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Monoclonal antibodies are therapeutic monoclonal Ig that act by highly specific binding to their target antigen and by interacting with the immune system. Their side effects are mainly related to their mechanism of action. The most frequent adverse effects are infusion reactions. Post-marketing surveillance is essential for identifying adverse reactions and improving knowledge of their mechanism of action., (© 2019 médecine/sciences – Inserm.)

The Milieu Intérieur project aims to define the boundaries of a healthy immune system in steady state and upon immune stimulation, and to elucidate environmental and hereditary determinants of its variability. The project is based on an in-depth immune phenotyping of 1 000 healthy donors. By correlating the cytometry measurements of peripheral blood immune cell composition in homeostasis, with the associated metadata, we have defined reference values of phenotypes related to sex and age, and found a significant impact of latent cytomegalovirus infection and smoking on measured phenotypes. In addition, we identified eleven novel Single-Nucleotide Polymorphisms (SNPs) associated with immune cell phenotypes. Immune response signatures were measured upon stimulation of fresh peripheral blood by 40 immune stimuli. Robust and standardized pipelines were established to quantify expression of 29 proteins and 572 genes and to explore genetic and non-genetic determinants of the variability of healthy immune response. The analytical approaches established by Milieu Intérieur and the collected data set represent an ideal reference for comparison studies of disease populations., (© 2019 médecine/sciences – Inserm.)

The world of lymphocytes has recently expanded. A new group of cells, innate lymphoid cells (ILCs) has been defined. It includes lymphoid cells that have been known for decades, such as natural killer (NK) cells, and lymphoid tissue--inducer (LTi) cells. NK cells recognize a vast array of tumor cells, which they help to eliminate through cytotoxicity and the production of cytokines, such as interferon-γ). (IFN-γ). Advances in our understanding of NK cell biology have led to a growing interest in the clinical manipulation of these cells in cancer. The other ILCs are found mostly in the mucosae and mucosal-associated lymphoid tissues, where they rapidly initiate immune responses to pathogens in the absence of specific sensitization. Here, we outline the basic features of ILCs and review the role of ILCs other than NK cells in cancer. Much of the role of ILCs in cancer remains unknown, but several findings should lead to further efforts to dissect the contribution of different ILC subsets to the promotion, maintenance, or elimination of tumors at various anatomic sites. This will require the development of standardized reagents and protocols for monitoring the presence and function of ILCs in human blood and tissue samples.

Natural killer (NK) cells are lymphocytes of the innate immune system that can kill tumor and infected cells. NK cells also secrete cytokines that participate in the shaping of the adaptive immune response. During the past few years, several studies have shown that the threshold of NK cell responsiveness is more adaptable than originally thought. NK cell reactivity is tuned by the environment and depends on the time of exposure of NK cells to their microenvironment. The impact of the NK cell response on immunity also depends on the intensity and the nature of the tumor or infections assaults. We review here how the local context impacts on NK cell responsiveness and shapes the outcome of NK cell activation., (© 2013 médecine/sciences – Inserm / SRMS.)

Study of dysregulations of the immune system resulting in abnormal bone homeostasis has led to the emergence of the field of osteoimmunology. Among the interactions between the immune system and bone, several signaling molecules and pathways previously identified in immune cells have been shown to be key players in the osteoclast, the bone resorbing cell. Osteoclast differentiation requires two signaling pathways: the RANK/RANKL pathway and the signal initiated by the ITAM-harboring adaptor proteins DAP12 and FcRgamma. Until recently, it was unclear how RANK and ITAM signals merge to cooperatively stimulate activation of NFATc1, the master transcription factor in osteoclastogenesis. A recent study from H. Takayanagi's group has shown that the tyrosine kinases Btk and Tec form a multiprotein complex with adaptor molecules such as BLNK, that is able to integrate these two signaling pathways and thus stimulate osteoclastogenesis. Taken together, these new data open novel clinical perspectives especially for osteoarticular inflammatory diseases.

An examination of the concepts used in immunology prompts us to wonder about the origins and the legitimacy of the notions of self and non-self, which constitute the core of the dominant theoretical model in this science. All theoretical reflection concerning immunology must aim at determining a criterion of immunogenicity, that is, an operational definition of the conditions in which an immune reaction occurs or does not occur. By criticizing both conceptually and experimentally the self/non-self vocabulary, we can demonstrate the inaccuracy and even the inadequacy of the dichotomy of self/non-self. Accordingly, the self/non-self model must be reexamined, or even rejected. On the basis of this critique, we can suggest an alternative theoretical hypothesis for immunology, based on the notion of continuity. The 'continuity hypothesis' developed here attempts to give a criterion of immunogenicity that avoids the reproaches leveled at the self model.

Control of the immune reaction can become a major goal, particularly in patients with autoimmune diseases or who express alloreactivity after organ transplantation. The most important side effect of this control is an immunodeficiency, a consequence of the wide spectrum of activity of the treatment. Thus, in order to limit the infectious risks, it would appear reasonable to try to develop new more selective strategies. A better definition of the cellular and molecular mechanisms implicated in the initiation and effector phases of autoimmune diseases authorizes the development of new therapeutic approaches able to target precise points of the immune system. There are a large number of potential targets, mainly directed at orientating the cytokinic response toward an antiinflammatory profile, neutralizating proinflammatory cytokines or their receptors, inducing regulatory lymphocytes in order to normalize the state of T and B cell tolerance, and modulating cellular cooperation and lymphocytic homing by blocking adhesion molecules. Some of these new approaches have already been validated in autoimmune diseases, others will follow soon.

Major advances achieved in immunology along the last decade have considerably improved our appraisal of the interactions between tumor cells and cells of the immune system (including lymphocytes), leading to the current development of immunotherapies as a new treatment strategy against cancer. Due to their localization in the brain, glioma are usually considered to arise in an immunoprivileged site, precluding immune intervention. Recent data challenge such a nihilism. Indeed, glioma infiltrating lymphocytes include T cell clonal expansions, suggesting a response against glioma antigens not yet identified. Furthermore, there is now cumulative evidence that activated T cells can traffic through the central nervous system and that T cells primed by astrocytoma cells in the periphery can recirculate and reach the brain to mediate their anti-tumor effects. Finally, multiple mechanisms by which glioma evade the immune response have been elucidated. However, there are still important enigmas, such as the nature of glioma antigens and the steps of antigen presentation in the brain. Responding to these crucial questions should facilitate the development of immunotherapies against brain tumors, avoiding deleterious auto-immune reactions.

The immune system is regulated in a complex fashion that allows flexibility in the response to pathogens and enables close control at multiple points, to prevent an undesired response. Indeed, for effective action, it is not only essential that the immune system possesses good effectors, but that the performance of the effectors be properly monitored back to avoid autoimmune reactions or excessive inflammatory response that might imperil the fitness of the organism. Herein, we show the importance of the dendritic cell population in the initiation of an effective immune response and we describe an experimental approach to optimize the dendritic cell-based immunotherapy in cancer murine models. We also characterize a T cell activation-limiting mechanism that is likely to play a physiological role in the down-regulation of the immune responses.

There is now increasing evidence that the hormonal form of vitamin D, 1,25(OH)2D3, is involved in the regulation of the immune system. Local production of the hormone in various infectious diseases can benefit the immune environment. 1,25(OH)2D3 exerts most of its actions only after it has bound to its specific nuclear receptor. These receptors are present in monocytes and activated lymphocytes. The hormone inhibits lymphocyte proliferation and immunoglobulin production in a dose-dependent fashion. It also blocks the accumulation of the mRNAs for IL-2, IFN-gamma and GM-CSF. It interferes with T helper cell (Th) function, reducing Th-induction of immunoglobulin production by B-cells and inhibits the passive transfer of cellular immunity by Th in vivo. The steroid hormone promotes suppressor cell activity and inhibits the generation of cytotoxic and NK cells. The expression of Class II antigen by lymphocytes and monocytes is also affected. In vivo, 1,25(OH)2D3 is particularly effective in preventing auto-immune diseases such as experimental auto-immune encephalomyelitis, murine lupus, and diabetes in NOD mice. Synthetic analogues of vitamin D3 that bind to receptors but have no hypercalcemic effect in vivo have recently been developed for therapeutic use.

All immune responses are assisted by different subpopulations of cells with complementary properties. Beside T and B lymphocytes specialized into effector killers, pro-inflammatory or antibody-producing cells, there are accessory and helper cells which exert various functions, such as antigen degradation and presentation, activating signal amplification and support of antigen-activated lymphocytic clones expansion and their functional differentiation. These cells, whose role is to co-operate with effector lymphocytes, are either lymphocytes, such as antigen-presenting B cells and helper T cells, or cells of haematopoietic origin belonging to the monocytic lineage, such as macrophages, monocytes and dendritic cells. Co-operation between subpopulations of the immune system takes place either by cell-to-cell interactions, or by indirect interactions via soluble mediators. Direct interactions postulate the involvement of receptor molecules and ligand-molecules expressed at cell surface. Indirect interactions are mediated by cytokines secreted by accessory or helper cells and acting at short distance to the point of secretion. Surface molecules and cytokines are well characterized both biochemically and functionally, and we are now in a position to manipulate the essential stages of cellular or hormonal immune response by using either cytokines and their inhibitors, or agonists or antagonists of surface receptors. Co-operation between cells participates in the autoregulation of the immune system. Through modulation of surface molecules and synthesis of cytokines the immune system can amplify discreet signals or repress untimely responses.(ABSTRACT TRUNCATED AT 250 WORDS)

The development of immune defense mechanisms begins early during fetal life but is not yet completed at birth. The earliest hematopoietic stem cells, which give rise to the lymphocytic and myelomonocytic cell lines, appear between the fourth and eight weeks postconception. T cells, responsible for cellular immune defense mechanisms, are first detectable at 12 weeks and seem to acquire their functional capabilities at the 16th week. B lymphocytes, responsible for humoral immunity, can be identified in the fetal liver at eight weeks and are functional at the 12-th-13th week, with the ability to produce specific IgM antibodies. Thus, in theory, fetuses of more than 16 weeks can produce a full immune response. Neonates still have incomplete development of a number of mechanisms involved in nonspecific immunity (natural killer, polynuclear and macrophage chemo-attraction, complement system).

Immunodeficiency cannot be considered today as an obligatory consequence of human ageing. When present it strikes mainly primary immune response (humoral as well as cellular). Ageing of regulation, as exhaustive of repertoire through idiotypic network saturation for instance, plays a major role in the disorders of ageing immune system. Other age associated conditions as malnutrition, infection, renal disease, stress, also influence deeply immune responses.

The variable regions of immunoglobulins express their own antigenetic determinants, the idiotopes (id) which, together, make up the idiotype. Idiotypes can be formed by the antigen-combining site itself, or lie out of its reach. They are encoded by germ-line, rearranged or mutated genes. Each id is under the control of anti-id antibody and behaves as the internal image of the antigen. The id-network is, most probably, incomplete, since each anti-id is degenerate and able to recognize several id. The Jerne's hypothesis has therefore been modified with the introduction of new concepts, such as regulatory or complementary id and parallel sets of id. The id and anti-id responses oscillate about one another, following immunization. These findings must be taken into account when hypothesizing on the physiopathology of autoimmunity. They have been put into practice to manipulate immune response, and consequently to design new vaccines and to treat patients with beta lymphocyte malignancies.