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1

Regulation of autoreactive B cells: checkpoints and activation

100%
Ding C., Yan J.
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2007
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vol. 55
|
issue 2
83-89
EN
It has become clear that the autoreactive B cells are a part of the normal na?ve B cell repertoire in the periphery, despite the fact that they undergo a series of checkpoints, which include receptor editing (revision), clonal deletion, and anergy. However, most of those B cells reactive against self antigen remain functionally na?ve for autoantibody production by differential peripheral checkpoints. Therefore, the presence of autoreactive B cells does not always signify disease. Regulation of their activation and effector functions will determine the ultimate outcome. Although autoreactive B cell tolerance is well maintained in the healthy individual, the existence of pathogenic autoantibodies in autoimmune diseases indicates that these tolerogenic checkpoints are broken. Recent studies have demonstrated that autoreactive B cells are regulated by a composite of factors, such as genetic susceptibility and environmental triggers such as bacterial and viral infections as well as other immune cells. Interestingly, Toll-like receptors, previously considered as pattern-recognition receptors to detect and sense pathogens, may also have a potential to recognize self antigens and regulate autoreactive B cells for activation. Understanding the mechanisms of autoreactive B cell regulation and activation may help in identifying novel targets for the treatment of autoimmune diseases.
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
|
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

Regulation of immunological mucosal tolerance

100%
Kraal G., Wolvers D. A. W.
Archivum Immunologiae et Therapiae Experimentalis
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2001
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vol. 49
|
issue 1 suppl.
1-6
EN
Mucosal tolerance is an immunological phenomenon specific to mucosal surfaces as found in the lungs and gastro-intestinal tract. It results in the suppression of immune responses to inhaled or ingested antigens and prevents the body from unwan-ted and unnecessary immuno-logical responses to harmless molecules, such as grass-pollen or food constituents. This imposes the difficult task for the immune system of keeping a balance between reacting and non-reacting, and disturbances of this balance result in allergies and possibly autoimmunity, as well as opportunistic infections and even an escape from tumor surveillance. Understanding the mechanisms that underlie mucosal tolerance is, therefore, important from different viewpoints. Maintenance or (re)induction of mu-cosal tolerance to, e.g., food proteins, airborne allergens or autoantigens is desirable to prevent or cure allergies and autoimmune diseases. However, induction of mucosal tolerance is an unwanted phenomenon in mucosal vaccination and in the case of mucosal tumors.
4

Mechanisms of development of tolerance to repeated injection of exogenous pyrogens

100%
Soszynski D.
Postępy Higieny i Medycyny Doświadczalnej
|
2000
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vol. 54
|
issue 4
537-551
EN
Pyrogenic tolerance has been recognized for many years in a variety of species although the mechanisms that are responsible for its development are not well understood. The development of pyrogenic tolerance is associated with the stepwise diminution of pathophysiological and behavioral responses induced by exogenous pyrogens, such as fever, reduction in food and water inteke. Several studies either in vivo or ex vivo have indicated the role of various proinflammatory cytokines in the development of pyrogenic tolerance. Most of these studies have indicated that pyrogenic tolerance is associated with down-regulation of cytokine production as well as their biological activity The mechanisms responsible for down-regulation of cytokine production during development of pyrogenic tolerance are unclear. Since glucocorticoids are required for induction of tolerance, it has been postulated that well known glucocorticoids-dependent negative feedback on the production and biological activity of cytokines may play an important role in development of pyrogenic tolerance. We can not, however, rule out possibility that other mechanisms may participate directly or indirectly in a suppression of cytokines response due to repeated exogenous pyrogen challenge. Either the enhanced uptake of exogenous pyrogens by the hepatic Kupffer cells or the desensitization to exogenous pyrogens by the loss of binding sites, have been proposed as an additional mechanisms which may participate in exogenous pyrogen hyporesponsiveness.
5

Revisiting the natural history of tuberculosis, the inclusion of constant reinfection, host tolerance, and damage-response frameworks leads to a better understanding of latent infection and its evolution towards active disease

100%
Cardona J.-P.
Archivum Immunologiae et Therapiae Experimentalis
|
2010
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vol. 58
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issue 1
7-14
EN
Once Mycobacterium tuberculosis infects a person it can persist for a long time in a process called latent tuberculosis infection (LTBI). LTBI has traditionally been considered to involve the bacilli remaining in a non-replicating state (dormant) in old lesions but still retaining their ability to induce reactivation and cause active tuberculosis (TB) once a disruption of the immune response takes place. The present review aims to challenge these concepts by including recent experimental data supporting LTBI as a constant endogenous reinfection process as well as the recently introduced concepts of damage-response and tolerance frameworks to explain TB induction. These frameworks highlight the key role of an exaggerated and intolerant host response against M. tuberculosis bacilli which induces the classical TB cavity in immunocompetent adults once the constant endogenous reinfection process has resulted in the presence of bacilli in the upper lobes, where they can grow faster and the immune response is delayed. This essay intends to provide new clues to understanding the induction of TB in non-immunosuppressed patients.
6

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
|
2001
|
vol. 49
|
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.
7

Modulation of auxiliary signals to T cells as a mechanism to induce transplant tolerance

100%
Gorczynski R. M.
Archivum Immunologiae et Therapiae Experimentalis
|
2005
|
vol. 53
|
issue 2
91-101
EN
Advances in the treatment of transplant rejection, autoimmune disease, allergy, and other conditions of altered immunoregulation have come from our improved knowledge of the multi-faceted nature of lymphocyte activation, incorporating not merely antigen triggering of specific receptors, but a myriad of other accessory signals, all operating within a defined environmental (cytokine) milieu. The review below focuses on just one aspect of this, the ability to manipulate costimulatory signals, or regulatory signals, as a means to induce long-standing immune suppression. Emphasis is placed on the dominant suppression mediated following activation of any one of a number of regulatory signals as a potentially more rational approach to clinical therapy, as the redundancy in costimulatory signals suggests that blockade of any one of these may be unlikely to produce permanent unresponsiveness. The role of regulatory T cells, induced following antigen presentation in the presence of immunoregulatory signals, is also discussed.
8

The common gamma c-cytokines and transplantation tolerance

88%
Vu M. D., Li X. C.
Archivum Immunologiae et Therapiae Experimentalis
|
2004
|
vol. 52
|
issue 4
267-273
EN
Transplant rejection, like tolerance, is a T cell-dependent event. There is compelling evidence to suggest that induction of transplant tolerance is an actively learned process in which T cells need to engage the alloantigens in order to learn to tolerate the allograft. A family of cytokines whose receptors use the same IL-2 receptor gamma chain (also called the common gamma c) plays an important role in regulating multiple aspects of the allograft response (i.e. rejection vs. tolerance). It is undeniable that gamma c-cytokines can drive clonal expansion and effector maturation of alloreactive T cells, and therefore, targeting such cytokines or their receptor components remains an attractive way of blocking transplant rejection. However, we just started to appreciate that gamma c-cytokines also regulate the acquisition of transplant tolerance via programming activated T cells for apoptotic cell death and via guiding the evolution of regulatory T cells. Thus, understanding precisely the role of gamma c-cytokines in regulating T cell homeostasis and T cell regulation is critically important in the induction of transplant tolerance.
9

Deconstructing B cell tolerance to basement membranes

88%
Foster M. H., Zhang Y., Clark A. G.
Archivum Immunologiae et Therapiae Experimentalis
|
2006
|
vol. 54
|
issue 4
227-237
EN
Basement membrane antigens are frequent targets of autoantibody attack in systemic and organ-restricted autoimmunity. These specialized and highly organized matrices are composed of multiple components with restricted tissue distributions and limited epitope exposure. To the dissect mechanisms controlling humoral autoimmunity to nephritogenic basement membrane antigens, we developed autoantibody transgenic models. In mice bearing the LamH Ig transgene encoding B cell receptors specific for laminin, autoreactive B cells are readily generated but actively regulated in vivo. In this model, anti-laminin B cells are immunologically censored by mechanisms that include central deletion, k light-chain editing, and anergy. Tolerance is maintained when the transgene is established in MRL and BXSB genetic backgrounds with inherited autoimmune susceptibility, and despite provocation with potent environmental stimulants. Collectively, these studies indicate that the pathogenic anti-laminin reactivity characteristic of systemic lupus is tightly regulated. A novel anti-collagen transgenic model is used to assess the tolerogenesis of a structurally distinct pathogenic basement membrane epitope and to determine if the reactivity to putative cryptic epitopes targeted in organ-restricted disease is regulated. These studies should provide insight into the molecular mechanisms controlling basement membrane autoreactivity and ultimately facilitate the development of novel strategies to inactivate autoreactive cells and treat autoimmune disease.
10

Immunotherapy of type 1 diabetes

88%
Li L., Yi Z., Tisch R., Wang B.
Archivum Immunologiae et Therapiae Experimentalis
|
2008
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vol. 56
|
issue 4
227-236
EN
Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing beta cells are destroyed. Diabetic patients manage their hyperglycemia by daily insulin injections. However, insulin therapy is by no means a cure. Accordingly, a significant effort has been ongoing to develop immunotherapies that effectively prevent and/or treat T1D in the clinic. This review focuses on antigen- and antibody-based immunotherapies and discusses the respective strengths and weaknesses of these approaches.
11

Mechanisms of mouse T lymphocyte-induced suppression of the IgG2ab allotype and T lymphocyte tolerance to IgG2ab

88%
Majlessi L., Bordenave G.
Archivum Immunologiae et Therapiae Experimentalis
|
2001
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vol. 49
|
issue 6
407-416
EN
In mice of the Igha immunoglobulin allotypic haplotype we found, the presence of T lymphocytes with an inherent inhibitory activity against the expression of the IgG2ab allotype (IgG2a of the Ighb immunoglobulin allotypic haplotype). This constitutive anti-IgG2ab T lymphocyte activity can be enhanced in vivo by what we called 'sensitization', which usually consists of one or two intravenous injections of B splenocytes from Ighb congenic mice. When injected at birth, the resulting anti-IgG2ab T splenocytes induce, with 100% success, total, specific and chronic (but experimentally reversible) suppression of IgG2ab in Igha/b F1 hybrid mice prepared by mating Igh congenic mice. Even if restricted to IgG2ab expression, this experimental model, which deals with an unambiguous case of T cell-mediated down-regulation of immunoglobulin production, provides a clear and powerful tool to dissect finely the behavior of the partners (T and B lymphocytes) intervening in regulation within the immune system. For example, we observed that CD4 T lymphocytes were necessary to obtain full recruitment of anti-IgG2ab CD8 T lymphocytes during the sensitization, that suppression induction in anti-IgG2ab T splenocytes of newborn recipients required cooperation between CD4 and CD8 T lymphocytes, and that CD8 T lymphocytes were essential for suppression maintenance. We showed that this suppression was not characterized by an accumulation of B lymphocytes containing the allotype they could not secrete or Cgamma2ab mRNA they could not translate. The recipient's immune system was not involved in the suppession maintenance; this was done by donor T lymphocytes, which ensured the chronicity of IgG2ab suppression throughout the recipient's life. We demonstrated that the mechanism of this suppression implied an MHC-restricted presentation by target B lymphocytes of Cgamma2ab peptides to the T cell receptor (TCR) of anti-IgG2ab T lymphocytes. Notwithstanding the requirement of a CD4-CD8 T lymphocyte cooperation during the induction phase, we functionally determined that the suppression induction implicated an MHC class I-, but not class II-restricted interaction. We also demonstrated the existence in vivo of alternative or concomitant use of perforine- and Fas-mediated cytotoxicity pathways in this T cell-induced IgG2ab suppression. Thus this suppression did not imply silencing IgG2ab production, but B lymphocyte destruction by CD8 T lymphocytes. Always using our suppression model, we demonstrated that an agonistic anti-CD40 treatment helps in recruiting CD8 cytotoxic T lymphocytes, involved in immune regulatory functions and that CD40 expression on Ighb B lymphocytes confronted with CD8 T lymphocyte effectors only operating via the Fas pathway was involved in the total suppression of IgG2ab expression. The selection and maintenance of such normal T cell activity against the IgG2ab allotype in mice of different genetic backgrounds remain somewhat enigmatic. Indeed, we did not observe any similar activity against other immunoglobulin allotypes or isotypes. The intestinal flora had no influence on the emergence of this anti-IgG2ab T lymphocyte activity, as it was untouched in germ-free Igha mice when compared with normal Igha mice. More recently, this model offered an opportunity to study problems pertaining to immune tolerance. For instance, we showed that the genetic elements involved in the building of anti-IgG2ab TCR were available in Igha and Ighb mice of different genetic backgrounds, but that somatic constraints, namely the perinatal presence of IgG2ab, effectively prevented their acquisition, while its absence led to their spontaneous emergence. Consequently, we were able to induce anti-IgG2ab T lymphocytes into a tolerance state by injecting Igha mice with soluble IgG2ab during the perinatal period. However, the full T lymphocyte tolerance obtained in this manner was not definitively acquired, as it had reversed spontaneously when investigated 3 to 6 months after the end of tolerogen treatment, even when this treatment had been prolonged from the perinatal period to 9 months of age. The mechanisms (induction and reversion) of this tolerance involves the physical elimination or the irreversible inactivation of the natural anti-IgG2ab T lymphocyte clones and their resurgence, from bone-marrow precursors, as long as the thymus remains operational, but not the establishment of a reversible, functional unresponsiveness (anergy) or an active, cell-mediated inhibition of anti-IgG2ab T clones. We attempted to elucidate, in Ighb mice, whether the natural T lymphocyte unresponsiveness to IgG2ab involved a central tolerance mechanism and to identify the type of tolerogen implicated in this tolerogenesis. The experiments principally showed that this natural T lymphocyte tolerance to IgG2ab was mediated by a thymic mechanism; that the capacity to induce it was gradually acquired by Ighb thymuses and was most probably due to potentially IgG2ab-producing/presenting cells, progressively colonizing the developing thymus; and that a significantly decreased postnatal Cgamma2ab gene transcription correlated with the emergence of anti-IgG2ab T lymphocytes in Igha/b F1 (postnatally deprived of their B lymphocyte compartment), which subjected them to autoimmune IgG2ab-allotype suppression.
12

Effects of selection for more vigorous seminal roots in two cross populations of oat (Avena sativa L.)

75%
Gorny A. G., Szolkowska A.
Journal of Applied Genetics
|
1996
|
vol. 37
|
issue 4
331-344
EN
Three steps of multi stage selection for more vigorous seminal roots were done in two cross combinations of oat. The total length of roots (TRL) was measured in seedlings of the F2 , F3 and F4 generations grown in filter paper rollers. On average, the finally selected F5 (or F6 ) progenies distinguished by 7 11% improved rooting ability than their midparents. Transgressive forms were selected only in one cross combination. Coefficients of realized heritability for TRL were low and ranged from 0.08 to 0.42 indicating a relatively high proportion of non additive gene effects in the variance of TRL. Tolerance of the F6 progenies to water and nutrient limitations was evaluated in pot and field experiments. Correlated selection effects were dependent upon initial cross combination. Only progenies from one cross combination exhibited an improved drought tolerance at the 8 9 Feekes' stage. The both enhanced rooting and decreased S : R ratio of the F6 progenies correlated with their improved tolerance to reduced P supply at the 4 leaf stage. However, no significant consistence occurred between indices of the tolerance to reduced nutrition at the vegetative growth and those at field maturity. Performed root selection identified more frequently high yielding genotypes with less stable grain yield. No progenies were obtained that outperform their parents under low input conditions. It was emphasized that root selection should be accompanied by selection for integrated response components.
13

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
|
2006
|
vol. 54
|
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.
14
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Effects of acute and chronic Triazolam treatments on brain GABA levels in albino rats

75%
Aburawi S. M., Elhuwuegi E. A. E., Elhuwuegi A. E., Ahmed A. S. S., Ahmed S. S., Saad S. S. F., Saad S. F., Attia A. A. S., Attia A. S.
Acta Neurobiologiae Experimentalis
|
2000
|
vol. 60
|
issue 4
447-455
EN
The present study investigated the effects of acute and chronic intraperitoneal administration of Triazolam on g-aminobutyric acid (GABA) levels in different brain areas of albino rats. Three experiments were conducted. In the first, five groups of rats were acutely treated with different doses of Triazolam (0.25 mg/kg-4.0 mg/kg). In the second experiment, rats were treated chronically with a single daily dose of Triazolam (started with 0.25 mg/kg and increased by time to 1.0 mg/kg) for 5 weeks, simulating clinical use. In the third, rats were treated chronically with three daily doses of Triazolam (started with 0.25 mg/kg and increased by time to 0.5 mg/kg) for 20 days, representing a form of drug abuse. Brain levels of GABA and plasma levels of Triazolam were measured using high performance liquid chromatography (HPLC). The acute Triazolam administration produced an increase in GABA levels in all brain areas studied. The chronic administration of single daily dose of Triazolam produced normal GABA levels in all brain areas except brain stem where the levels were significantly decreased, this indicates the development of tolerance to Triazolam action on increasing GABA content. The chronic administration of three daily doses of Triazolam produced a decrease in GABA levels in all brain regions studied. In conclusion, chronic single daily dose treatment (representing normal use) produces tolerance to Triazolam effects on brain GABA levels, while chronic three daily doses administration (akin to drug abuse) causes a fall in GABA levels.
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