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1

New insights into the pathophysiology and in vivo function of IgG Fc receptors through gene deletion studies

100%
Baumann U., Schmidt R. E., Gessner J. E.
Archivum Immunologiae et Therapiae Experimentalis
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2003
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vol. 51
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issue 6
399-406
EN
Fc-receptors for IgG (Fc gammaRs) are critically involved at multiple stages of an immune response, ranging from antigen presentation and regulation of antibody production to the end-stage effector mechanisms of inflammation. Immunolglobulin G autoantibodies that are detectable in the majority of autoimmune diseases are ligands for Fc gammaRs. The three classes, Fc gammaRI, Fc gammaRII, and Fc gammaRIII, vary in their antibody affinity, cellular expression and in vivo function. We review the current knowledge on regulation and diverse functions of the distinct Fc gammaRs and describe the evidence of their important immunoregulatory roles in autoimmunity based on recent work in animal models.
2

Induction and maintenance of self tolerance: the role of CD4+CD25+ regulatory T cells

100%
Bala K. K., Moudgil K. D.
Archivum Immunologiae et Therapiae Experimentalis
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2006
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vol. 54
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issue 5
307-321
EN
The immune system responds vigorously to invading pathogens (non-self, foreign), while remaining unresponsive (tolerant) to the body's own components and circulating constituents (self). This indifference to self components is a result of finely orchestrated events of thymic negative selection (central tolerance) of developing T cells that are autoaggressive combined with those operative in the periphery (peripheral tolerance) to control the activity of potentially autoreactive T cells that escaped thymic tolerance. Recently, autoimmune regulator expressed in the thymus has been identified as a critical mediator of central tolerance towards tissue-specific antigens. In the periphery, a variety of regulatory T cells are involved in effecting tolerance. There is immense interest and excitement about the newly identified subset of CD4+CD25+ T cells. This is a unique subset of CD4+ T cells that bear CD25 (IL-2Ra chain) on the cell surface in the na?ve state and express FoxP3 as a unique marker. These cells suppress the activity of autoreactive effector T cells primarily via cell-cell contact. The deficiency and/or altered function of CD4+CD25+ T cells is associated with autoimmunity. Mice deficient in FoxP3 (scurfy mice) bear an autoimmune phenotype, and human males with mutations in the corresponding gene express the phenotype of widespread autoimmunity, the immune dysregulation, polyendocrinopathy and enteropathy, and X-linked syndrome. In vitro expansion of antigen-specific CD4+CD25+ T cells and their adoptive transfer into patients suffering from autoimmunity is emerging as a promising new therapeutic approach for these debilitating disorders. Development of tolerance to self antigens involves processes occurring within the thymus (central tolerance) and at extra-thymic sites (peripheral tolerance).
3

Anti-GBM glomerulonephritis: a T cell-mediated autoimmune disease?

100%
Lou Y.-H.
Archivum Immunologiae et Therapiae Experimentalis
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2004
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vol. 52
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issue 2
96-103
EN
Anti-glomerular basement membrane (GBM) glomerulonephritis, which was among the earliest recognized human autoimmune diseases, is characterized by the presence of anti- -GBM antibody. It has been a prototypical example of autoantibody-mediated autoimmune disease. However, decades of research on this disease, based either on clinical observations or experimental models, have revealed that T cell-mediated cellular immunity may potentially be a more important mediator of glomerulonephritis. We have made several breakthroughs in understanding the T cell-mediated mechanism causing this disease in a rat model based on Goodpasture's antigen, non-collagen domain 1 of ?3 chain of type IV collagen (Col4alpha3NC1). We demonstrated that anti-GBM glomerulonephritis was induced by either passive transfer of Col4alpah3NC1-specific T cells or active immunization with the nephritogenic T cell epitope of Col4alpha3NC1. Immunization with the T cell epitope also triggered production of anti-GBM antibodies to diversified GBM antigens. Thus, a single nephritogenic T cell epitope alone is sufficient to induce the clinical spectrum of anti-GBM glomerulonephritis, including proteinuria, glomerular injury, and anti-GBM antibody. A possible T cell-mediated mechanism for causing human anti-GBM disease is proposed.
4

Is it wise to target the late costimulatory molecule OX40 as a therapeutic target?

100%
Cavanagh M. M., Hussell T.
Archivum Immunologiae et Therapiae Experimentalis
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2008
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vol. 56
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issue 5
291-297
EN
The immune response triggered following pathogen recognition, though required to clear the infection, can be detrimental if it is produced in excess or fails to resolve promptly. Excessive inflammation contributes to infectious and noninfectious pathologies in the gut (such as inflammatory bowel disease), lung (such as bronchiolitis), and in a variety of autoimmune conditions. T cells contribute significantly to pathology during inflammation. Global anti-inflammatory strategies can alleviate the consequences of exuberant inflammation by suppressing T cell activity, but may leave the patient vulnerable to opportunistic infection. More specific therapies aim to suppress only those T cells involved in the disease process, and one such approach is to target late costimulatory molecules. These are not expressed on na?ve or resting memory cells. Rather, they have a specific window of expression and their ligation results in the production of abundant inflammatory cytokines. By targeting these molecules, it is hoped that inflammation will reduce, but that therapies will be specific enough to avoid, global immune suppression. This review focuses on the late costimulatory molecule OX40, compare it with other T cell costimulators, and highlight why it is a more suitable target for immune intervention than other immune suppressive strategies.
5

B cell tolerance to self in systemic autoimmunity

100%
Zouali M.
Archivum Immunologiae et Therapiae Experimentalis
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2001
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vol. 49
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issue 5
361-366
EN
After a century of research and despite intensive scrutiny, the origin of autoantibody production remains an enigma. Recently, the essential role of B cells in promoting systemic autoimmunity in mice seems more important than previously thought: self-reactive B cells can be subject to positive selection and a deficiency in serum IgM predisposes to the development of IgG antibodies to autoantigens. Studies of the B cell repertoire expressed in systemic autoimmune diseases have provided important clues. In human lupus, quantitation of this repertoire reveals the presence of an expansion of IgG clonotypes that impart reactivity with disease-related autoantigens. The nucleotide sequences of autoantibodies derived from these patients and expressing nephritogenic idiotopes (present in immune complexes and renal eluates of subjects with active disease) show features of diversification with a high rate of replacement/silent mutations and clustering of the mutations in the hypervariable regions, suggesting than an antigen-driven process plays a role in the generation of pathogenic autoantibodies. Currently, the contributions of apoptosis and of cell receptor signaling to this triggering are being appreciated. Pursuing these and related issues will have an important impact on autoimmune research.
6

Epitope spreading: a mechanism for progression of autoimmune disease

100%
Tuohy V. K., Kinkel P.
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vol. 48
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issue 5
347-352
EN
Autoimmune diseases are typically characterized by a persistent inflammatory self-recognition process that ultimately leads to chronic progressive disability. Over the past several years we have addressed the fundamental question of why autoimmune diseases are chronic. Our working hypothesis in these studies has been that autoimmunity involves a continuous acquisition of new self-recognition events, thereby providing an inflammatory steady-state that leads to chronicity. This acquired T cell neoautoreactivity is commonly referred to as epitope spreading. By studying mulitple sclerosis (MS) and its related animal model, experimental autoimmune encephalomyelitis (EAE), we have found that chronic progression of autoimmune disease is invariably linked to the development of any epitope-spreading process that manifests as a cascade of inflammatory T cell neoautoreactivities to a sequential series of predictable new target self-antigens. However, our most recent observations indicated that the emergence of epitope spreading is accompanied by a concurrent regression of the established primary autoreactivity associated with disease onset. Thus, our studies indicate that progression of autoimmune disease involves a shifting of T cell autoreactivity from primary initiating self-determinants to defined cascades of secondary determinants that sustain the inflammatory self-recognition process during progression to chronicity. Our data support the view that the natural development of self-recognition during autoimmune disease may best be understood when considered in the temporal context of an ?epitope du jour? and ?moving target? perspective.
7

The immunopathology of primary biliary cirrhosis: thoughts for the millennium

100%
Sasaki M., Ansari A. A., Nakanuma Y., Coppel R. L., Keeffe E. B., Gershwin M. E.
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vol. 48
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issue 1
1-10
EN
Primary biliary cirrhosis is an organ specific autoimmune disease that produces progressive cholestatic liver failure. It is predominantly a disease of women characterized by chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and ultimately fibrosis. The serologic hallmark of primary biliary cirrhosis (PBC) is the presence of antibodies to mitochondria. The mechanisms by which and if which such antibodies produce liver tissue injury is unknown. However, the presence of these antibodies have allowed detailed immunological definition of the antigenic epitopes, the nature of reacting autoantibodies and the characterization of T cell responses. Several mechanisms may now be proposed regarding the immune mediated bile duct damage in PBC, including the possible role of T cell-mediated cytotoxicity and intracellular interaction between the IgA class of antimitochondrial antibodies (AMA) and mitochondrial autoantigens. The advent of molecular biology, the ability to clone and define epitopes, and the use of in situ nucleic acid hybridization, have all led to advances in understanding the natural history of immunopathology in PBC. There are major questions which remain unanswered, including, of course, etiology, but also including the questions of why there is female predominance, the absence of PBC in children, the relative ineffectiveness of immunosuppressive drugs, and the specific role of mitochondrial antigens. In this review, we focus on these issues and particularly on the immunobiology of patients with this disease.
8

Genetics of experimental autoimmune encephalomyelitis in the mouse

100%
Andersson A., Karlsson J.
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issue 5
316-325
EN
Multiple sclerosis (MS) is an inflammatory, demyelinating disease in the central nervous system (CNS) affecting approximately 0.1% of the population in the northern part of the world. The factors behind the initiation of the inflammatory response are not known at present, but MS is considered as a complex disease depending on genetic as well as environmental factors. Experimental autoimmune encephalomyelitis (EAE) is the prevailing experimental rodent model for multiple sclerosis (MS). Disease is induced in genetically susceptible mice or rats by immunization with myelin proteins or peptides, which leads to an infiltration of leukocytes into the CNS. EAE has been subjected to investigations of genetic susceptibility to disease development. By the identification of genes predisposing to EAE, the hope is to get clues as to what genetic elements are also important in MS. To date, more than 25 Eae loci have been described in the mouse. The quantitative trait loci are linked to different disease traits and several show sex specificity. Here we discuss the current state of the genetics controlling susceptibility to EAE.
9

Wegener?s granulomatosis ? autoimmunity to neutrophil proteinase 3

100%
Watorek E., Boratynska M., Klinger M.
Archivum Immunologiae et Therapiae Experimentalis
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2003
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vol. 51
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issue 3
157-167
EN
Wegener?s granulomatosis is a small vessel vasculitis, associated with various clinical manifestations, among which the most common are respiratory tract disease and glomerulonephritis leading to renal failure. Pathogenesis of vascular injury in Wegener?s granulomatosis is ascribed to antineutrophil cytoplasmic antibodies directed (ANCA) mainly against proteinase 3, an enzyme from neutrophil granules. The reasons for breakdown of self-tolerance to proteinase 3 are unknown and together with molecular mechanisms underlying this immunoinflammation are the subject of research. Standard treatment of Wegener?s granulomatosis consists of cyclophosphamide and corticosteroids. In patients resistant to that therapy or with the refractory disease some alternative strategies involving tumor necrosis factor blocade, polyclonal antithymocyte globulin or monoclonal anti-T cell antibodies are applied.
10

The role of T cells in rheumatoid arthritis

100%
Weyand C. M., Bryl E., Goronzy J. J.
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vol. 48
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issue 5
429-435
EN
In rheumatoid arthritis (RA), T cells infiltrate into the synovial membrane where they initiate and maintain activation of macrophages and synovial fibroblasts, transforming them into tissue-destructive effector cells. The diversity of the disease process and the formation of complex lymphoid microstructures indicates that multiple T cell activation pathways are involved. This model is supported by the association of distinct disease patterns with different variants and combinations of HLA class II molecules. T cell pathology in RA, however, is not limited to the joint. Affected patients have major abnormalities in the T cell pool with a marked contraction in T cell receptor diversity and an outgrowth of large clonal populations. Clonally expanded CD4+ T cells lose expression of the CD28 molecule and gain expression of perforin and granzyme. Consequently, the functional profile of expanded CD4+CD28null T cells is fundamentally changed and is shifted towards tissue-injurious capabilities. CD4+CD28null T cells are particularly important in patients with extraarticular manifestations of RA, where they may have a direct role in vascular injury. Understanding the mechanisms underlying the loss of T cell diversity and the emergence of pro-inflammatory CD4+CD28- T cell clonotypes may have implications for other autoimmune syndromes.
11

The physiological role of regulatory T cells in the prevention of autoimmunity: generation, specificity and mode of action

100%
Seddon B.
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vol. 48
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issue 5
339-346
EN
Until recently, the traditional view was that tolerance to self antigens was maintained by a combination of physical deletion intrathymically and functional deletion in the periphery of autoreactive T cells. There is now, however, abundant evidence that the normal T cell repertoire contains overtly autoreactive T cells whose pathogenic potential is held in check by the activity of a distinct subset of peripheral T cells, so called regulatory or suppressor T cells. This article examines data from one model of rodent autoimmunity, where autoimmune pathology develops following thymectomy and irradiation of normal laboratory rats, which characterise the development and function of these so called regulatory T cells.
12

Evidence for an immunoregulatory role of OX2 with its counter ligand (OX2L) in the regulation of transplant rejection, fetal loss, autoimmunity and tumor growth

100%
Gorczynski R. M.
Archivum Immunologiae et Therapiae Experimentalis
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2001
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vol. 49
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issue 4
303-310
EN
Transplantation has emerged as an effective treatment for patients with end-stage organ failure. Current regimens of non-specific immunosuppressive drug treatment, which are needed life-long to prevent graft rejection, have numerous adverse side effects and increase the risk of opportunistic infections and malignancy. A major goal is to develop immunotherapeutic protocols that achieve specific tolerance. Such protocols would decrease and eventually eliminate the reliance on non-specific drug therapy. We showed that portal vein (pv) delivery of donor antigen prolongs the survival of vascularized and non-vascularized allo- and xeno-grafts, and that increased graft survival is associated with altered cytokine production and augmented expression of the molecule OX2. This review documents further evidence for a more general immunoregulatory role for the interactions of OX2 and its ligand, OX2L.
13
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Post intoxicative therapeutic immunization with myelin oligodendrocyte glycoproteine (MOG 35-55) suppresses spontaneous regeneration of dopaminergic neurons injured with 1-methyl-4 phenyl-1,2,3,6-tetrahydropiridine (MPTP)

88%
Balkowiec-Iskra E., Kurkowska-Jastrzebska I., Joniec I., Czlonkowska A., Czlonkowski A.
Acta Neurobiologiae Experimentalis
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2003
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vol. 63
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issue 2
109-115
EN
The pathological process of neurodegeneration is accompanied by an inflammatory reaction that is believed to contribute to the pathogenesis of neurodegenerative diseases. The aim of our study was to evaluate the influence of autoimmune reaction induced by post-traumatic vaccination with myelin self-antigen on spontaneous regeneration of dopaminergic neurons, injured with MPTP. C57BL mice were intoxicated with 40 mg/kg MPTP and seven days later immunized with MOG 35-55 peptide in CFA. On 7th day following intoxication, the MPTP treated mice showed decrease of dopamine level by 63% as compared to the control mice. However, starting from the 14th day following intoxication, a spectacular increase of dopamine content was observed. Immunization with MOG resulted in statistically significant reduction of the increase in striatum as compared to non-immunized animals, and was lower by 23%, 17% and 15% on days 14, 28 and 50, respectively. Our results show suppressive influence of autoimmune reaction induced after injury on regeneration of dopamine cells intoxicated with MPTP.
14

Skin-induced tolerance and its reversal by Toll-like receptor ligands

88%
Szczepanik M.
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2007
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vol. 55
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issue 3
161-172
EN
In 1970, Gershon was the first to propose that T cells, in addition to their helper activity, can also play a role as regulatory cells capable of suppressing immune responses. However, the initial strong interest in T cell-mediated suppression was followed by a period of doubt and skepticism. Since the late 1990s the 'S' word started to be used in immunology again and interest in T suppressor cells has grown, ushering in a new renaissance for the field. In this article the author presents the current knowledge about a new subject called 'skin-induced tolerance'. Suppression is induced via epicutaneous immunization and is described in both Th1- and Tc1-mediated contact sensitivity reactions. The subject of skin-induced tolerance is also considered in the regulation of experimental models of autoimmune diseases such as allergic autoimmune encephalomyelitis and collagen-induced arthritis and finally in an animal model of graft rejection. The last part of this presentation will introduce the very fresh subject of ?contrasuppression', or the reversal of skin-induced suppression.
15

Regulation of immune responses by natural killer T cells

88%
Sharif S., Delovitch T. L.
Archivum Immunologiae et Therapiae Experimentalis
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2001
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vol. 49
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issue 1 suppl.
23-32
EN
Natural killer T (NKT) cells, which comprise a minor population of T cells in primary and secondary lymphoid organs, possess phenotypic characteristics of both NK and T cells. NKT cells respond to various external stimuli by an early burst of cytokines, including IL-4 and IFN-. Thus, a key immunoregulatory role has been attributed to them. Autoimmune diseases, especially type I diabetes (TID), may be caused by dysregulation of the immune system, which leads to hyporesponsiveness of regulatory T helper 2 (Th2) cells and promotion of autoimmune Th1 cells. Furthermore, several lines of evidence exist to support the notion that an NKT cell deficiency in individuals at risk of TID may be causal to TID. As a result, targeting NKT cells using immunotherapeutic agents may prove beneficial in the prevention or recurrence of TID. Indeed, our data demonstrate that stimulation of NKT cells with a specific ligand prevents the onset and recurrence of TID in non-obese diabetic (NOD) mice.
16

Molecular aspects in the pathogenesis of human systemic lupus erythematosus

88%
Liossis S.-N. C., Tsokos G. C.
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vol. 48
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issue 1
11-19
EN
Systemic lupus erythematosus is a common and often devastating systemic autoimmune disease of unknown etiology. In this communication we review the latest developments of the molecular pathogenesis of human lupus. Novel genetic studies of multiplex lupus families have revealed potential disease-associated genome intervals, put special emphasis on genetic loci mapping in the long arm of chromosome 1 and have underscored the complexity of the underlying genetic background. New data have emerged on the role of estrogens in the function of lymphocytes and a number of studies have recently emphasized the relative Th-1/Th-2 cytokine imbalance in favor of a Th-2 type cytokine immune response. Finally, novel experiments have revealed an abnormal antigen receptor- -mediated signaling process in lupus T and B cells, which may influence the aberrant expression and function of costimulatory molecules as well as of other aspects of immune cell function. It is important to decipher the underlying molecular mechanisms that govern the expression of human lupus, because we may design novel, rational approaches in the treatment of a human lupus, a disease that has high morbidity and mortality.
17

Modulating the immune response by oral zinc supplementation: a single approach for multiple diseases

88%
Overbeck S., Rink L., Haase H.
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issue 1
15-30
EN
Zinc is required for multiple cellular tasks, and especially the immune system depends on a sufficient availability of this essential trace element. During the last decades, many studies attempted to affect the outcome of various diseases by zinc supplementation. These efforts either aimed at supporting immunity by zinc administration or at correcting a loss of zinc secondary to the disease to restore the zinc-dependent functions of the immune system. This review aims to summarize the respective findings and to discuss possible molecular mechanisms by which zinc could influence viral, bacterial, and parasitic infections, autoimmune diseases, and the response to vaccination. Zinc supplementation in diseases such as diarrhea, chronic hepatitis C, shigellosis, leprosy, tuberculosis, pneumonia, acute lower respiratory infection, and leishmaniasis seems beneficial. In contrast, the results for the common cold and malaria are still not conclusive, and zinc was ineffective in most vaccination and rheumatoid arthritis studies. For AIDS and type 1 diabetes, zinc supplementation may even be a risk factor for increased mortality or deterioration of the glucose metabolism, respectively. In these cases, zinc supplementation should be used with care and limited to clearly zinc-deficient individuals.
18

Antigen non-specific activation of CD8+ T lymphocytes by cytokines: relevance to immunity, autoimmunity and cancer

88%
Ramanathan S., Gagnon J., Ilangumaran S.
Archivum Immunologiae et Therapiae Experimentalis
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2008
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vol. 56
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issue 5
311-323
EN
Development of T lymphocytes and their survival in the periphery are dependent on signals emanating from cytokine receptors as well as the T cell antigen receptor (TCR). These two signaling pathways play distinct and complementary roles at various stages of T cell development, maturation, survival, activation and differentiation. During immune response to foreign antigens initiated by TCR signaling, cytokines play a key role in the expansion of activated T cells. Even though the initial activation of T cells occurs via the TCR, this requirement can be overcome under certain circumstances. During lymphopenia, cytokines trigger memory CD8+ T cells to undergo antigen non-specific homeostatic expansion, whereas na?ve CD8+ T cells require both cytokines and TCR signaling. Recent reports show certain combinations of cytokines can induce proliferation and effector functions of na?ve CD8+ T cells without concomitant stimulation via the TCR. While such antigen non-specific stimulation of na?ve T cells might significantly boost the adaptive immune response, it could also have an undesirable effect of triggering potentially autoreactive cells. Understanding the mechanisms and the regulation of cytokine-driven stimulation of na?ve CD8+ T cells may lead to novel strategies of intervention for autoimmune diseases. On the other hand, in vitro expansion of na?ve CD8+ T cells by certain combinations of cytokines could be used to generate tumor-specific cells with ideal properties for cellular immunotherapy of cancer.
19

Treating autoimmune diseases through restoration of antigen-specific immune tolerance

75%
Wolfraim L. A.
Archivum Immunologiae et Therapiae Experimentalis
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2006
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vol. 54
|
issue 1
1-13
EN
The first line of treatment for many human autoimmune diseases involves the use of anti-inflammatory or immunosuppressive drugs such as prednisone or other steroids that not only suppress the underlying autoimmune disease, but lead to global suppression of the immune system. The sequelae of this approach include increased risk of infection, carcinogenesis, and osteoporosis. Moreover, such broad spectrum immunosuppression tends to have transient therapeutic benefit, as in many cases the disease becomes refractory to these drugs. There is a clear need for more specific means to restore immune tolerance to the specific autoantigens implicated in disease pathology. This review provides an overview of some of these newer, more specific therapeutic approaches to restoring immune tolerance to autoantigens, with an emphasis on those approaches that have been or will soon be tested in controlled clinical trials. Covered here are peptide- or protein-based therapeutics, oral tolerance, and cellular and gene therapy approaches to restoring antigen-specific immune tolerance.
20

Association of CD45dimVLA-4+ cells with the NKT cell lineage and their selective expression of IL-13, IP-15, and CCR3 transcripts

75%
Matejuk A., Afentoulis M.
Archivum Immunologiae et Therapiae Experimentalis
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2006
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vol. 54
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issue 3
183-191
EN
Estrogen (E2) was shown to prevent experimental autoimmune encephalomyelitis (EAE) and to produce a novel population of regulatory CD45dimVLA-4+ cells. Although their appearance was dependent upon an elevated hormonal level, E2 was not required for their production, as they also were induced by immunization with Mycobacterium tuberculosis as a component of complete Freund's adjuvant. Materials and Methods: Molecular techniques, including ribonuclease protection assays and quantitative RT-PCR, were used to provide further characterization of CD45dimVLA-4+ cells. Moreover, we determined the developmental requirements of the CD45dimVLA-4+ cells using genetically modified mice and extensive flow cytometry analysis. Results: Characterization of CD45dimVLA-4+ mRNA profile revealed highly elevated levels of CD16, CD44, CCR3, IP-15, and IL-13 transcripts compared with their CD45highVLA-4+ counterparts. Furthermore, we found up-regulation of anti-apoptotic bcl-w and bcl-xl genes and transcripts encoding the TCR and CD8 homodimer. The production of CD45dimVLA-4+ cells was evident in nude mice and in MHC class II- and 2-microglobulin, but not in CD1-deficient mice, suggesting a crucial role for CD1 in their induction.
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