both the pathogenesis and the immunoregulation of autoimmune diseases. Studies with arthritogenic and diabetogenic T cell clones have identified immunogenic epitopes of hsp. These have been shown to ameliorate adjuvant arthritis in Lewis rats, and insulin-dependent diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice. Such studies may have important therapeutic implications for the future treatment of human autoimmune disease.Dedicated to Professor Hermann A. Moser on the occasion of his 71st birthday.     

Intestinal epithelial barrier and mucosal immunity

Regulated mechanisms sustain the ability of the gut immune system to discriminate harmless food antigens (Ag) and commensal bacteria from pathogenic microorganisms, resulting in tolerance versus protective immunity, respectively. Antigens of the gut commensals are not simply ignored, but rather trigger an active immunosuppressive process, more commonly known as oral tolerance, which prevents the outcome of immunopathology. Both intrinsic properties of the gut microenvironment and cellular actors, as well as peripheral events induced by systemic dissemination of oral Ag, promote the induction of regulatory mechanisms that ensure maintenance of gut homeostasis. The aim of this review is to provide a synthetic update on the mechanisms of oral tolerance, with particular emphasis on the complex interplay between regulatory CD4+ T cells, dendritic cells and the gut microenvironment.     

What's new in the field of cancer vaccines?

The observation that in some cases tumors undergo spontaneous regression concomitantly with autoimmune manifestations has been interpreted as an indication of the involvement of the immune system in tumor rejection. This raised the conceptual possibility that the immune system could be used against the tumor. However, since tumor cells are poorly immunogenic by themselves, early attempts to develop immune-based approaches for cancer therapy saw the use of tumor cells transduced with genes coding for cytokines or costimulatory molecules to enhance in vivo immunity. The identification of cytotoxic T lymphocyte (CTL)-defined tumor associated antigens has allowed the development of new strategies for cancer immunotherapy. Novel adjuvants have been identified, and different modes of antigen delivery were devised which aim at inducing efficient CTL responses in patients. This review will discuss some of what is currently considered as relevant aspects of antitumor immunization.Received 19 July 2002; received after revision 11 December 2002; accepted 13 December 2002     

Cross-presentation of IgG-containing immune complexes

IgG is a molecule that functionally combines facets of both innate and adaptive immunity and therefore bridges both arms of the immune system. On the one hand, IgG is created by adaptive immune cells, but can be generated by B cells independently of T cell help. On the other hand, once secreted, IgG can rapidly deliver antigens into intracellular processing pathways, which enable efficient priming of T cell responses towards epitopes from the cognate antigen initially bound by the IgG. While this process has long been known to participate in CD4⁺ T cell activation, IgG-mediated delivery of exogenous antigens into a major histocompatibility complex (MHC) class I processing pathway has received less attention. The coordinated engagement of IgG with IgG receptors expressed on the cell-surface (FcγR) and within the endolysosomal system (FcRn) is a highly potent means to deliver antigen into processing pathways that promote cross-presentation of MHC class I and presentation of MHC class II-restricted epitopes within the same dendritic cell. This review focuses on the mechanisms by which IgG-containing immune complexes mediate such cross-presentation and the implications that this understanding has for manipulation of immune-mediated diseases that depend upon or are due to the activities of CD8⁺ T cells.     

Suppressor mechanisms in tumor immunity

There are many parallels between T cell-mediated suppression of tumor immunity and suppression of immune responses to haptens and polypeptides. We propose a cell interaction model which takes this into account and outlines a regulatory pathway for suppression of immunity to tumor antigens. Free antigen or antigen/antibody complexes trigger an inducer T cell subset, Tsi, which is tumor-specific. This cell activates a non-immune T cell population, pre Tse, to generate effector suppressor cells, Tse. The Tse are specific for either the idiotype of Tsi or for antigen complexed with a soluble factor made by the Tsi, but the suppression they mediate is antigenically nonspecific. Tumor antigen-specific suppressor factors, TsF, play a major role in the communication between different suppressor cells. Characterization of polyclonal and monoclonal factors produced by Tsi, called TsFi, indicates that they both bind to tumor antigen and contain tumor-specific (idiotypic?) determinants.     

Cationic host defence peptides: Innate immune regulatory peptides as a novel approach for treating infections

An increase in antibiotic resistance and the emergence of new pathogens has led to an urgent need for alternative approaches to infection management. Immunomodulatory molecules that do not target the pathogen directly, but rather selectively enhance and/or alter host defence mechanisms, are attractive candidates for therapeutic development. Natural cationic host defence peptides represent lead molecules that boost innate immune responses and selectively modulate pathogen-induced inflammatory responses. This review discusses recent evidence exploring the mechanisms of cationic host defence peptides as innate immune regulators, their role in the interface of innate and adaptive immunity, and their potential application as beneficial therapeutics in overcoming infectious diseases. Received 3 November 2006; received after revision 14 December 2006; accepted 22 January 2007