Showing papers in "Advances in Immunology in 2004"

Immune response against dying tumor cells.

Abstract: Publisher Summary This chapter provides clear evidence in favor of tumor escape mechanisms. Melanomas from patients experiencing partial responses after T-cell–based immunotherapies reportedly lose β 2 -microglobulin expression or down modulate the target antigen. The central dilemma of cancer immunotherapy resides in the striking contrast between the lack of spontaneous antitumor immune responses and the apparent possibility to induce active antitumor immune responses experimentally. Irradiation and chemotherapy mostly induce a type of cell death, apoptosis that is widely thought to be immunologically silent or even tolerogenic. Thus, paradoxically, the standard treatments that are used in the clinical management of both solid and diffuse tumors would suppress any possibility that the patient's immune system eradicates those residual tumor cells that will ultimately cause relapse. This chapter examines this hypothetical scenario and the way the modality of tumor cell death and/or the immune system can be manipulated so dying tumor cells become immunogenic. Antitumor responses can be induced by vaccination by providing a formulation of concentrated tumor antigens whose optimal presentation is ensured in vitro or in vivo by the application of suitable immunostimulatory agents. Most of the studies performed concentrate on the dichotomy of apoptosis and necrosis incurring in important methodological problems that are discussed in this chapter.

Selection of the T-cell repertoire: receptor-controlled checkpoints in T-cell development.

Abstract: Publisher Summary This chapter focuses on T-cell development with special emphasis on antigen receptor-controlled differentiation programs. Development of T cells is tightly associated with the adaptation of adaptive immune system to self major histocompatibility complex (MHC)-peptide complexes. Shortly, before T-cell development could be approached by molecular techniques, hypotheses on the control of development correctly predicted positive selection that results in the alignment of functional commitment and receptor specificity of mature T cells and negative selection as essential component of self–nonself discrimination. Immunologists who have a greater interest in immune function and self–nonself discrimination by the immune system find themselves confronted with exciting questions concerning the regulation of ectopic antigen expression and its impact on negative selection, as well as new aspects of immunoregulation carried out by another lineage of CD4 + /CD25 + T cells. The interplay of the innate and adaptive immune system has come much more into focus with the recognition of lineages of T cells that are selected by nonclassical MHC molecules.

The role of antibodies in mouse models of rheumatoid arthritis, and relevance to human disease.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting approximately 1% of the world’s population (Lee and Weinblatt, 2001). Although inflammatory lesions in the skin, lungs, and other organs are common, the disease hallmark is severe, often destructive, inflammation of peripheral joints. Although manifestations vary among patients, RA is usually a symmetric polyarthritis affecting distal [metacarpophalangeal (MCP), metatarsophalangeal (MTP), proximal interphalangeal (PIP), wrist, and ankle] more than intermediate (knee, elbow) and more than proximal (hip, shoulder) joints, and sparing the distal interphalangeal (DIP) joints. The cervical spine is often affected, but not the remainder of the axial skeleton. Synovial tendon sheaths and bursae are frequently involved. Microscopically, the characteristic lesion of RA is a novel tissue called pannus, composed of a greatly expanded number of both type 1 (macrophage-like) and type 2 (fibroblast-like) synoviocytes, as well as new blood vessels and a mononuclear cell infiltrate that is often follicular and can contain germinal centers. Although neutrophils are the predominant cell in inflamed synovial fluid, they are sparse in pannus. Pannus overgrows and erodes articular cartilage; destroys bone, especially at the junction of bone and cartilage; and erodes through tendons and ligaments. Together, these processes often destroy joint function, usually over the course of many years.

CD4/CD8 coreceptors in thymocyte development, selection, and lineage commitment: analysis of the CD4/CD8 lineage decision.

Abstract: Publisher Summary The initial dichotomy between instructional and stochastic/selection models of lineage commitment fueled a large number of experiments and provided a common intellectual structure for understanding results obtained in widely disparate experimental systems The more recent formulation of the kinetic signaling model, and the appreciation that signaled thymocytes can reverse course by undergoing coreceptor reversal, adds an entirely new dimension to the lineage commitment debate It will not be too long before one has both a cellular and a molecular understanding of how bipotential double positive thymocytes integrate environmental cues to determine their appropriate cell fate

Development and function of T helper 1 cells.

Abstract: Publisher Summary The immune system has developed to be highly specialized and effective in eradicating a wide variety of pathogens with minimum immunopathology. The adaptive arm of the immune response, consisting of antigen-specific T and B cells, interacts with cells of the innate immune system to mediate an effective response to infectious pathogens. Heterogeneity of T cell responses to pathogens can determine the resistance or susceptibility of a host to such infectious agents. T helper 1 cells have been also implicated in animal models of organ-specific autoimmune diseases, such as multiple sclerosis and insulin-dependent diabetes, as well as chronic inflammatory diseases, including inflammatory bowel disease.

HMGB1 in the immunology of sepsis (not septic shock) and arthritis.

Abstract: Publisher Summary This chapter discusses evidence implicating high mobility group box 1 (HMGB1) as an immunological mediator of severe sepsis An important contrast is made to distinguish the immunology of sepsis as distinct from the immunology of septic shock, a syndrome mediated by tumor necrosis factor (TNF) HMGB1 is produced during severe sepsis in humans and animals, and passive immunization with neutralizing anti-HMGB1 antibodies prevents lethality from established sepsis in animals HMGB1 administration does not cause shock, but it is lethal, in part by causing epithelial cell barrier dysfunction It is a proinflammatory mediator that contributes to the development of arthritis in animals and is produced in humans with rheumatoid arthritis; monoclonal anti-HMGB1 antibodies are in preclinical development for this therapeutic target The identification of these immunological and cytokine activities of HMGB1 has renewed interest in a molecule first described as an abundant nuclear and cytosolic DNA-binding protein There is only one Food and Drug Administration (FDA) approved treatment for sepsis, activated protein C, a partially effective anti-inflammatory and anti-coagulant therapy approved for use in a subset of patients with severe sepsis

Th2 cells: orchestrating barrier immunity.

Abstract: Publisher Summary This chapter summarizes recent insights regarding the generation of T helper (Th) 2 cells and factors regulating expression of IL-4—the canonical cytokine secreted by these cells. Th2 cells orchestrate a stereotyped cell response characterized by eosinophil and basophil infiltration, mast cell hyperplasia, and changes in epithelial mucus and water secretion. Th2 cells have been demonstrated to mediate protection against not only a variety of intestinal helminthes but also ectoparasites that invade at epithelial barriers. When activated systemically, Th2 cells protect against the tissue-damaging proinflammatory actions of Th1 cells. When dysregulated, Th2 cells drive chronic atopic diseases of wide prevalence such as allergy and asthma. Basic insights into the understanding of the generation, activation, tissue localization, and turnover of Th2 cells will provide numerous opportunities for sustained benefits to human health.

The CD4/CD8 lineage choice: new insights into epigenetic regulation during T cell development.

Abstract: Publisher Summary Close examination of how the CD4 and CD8 genes are regulated during T lymphocyte development, not only in the thymus but also in secondary lymphoid organs, has provided with valuable insight into mechanisms of lineage specification. Studies in this area promise to uncover how helper versus cytotoxic T cells differentiate, and, possibly, even how effector T cells give rise to subsets of long-lived memory T cells with specialized activation properties. In a more general sense, examination of these loci has provided a unique opportunity to study epigenetic regulation in vertebrate development. The CD4 locus remains the only vertebrate gene currently shown to undergo developmentally regulated epigenetic silencing, and as such, it presents an ideal system for analyzing how heterochromatin is established during developmental processes in higher eukaryotes.

The pathogenesis of diabetes in the NOD mouse.

Abstract: Publisher Summary This chapter discusses the origin of the nonobese diabetic (NOD) mouse, the pathogenesis of diabetes, and the role of the immune cells in pathogenesis and some of the important discoveries that have facilitated and expanded the understanding of both immunity and autoimmunity. With the development of spontaneous diabetes, the NOD mouse shares many pathological features with human type 1 diabetes (T1D) making it a valuable model for research. Disease is associated with specific major histocompatibility complex (MHC) alleles, anti-insulin autoantibodies precede diabetes, and β-cell–specific cellular responses are discussed. Some important advantages of the NOD mouse autoimmune model for diabetes include access to the pancreas at preclinical stages in the immunopathology, the ability to breed and genetically manipulate animals, and the capacity to employ intervention strategies at preclinical and postclinical disease stages. The NOD mouse model has provided researchers with an excellent opportunity to examine islets at various stages of the diabetes disease process.

Multitasking of helix-loop-helix proteins in lymphopoiesis.

Abstract: Publisher Summary This chapter focuses on basic helix-loop-helix (bHLH) proteins involved in lymphoid development and tumorigenesis. Functions and properties of the bHLH proteins are introduced that facilitate the understanding of their roles in the development and function of the lymphoid system. The bHLH family of transcription factors plays a pivotal role in cellular differentiation, influencing diverse systems, such as skeletal and cardiac muscle, pancreas, neuronal cells, adipocytes, chondrocytes, erythrocytes, and lymphocytes. This family consists of several dozen members that are expressed either ubiquitously or tissue specifically. Much of the investigation concerning the biological role of bHLH proteins in lymphoid cells relies on studies using transgenic or knockout mice. The chapter establishes that E proteins play multiple roles during lymphocyte development, partly by acting as ‘‘yin’’ and ‘‘yang’’ in antigen receptor signaling. On the one hand, E proteins are instrumental in the production of premature and mature antigen receptors that are crucial driving forces of lymphocyte differentiation. On the other hand, E proteins are also responsible for gauging the signaling strength of TCRs to ensure the survival of developing T lymphocytes.

An integrated model of immunoregulation mediated by regulatory T cell subsets.

Abstract: Publisher Summary The immune system is capable of mounting effective immune responses to a virtually infinite variety of foreign pathogens or tumor cells, while avoiding harmful immune responses to self. This is achieved by central thymic selection and peripheral regulation. It is clear that thymocytes expressing T cell receptors with high affinity for self-peptide/MHC complexes undergo apoptosis and are deleted centrally in the thymus. Recent experiments have highlighted the fact that central thymic negative selection eliminates the majority potentially pathogenic self-reactive T cells, however, many selfreactive T cells with low to intermediate affinity for self antigen escape thymic negative selection and are released into the periphery. Although these selfreactive T cells display relatively low-avidity to self peptide/MHC complexes, they are capable of self peptide-driven proliferation, and some may differentiate into potentially pathogenic effector cells.

Interactions between NK cells and B lymphocytes.

Abstract: Publisher Summary This chapter focuses on interactions between natural killer (NK) Cells and B Lymphocytes. Through studies of the extent of NK cell participation during the early phases of infection by a number of organisms, NK cells have long been well established as being an important element of innate immunity that can boost immune resistance before the development of specific immunity. They are also important in shaping the nature of the B- and T-cell responses. Natural killer cells constitute one of the key components of the innate immune system in that they can be rapidly activated without the need for expansion of antigen-specific clones. B lymphocytes, by contrast, are important constituents of the specific immune system because of the presence of clonally distributed antigen receptors and the persistence of the progeny of specific clones that can continue to produce the relevant antibodies. The most direct way of demonstrating that NK and B cells can interact is to isolate purified populations of each cell type, coculture them, and determine the effect of these interactions on parameters of cellular activation, such as induction of activation markers, proliferation, cytokine production, and in the case of B lymphocytes, immunoglobulin secretion, and isotype switching.

Customized antigens for desensitizing allergic patients.

Abstract: Publisher Summary The most effective allergy treatment is one that specifically and with maximum safety cures clinical symptoms caused by allergens in any given patient. In this chapter, allergen-specific immunotherapy (SIT) offers the best possibility of accomplishing this goal. The process is highly specific because the treatment is targeted at those allergens that the patient and the physician identified as the responsible ones. For the best performance of this tailor-made type of treatment, the first crucial step is the exact identification of the molecules causing the allergic reaction—that is, a clear diagnosis establishing the association between the disease manifestation and the immunoglobulin (IgE)-mediated immune reactions. This is accomplished with a molecule-based diagnosis. Genetic immunization is an attractive alternative for SIT using protein antigens. Intramuscular or intradermal injection of plasmid DNA encoding clinically relevant allergens can induce long-lasting immune responses with a Th1 bias and promote the formation of interferon-γ–producing CD4 + T cells. Molecular cloning and recombinant production of allergens opened new possibilities for the increasing problem of allergies. The concept of molecule based diagnosis is implemented in this field. Molecule-based diagnosis allows not only the precise identification of allergen recognition patterns of individual patients and the quantification of IgE levels to each allergen, but also helps to predict potential sensitization to multiple allergenic sources resulting from the cross-reactivity phenomenon.

Lineage commitment and developmental plasticity in early lymphoid progenitor subsets

Abstract: Publisher Summary This chapter provides a current understanding of hematolymphoid development from rare hematopoietic stem cells that give rise to progenitor subsets that progressively lose fate potential as they differentiate down their respective lineages. The ability to prospectively isolate the major branchpoints along the hematopoietic tree allows a molecular profiling of each, both at the population and single-cell level. Transcriptional profiling at the population level has shown that the master regulator genes identified from mouse knockout studies are expressed in the progenitor subsets upstream of the noted defective lineages. Single-cell profiling has supported the hypothesis of priming stages, whereby promiscuous, low-level expression of many genes appears to maintain flexibility in cell fate choices.

CD8+ effector cells.

Abstract: Publisher Summary The term “effector cell” best describes differentiated T cells with immediate TcR-triggered cytotoxicity or cytokine secretion, as detected in short-term assays, which are currently only feasible in vitro. Investigators agree that antigen recognition by naive CD8+ T cells does not result in either type of effector function (the IL-2 produced by naive T cells is not considered an effector cytokine). After an initial encounter with antigen, a differentiation process occurs enabling an effector function in subsequent antigen encounters. However, different effector functions have different differentiation pathways, and some subsets of post-naive CD8+ T cells have potent TcR-triggered secretory function for some cytokines but not for cytotoxic effector function. Major cellular and molecular questions about these differentiation pathways remain unanswered.

Generation, maintenance, and function of memory T cells.

Abstract: Publisher Summary Edward Jenner's recognition of immune memory represents one of the oldest and most significant of immunological observations. However, it has also proved to be one of the most difficult to understand on both cellular and molecular level. Recently, significant advances have been made in understanding where memory T cells, particularly CD8 + T cells, come from, what they can do, and what maintains them. While the factors that control this unique phenotype are unknown, they may be dependent to some extent on IL-7 and/or IL-15 for their expression, given these cytokines' critical role in the long-term maintenance of memory CD8 + T cells.