169 research outputs found
The Activation of Lymphocytes Is in Their CARMA
AbstractLymphocyte activation via antigen receptors initiates adaptive immune responses. Two papers in this issue of Immunity demonstrate that CARMA-1, a CARD carrying member of the MAGUK family proteins, is essential for lymphocyte activation. CARMA-1 functions by coupling antigen receptor signals to NF-κB induction and JNK activation
Antigen-dependent Proliferation of CD4+ CD25+ Regulatory T Cells In Vivo
The failure of CD25+ regulatory T cells (Tregs) to proliferate after T cell receptor (TCR) stimulation in vitro has lead to their classification as naturally anergic. Here we use Tregs expressing a transgenic TCR to show that despite anergy in vitro, Tregs proliferate in response to immunization in vivo. Tregs also proliferate and accumulate locally in response to transgenically expressed tissue antigen whereas their CD25− counterparts are depleted at such sites. Collectively, these data suggest that the anergic state that characterizes CD25+ Tregs in vitro may not accurately reflect their responsiveness in vivo. These observations support a model in which Treg population dynamics are shaped by the local antigenic environment
Sequential development of interleukin 2–dependent effector and regulatory T cells in response to endogenous systemic antigen
Transfer of naive antigen-specific CD4+ T cells into lymphopenic mice that express an endogenous antigen as a systemic, secreted protein results in severe autoimmunity resembling graft-versus-host disease. T cells that respond to this endogenous antigen develop into effector cells that cause the disease. Recovery from this disease is associated with the subsequent generation of FoxP3+CD25+ regulatory cells in the periphery. Both pathogenic effector cells and protective regulatory cells develop from the same antigen-specific T cell population after activation, and their generation may occur in parallel or sequentially. Interleukin (IL)-2 plays a dual role in this systemic T cell reaction. In the absence of IL-2, the acute disease is mild because of reduced T cell effector function, but a chronic and progressive disease develops late and is associated with a failure to generate FoxP3+ regulatory T (T reg) cells in the periphery. Thus, a peripheral T cell reaction to a systemic antigen goes through a phase of effector cell–mediated pathology followed by T reg cell–mediated recovery, and both require the growth factor IL-2
Functional Tolerance is Maintained Despite Proliferation of CD4 T Cells after Encounter with Tissue-derived Antigen
Since negative selection in the thymus is incomplete, some self-reactive T cells are able to mature and seed the periphery. To study how these T cells interact following encounter with the self-protein they recognize in the periphery, we have developed an adoptive transfer system in which HEL-specific TCR transgenic CD4 T cells are transferred to mice expressing HEL protein in the pancreas under the control of the rat insulin promoter. Here we show that after adoptive transfer of HEL-specific T cells functional tolerance is maintained despite evidence that the T cells encounter and respond to pancreas-expressed antigen. Even the provision of an additional activation stimulus by peripheral immunization with HEL protein is insufficient to induce the T cells to cause autoimmune tissue injury. However, in the presence of blocking anti-CTLA-4-mAb, immunized adoptive transfer recipients rapidly developed diabetes. These data suggest that the CTLA-4 pathway regulates the pathogenicity of antigen-specific T cells following a peripheral activation stimulus
Role of IL-17 and regulatory T lymphocytes in a systemic autoimmune disease
To explore the interactions between regulatory T cells and pathogenic effector cytokines, we have developed a model of a T cell–mediated systemic autoimmune disorder resembling graft-versus-host disease. The cytokine responsible for tissue inflammation in this disorder is interleukin (IL)-17, whereas interferon (IFN)-γ produced by Th1 cells has a protective effect in this setting. Because of the interest in potential therapeutic approaches utilizing transfer of regulatory T cells and inhibition of the IL-2 pathway, we have explored the roles of these in the systemic disease. We demonstrate that the production of IL-17 and tissue infiltration by IL-17–producing cells occur and are even enhanced in the absence of IL-2. Regulatory T cells favor IL-17 production but prevent the disease when administered early in the course by suppressing expansion of T cells. Thus, the pathogenic or protective effects of cytokines and the therapeutic capacity of regulatory T cells are crucially dependent on the timing and the nature of the disease
Cooperative Roles of CTLA-4 and Regulatory T Cells in Tolerance to an Islet Cell Antigen
Adoptive transfer of ovalbumin (OVA)-specific T cells from the DO.11 TCR transgenic mouse on a Rag−/− background into mice expressing OVA in pancreatic islet cells induces acute insulitis and diabetes only if endogenous lymphocytes, including regulatory T cells, are removed. When wild-type OVA-specific/Rag−/− T cells, which are all CD25−, are transferred into islet antigen–expressing mice, peripheral immunization with OVA in adjuvant is needed to induce diabetes. In contrast, naive CTLA-4−/−/Rag−/− OVA-specific T cells (also CD25−) develop into Th1 effectors and induce disease upon recognition of the self-antigen alone. These results suggest that CTLA-4 functions to increase the activation threshold of autoreactive T cells, because in its absence self-antigen is sufficient to trigger autoimmunity without peripheral immunization. Further, CTLA-4 and regulatory T cells act cooperatively to maintain tolerance, indicating that the function of CTLA-4 is independent of regulatory cells, and deficiency of both is required to induce pathologic immune responses against the islet self-antigen
Improvement of dissolution properties of albendazole fromdifferent methods of solid dispersion
Poor aqueous solubility of drugs results in poor absorption and bioavailability. The objective of solid dispersion technology is to
increase the dissolution properties of highly lipophilic drugs, by using different hydrophilic carriers thereby improving their
bioavailability. This technology is useful for enhancing the dissolution, absorption and therapeutic efficacy of drugs in dosage forms.
Albendazole is a broad-spectrum antihelmintic agent used for the treatment of a variety of parasitic worm infestations. It is
practically insoluble in water but slightly soluble in solvents like chloroform, methanol, ethyl acetate, and acetonitrile. The aim of
our study was to improve the dissolution profile of albendazole using HPMC K 100 LV, Kollidon VA64 and Mannitol as carriers by
solid dispersion techniques. From the prepared solid dispersion, formulation code CSF5 showed better result where carrier was
HMPC K 100 LV at 1:10 ratio in solvent evaporation method. The HPMC K 100 LV showed better result for both kneading and
solvent evaporation methods. Moreover, among the method employed, solvent evaporation method showed better solubility of drug
at 60 min also at 1:10 ratio which was 78.86%. Results indicated that current formulation of solid dispersion is a promising approach
for enhancing drug solubility and dissolution
Role of Interleukin 12 and Costimulators in T Cell Anergy In Vivo
The induction of T cell anergy in vivo is thought to result from antigen recognition in the absence of co-stimulation and inflammation, and is associated with a block in T cell proliferation and Th1 differentiation. Here we have examined the role of interleukin (IL)-12, a potent inducer of Th1 responses, in regulating this process. T cell tolerance was induced by the administration of protein antigen without adjuvant in normal mice, and in recipients of adoptively transferred T cells from T cell receptor transgenic mice. The administration of IL-12 at the time of tolerance induction stimulates Th1 differentiation, but does not promote antigen-specific T cell proliferation. Conversely, inhibiting CTLA-4 engagement during anergy induction reverses the block in T cell proliferation, but does not promote full Th1 differentiation. T cells exposed to tolerogenic antigen in the presence of both IL-12 and anti–CTLA-4 antibody are not anergized, and behave identically to T cells which have encountered immunogenic antigen. These results suggest that two processes contribute to the induction of anergy in vivo; CTLA-4 engagement, which leads to a block in the ability of T cells to proliferate to antigen, and the absence of a prototypic inflammatory cytokine, IL-12, which prevents the differentiation of T cells into Th1 effector cells. The combination of IL-12 and anti–CTLA-4 antibody is sufficient to convert a normally tolerogenic stimulus to an immunogenic one
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