3,101 research outputs found
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CD28 Ligation Increases Macrophage Suppression of T Cell Proliferation
When compared to spleen or lymph node cells, resident peritoneal cavity cells respond poorly to T cell activation in vitro. The greater proportional representation of macrophages in this cell source has been shown to actively suppress the T cell response. Peritoneal macrophages exhibit an immature phenotype that reduces their efficacy as antigen presenting cells. Furthermore, these cells readily express inducible nitric oxide synthase (iNOS), an enzyme that promotes T cell tolerance by catabolism of the limiting amino acid arginine. Here, we investigate the ability of exogenous T cell costimulation to recover the peritoneal T cell response. We show that CD28 ligation failed to recover the peritoneal T cell response and actually suppressed responses that had been recovered by inhibiting iNOS. As indicated by cytokine ELISpot and neutralizing mAb treatment, this “co-suppression” response was due to CD28 ligation increasing the number of IFNγ-secreting cells. Our results illustrate that cellular composition and cytokine milieu influence T cell costimulation biology
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Study and Therapeutic Interference of T Cell Function in Pressure Overload-induced Heart Failure
Heart failure (HF) is a leading cause of mortality. Inflammation is implicated in HF, yet clinical trials targeting pro-inflammatory cytokines in HF were unsuccessful, possibly due to redundant functions of individual cytokines. We attempted to identify and exploit better targets in cardiac inflammation so as to enable an immunotherapy of HF.
We linked T cells with HF development in the gold-standard mouse model of HF and in human HF patients. We inhibited T cell function in vivo via T cell costimulation blockade, through FDA-approved rheumatoid arthritis drug abatacept (CTLA-Ig). Administration of abatacept led to highly significant delay in progression and decreased severity of cardiac dysfunction in the mouse HF model. The therapeutic effect occurred via inhibition of activation and cardiac infiltration of T cells and macrophages, leading to reduced cardiomyocyte death. Treatment also induced production of anti-inflammatory cytokine interleukin-10 (IL-10). IL-10-deficient mice were refractive to treatment, whilst protection could be rescued by transfer of IL-10-sufficient B cells. These results suggest that T cell costimulation blockade could be therapeutically exploited as a possible HF treatment
High-Affinity Small Molecule Inhibitors of T Cell Costimulation: Compounds for Immunotherapy
SummaryCostimulatory molecules are important regulators of T cell activation and thus favored targets for therapeutic manipulation of immune responses. One of the key costimulatory receptors is CD80, which binds the T cell ligands, CD28, and CTLA-4. We describe a set of small compounds that bind with high specificity and low nanomolar affinity to CD80. The compounds have relatively slow off-rates and block both CD28 and CTLA-4 binding, implying that they occlude the shared ligand binding site. The compounds inhibit proinflammatory cytokine release in T cell assays with submicromolar potency, and as such, they represent promising leads for the development of novel therapeutics for immune-mediated inflammatory disease. Our results also suggest that other predominantly β proteins, such as those that dominate the cell surface, may also be accessible as potentially therapeutic targets
Selective DNAM-1 expression on small peritoneal macrophages contributes to CD4+ T cell costimulation
Mouse peritoneal macrophages consist of two subsets: large peritoneal macrophages (LPMs) and small peritoneal macrophages (SPMs), defined as CD11bhiF4/80hi and CD11b+F4/80lo cells, respectively. We reveal that SPMs, but not LPMs, have the ability to present antigens to naïve CD4+ T cells. Coculture of SPMs with naïve ovalbumin (OVA) specific CD4+ T cells (OT-II) in the presence of OVA peptide effectively induced CD4+ T cells priming. SPMs, but not LPMs, strongly express DNAM-1, an activating immunoreceptor. Although antigen uptake and processing were comparable between WT and DNAM-1-deficient SPMs, deficiency of DNAM-1 on SPMs or blockade of DNAM-1 and its ligand interaction impaired CD4+ T cells priming by SPMs. Furthermore, T and B cell responses in mediastinal lymph nodes of mice intraperitoneally immunized with trinitrophenyl (TNP)–OVA protein in Alum adjuvant were enhanced by intraperitoneally transferred wild-type, but not DNAM-1-deficient, SPMs. We propose that SPMs are functionally distinct from LPMs, and DNAM-1 plays a costimulatory role in antigen presentation by SPMs
Rheumatoid arthritis
Rheumatoid arthritis is a chronic inflammatory joint disease, which can cause cartilage and bone damage as well as disability. Early diagnosis is key to optimal therapeutic success, particularly in patients with well-characterised risk factors for poor outcomes such as high disease activity, presence of autoantibodies, and early joint damage. Treatment algorithms involve measuring disease activity with composite indices, applying a treatment-to-target strategy, and use of conventional, biological, and newz non-biological disease-modifying antirheumatic drugs. After the treatment target of stringent remission (or at least low disease activity) is maintained, dose reduction should be attempted. Although the prospects for most patients are now favourable, many still do not respond to current therapies. Accordingly, new therapies are urgently required. In this Seminar, we describe current insights into genetics and aetiology, pathophysiology, epidemiology, assessment, therapeutic agents, and treatment strategies together with unmet needs of patients with rheumatoid arthritis
PlGF, immune system and hypertension
The huge diffusion of hypertension and its
associated complications has a significant impact on
public health [1]. However, despite the high prevalence
of essential hypertension and many efforts of research,
the basic pathophysiological causes remain puzzling
Guidelines for initiation of anti-tumour necrosis factor therapy in rheumatoid arthritis: similarities and differences across Europe.
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