tbuckley/cabot-search huggingface dataset:
Suppressor T cells, rebranded as regulatory T cells, emerge from the wilderness bearing surface markers
Authors: T T MacDonald
Journal: Gut (2002)

Regulatory T cells express the glucocorticoid-induced tumour necrosis factor receptor family related gene (GITR) and antibodies against this receptor block regulatory cell activity. Signaling through this receptor may be involved in diseases where normal immune tolerance is broken, such as inflammatory bowel disease or autoimmune gastritis. The 1970s and early 1980s were the heyday of cellular immunology. Complicated circuits of T cells were constructed in which helper cells were inhibited by suppressor cells which in turn were inhibited by contrasuppressor cells, and so on. By and large the actual experiments involved mixing different populations of T cells and B cells together in vitro and measuring the antibody response to the major human pathogens, sheep erythrocytes, or haptenated synthetic polymers. If the response went down, suppressor cell activity was evident. Suppressor cells were considered to be a lineage of CD8+ T cells, so that CD8 cells were either cytotoxic cells or suppressor cells. In the early to mid 1980s however, suppressor T cell research fell dramatically out of fashion. As molecular immunology took over, cellular immunology was seen as unsophisticated black magic. CD4+ helper T cells were cloned, as were cytotoxic CD8 T cell clones, but no suppressor T cell clones were made. In fact cellular immunology became a term of abuse. For those of us who teach immunology to medical students the existence of suppressor T cells was an embarrassment, dealt with by the phrase "nobody believes in these cells anymore". Shimizu J, Yamazaki S, Takahashi T, et al . Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol2002;3:135–42. [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] CD25(+)CD4(+) regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance. We show here that glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR, also known as TNFRSF18)—a … [1]: {openurl}?query=rft.jtitle%253DNature%2Bimmunology%26rft.stitle%253DNat%2BImmunol%26rft.aulast%253DShimizu%26rft.auinit1%253DJ.%26rft.volume%253D3%26rft.issue%253D2%26rft.spage%253D135%26rft.epage%253D142%26rft.atitle%253DStimulation%2Bof%2BCD25%2528%252B%2529CD4%2528%252B%2529%2Bregulatory%2BT%2Bcells%2Bthrough%2BGITR%2Bbreaks%2Bimmunological%2Bself-tolerance.%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fni759%26rft_id%253Dinfo%253Apmid%252F11812990%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1038/ni759&link_type=DOI [3]: /lookup/external-ref?access_num=11812990&link_type=MED&atom=%2Fgutjnl%2F51%2F3%2F311.atom [4]: /lookup/external-ref?access_num=000173562400013&link_type=ISI
Plasma Adiponectin Plays an Important Role in Improving Insulin Resistance With Glimepiride in Elderly Type 2 Diabetic Subjects
Authors: Taku Tsunekawa, Toshio Hayashi, Yusuke Suzuki, Hisako Matsui-Hirai, Hatsuyo Kano, Akiko Fukatsu, Noriko Nomura, Asaka Miyazaki, Akihisa Iguchi
Journal: Diabetes Care (2003)

OBJECTIVE—We investigated the effect of glimepiride, a third-generation sulfonylurea hypoglycemic agent, on insulin resistance in elderly patients with type 2 diabetes, in connection with plasma adiponectin and 8-epi-prostagrandin F2α (8-epi-PGF2α), an oxidative stress marker. RESEARCH DESIGN AND METHODS—A total of 17 elderly patients with type 2 diabetes received 12 weeks of treatment with glimepiride. Homeostasis assessment model of insulin resistance (HOMA-IR), homeostasis assessment model of β-cell function, HbA1c, C-peptide in 24-h pooled urine (urine CPR), and plasma concentrations of 8-epi-PGF2α, tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor type 1, and adiponectin were measured at various times. The metabolic clearance rate of glucose (MCR-g) was also assessed by a hyperinsulinemic-euglycemic clamp. RESULTS—After 8 weeks of glimepiride treatment, significant reductions were observed in HbA1c (from 8.4 ± 1.9 to 6.9 ± 1.0%), HOMA-IR (from 2.54 ± 2.25 to 1.69 ± 0.95%), and plasma TNF-α concentrations (from 4.0 ± 2.0 to 2.6 ± 2.5 pg/ml). MCR-g was significantly increased from 3.92 ± 1.09 to 5.73 ± 1.47 mg · kg−1 · min−1. Plasma adiponectin increased from 6.61 ± 3.06 to 10.2 ± 7.14 μg/ml. In control subjects, who maintained conventional treatment, no significant changes were observed in any of these markers. CONCLUSIONS—Glimepiride remarkably improved insulin resistance, suggested by a significant reduction in HOMA-IR, an increase in MCR-g, and a reduction in HbA1c without changing extrapancreatic β-cell function and urine CPR. Increased plasma adiponectin and decreased plasma TNF-α may underlie the improvement of insulin resistance with glimepiride.
Bidirectional Interactions between Antigen-bearing Respiratory Tract Dendritic Cells (DCs) and T Cells Precede the Late Phase Reaction in Experimental Asthma
Authors: Joong C. Huh, Deborah H. Strickland, Frode L. Jahnsen, Debra J. Turner, Jenny A. Thomas, Sylvia Napoli, Iriani Tobagus, Philip A. Stumbles, Peter D. Sly, Patrick G. Holt
Journal: The Journal of Experimental Medicine (2003)

The airway mucosal response to allergen in asthma involves influx of activated T helper type 2 cells and eosinophils, transient airflow obstruction, and airways hyperresponsiveness (AHR). The mechanism(s) underlying transient T cell activation during this inflammatory response is unclear. We present evidence that this response is regulated via bidirectional interactions between airway mucosal dendritic cells (AMDC) and T memory cells. After aerosol challenge, resident AMDC acquire antigen and rapidly mature into potent antigen-presenting cells (APCs) after cognate interactions with T memory cells. This process is restricted to dendritic cells (DCs) in the mucosae of the conducting airways, and is not seen in peripheral lung. Within 24 h, antigen-bearing mature DCs disappear from the airway wall, leaving in their wake activated interleukin 2R+ T cells and AHR. Antigen-bearing activated DCs appear in regional lymph nodes at 24 h, suggesting onward migration from the airway. Transient up-regulation of CD86 on AMDC accompanies this process, which can be reproduced by coculture of resting AMDC with T memory cells plus antigen. The APC activity of AMDC can be partially inhibited by anti-CD86, suggesting that CD86 may play an active role in this process and/or is a surrogate for other relevant costimulators. These findings provide a plausible model for local T cell activation at the lesional site in asthma, and for the transient nature of this inflammatory response.
Multiple, conserved cryptic recombination signals in VH gene segments: detection of cleavage products only in pro–B cells
Authors: Marco Davila, Feifei Liu, Lindsay G. Cowell, Anne E. Lieberman, Emily Heikamp, Anjali Patel, Garnett Kelsoe
Journal: The Journal of Experimental Medicine (2007)

Receptor editing is believed to play the major role in purging newly formed B cell compartments of autoreactivity by the induction of secondary V(D)J rearrangements. In the process of immunoglobulin heavy (H) chain editing, these secondary rearrangements are mediated by direct VH-to-JH joining or cryptic recombination signals (cRSs) within VH gene segments. Using a statistical model of RS, we have identified potential cRSs within VH gene segments at conserved sites flanking complementarity-determining regions 1 and 2. These cRSs are active in extrachromosomal recombination assays and cleaved during normal B cell development. Cleavage of multiple VH cRSs was observed in the bone marrow of C57BL/6 and RAG2:GFP and μMT congenic animals, and we determined that cRS cleavage efficiencies are 30–50-fold lower than a physiological RS. cRS signal ends are abundant in pro–B cells, including those recovered from μMT mice, but undetectable in pre– or immature B cells. Thus, VH cRS cleavage regularly occurs before the generation of functional preBCR and BCR. Conservation of cRSs distal from the 3′ end of VH gene segments suggests a function for these cryptic signals other than VH gene replacement.
Peripheral blood stem cell transplantation in 16 patients with POEMS syndrome, and a review of the literature
Authors: Angela Dispenzieri, Alvaro Moreno-Aspitia, Guillermo A. Suarez, Martha Q. Lacy, Gerardo Colon-Otero, Ayalew Tefferi, Mark R. Litzow, Vivek Roy, William J. Hogan, Robert A. Kyle, Morie A. Gertz
Journal: Blood (2004)
Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents
Authors: Reema Jasuja, Freda H. Passam, Daniel R. Kennedy, Sarah H. Kim, Lotte van Hessem, Lin Lin, Sheryl R. Bowley, Sucharit S. Joshi, James R. Dilks, Bruce Furie, Barbara C. Furie, Robert Flaumenhaft
Journal: Journal of Clinical Investigation (2012)

Thrombosis, or blood clot formation, and its sequelae remain a leading cause of morbidity and mortality, and recurrent thrombosis is common despite current optimal therapy. Protein disulfide isomerase (PDI) is an oxidoreductase that has recently been shown to participate in thrombus formation. While currently available antithrombotic agents inhibit either platelet aggregation or fibrin generation, inhibition of secreted PDI blocks the earliest stages of thrombus formation, suppressing both pathways. Here, we explored extracellular PDI as an alternative target of antithrombotic therapy. A high-throughput screen identified quercetin-3-rutinoside as an inhibitor of PDI reductase activity in vitro. Inhibition of PDI was selective, as quercetin-3-rutinoside failed to inhibit the reductase activity of several other thiol isomerases found in the vasculature. Cellular assays showed that quercetin-3-rutinoside inhibited aggregation of human and mouse platelets and endothelial cell-mediated fibrin generation in human endothelial cells. Using intravital microscopy in mice, we demonstrated that quercetin-3-rutinoside blocks thrombus formation in vivo by inhibiting PDI. Infusion of recombinant PDI reversed the antithrombotic effect of quercetin-3-rutinoside. Thus, PDI is a viable target for small molecule inhibition of thrombus formation, and its inhibition may prove to be a useful adjunct in refractory thrombotic diseases that are not controlled with conventional antithrombotic agents.
Late onset systemic lupus erythematosus in southern Chinese
Authors: C. T. K. Ho, C. C. Mok, C. S. Lau, R. W. S. Wong
Journal: Annals of the Rheumatic Diseases (1998)

<h3>OBJECTIVE</h3> Systemic lupus erythematosus (SLE) is a multisystem disorder that predominately affects women of the reproductive age. Onset of the disease beyond the age of 50 years is unusual. This study was undertaken to compare retrospectively the clinical and laboratory features between early and late onset (onset of disease beyond the age of 50 years) SLE patients in a Chinese population. <h3>METHODS</h3> Case records of all SLE patients who attended our rheumatology clinics between 1971 and 1997 were reviewed. Patients with a disease onset beyond the age of 50 years were identified. One hundred consecutive SLE patients who had their disease onset before the age of 50 were recruited as controls. The presenting clinical features, autoantibody profile, number of major organs involved, number of major relapses, and the use of cytotoxic agents in the two groups of patients were obtained and compared. <h3>RESULTS</h3> 25 patients with late onset SLE were identified. All the female patients in the late onset group were postmenopausal. The female to male ratio was 3.2 to 1, compared with 13.3 to 1 in the control group (p&lt;0.02). Both groups had a comparable duration of disease. There were no significant differences in the presenting features between the two groups except for a lower prevalence of malar rash (24% <i>v</i>86%, p&lt;0.0001) and a higher prevalence of rheumatoid factor (32%<i>v</i> 1%, p&lt;0.0001) in the late onset patients. On subsequent visits, the late onset group had a lower prevalence of lupus nephritis (4% <i>v</i> 51%, p&lt;0.001), fewer major organs involved (mean number of major organs involved; 0.3<i> v</i> 0.9, p&lt;0.02), fewer major relapses (mean number of major relapses/patient; 0.08<i>v</i> 0.47, p&lt;0.002, number of major relapses/patient year; 0.009 <i>v</i> 0.12, p&lt;0.001), and required fewer cytotoxic agents for disease control (percentage of patients on cytotoxic agents; 32%<i>v</i> 79%, p&lt;0.002). <h3>CONCLUSION</h3> Late onset SLE in Chinese tends to run a more benign course with fewer major organ involvement and fewer major relapses. The significantly higher incidence of male sex in late onset SLE and the milder disease course in the postmenopausal female patients suggest that oestrogen status may influence disease activity.
Hemodynamic Effects of Methoxamine in Mitral Valve Disease
Authors: C. ALPHEUS STANFILED, PAUL N. YU
Journal: Circulation Research (1960)

The hemodynamic changes following elevation of systemic arterial pressure and total systemic resistance by methoxamine were studied by right heart catheterization in 18 patients with mitral valve disease and 4 patients with no significant cardiovascular abnormality. This is the first detailed report of the circulatory effects of this drug in man. Changes in oxygen consumption, arterial oxygen saturation, stroke index and pulmonary artery to pulmonary "capillary" mean pressure gradient were insignificant. Forward cardiac index and heart rate decreased significantly while arteriovenous oxygen difference increased markedly in all groups of patients. The hemodynamic mechanisms involved in the changes observed during methoxamine infusion are discussed. Characteristic of patients with mitral insufficiency were significant increments of pulmonary arterial mean, pulmonary "capillary" mean, and pulmonary "capillary" V peak pressures. These subjects also had significantly greater increments in "left heart" resistance than patients without mitral insufficiency. An elevation of pulmonary "capillary" V peak pressure of 35 per cent or more of the elevation of systemic arterial systolic pressure was found to be a useful index of the presence of mitral insufficiency. Study of the pulmonary "capillary" pressure records during methoxamine infusion may obviate the necessity of left heart catheterization in the detection of significant mitral insufficiency.
ACQUIRED TOLERANCE TO SKIN HOMOGRAFTS IN MICE
Authors: Bertie F. Argyris
Journal: The Journal of Experimental Medicine (1963)

Acquired tolerance to CBA skin homografts is lost in a large number of C3H mice neonatally injected with CBA spleen cells. The skin homografts persist for at least 2 months but then exhibit a chronic rejection pattern which may last up to 7 months. Histological analysis of the lymphoid tissues reveals the onset of an immune response in the axillary lymph nodes of many 4-month-old tolerant mice. This immune response which appears before external indications of graft rejection are evident, is manifested as an increase in number of germinal centers and plasma cells in the cortex and medulla, respectively. In older tolerant mice, an even larger proportion show these histological indications of immunological activity. During graft contraction and shortly after graft rejection, the immune response is still limited to the lymph nodes. After rejection of a second graft by post-tolerant mice, histological indications of an immune response are not only found in lymph nodes but also in spleen. The data suggest the development of a host versus graft reaction in seemingly tolerant C3H mice, which increases in severity with the age of the animal. The results are discussed from the point of view that tolerance is dependent upon a critical balance between the immune potential of the host and the population of donor cells. As mice mature, their immune potential may increase. The resulting host versus graft reaction increases, culminating in the rejection of skin graft and donor lymphoid cells.
Adalimumab for long-term treatment of psoriatic arthritis: 2-year data from the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT)
Authors: P J Mease, P Ory, J T Sharp, C T Ritchlin, F Van den Bosch, F Wellborne, C Birbara, G T D Thomson, R J Perdok, J Medich, R L Wong, D D Gladman
Journal: Annals of the Rheumatic Diseases (2008)

Objective: To evaluate the long-term effectiveness and tolerability of adalimumab in the treatment of psoriatic arthritis (PsA). Methods: Patients with PsA who completed a 24-week, double-blind study of adalimumab versus placebo were eligible to enroll in an open-label extension study and receive adalimumab 40 mg subcutaneously every other week for up to an additional 120 weeks. At the time of this analysis, available efficacy evaluations throughout 2 years of treatment (n = 245) included American College of Rheumatology (ACR) 20%, 50% and 70% improvement scores, measures of joint disease and skin disease, disability and quality of life; modified total Sharp scores (mTSS) were available for 2.75 years of treatment for patients who received adalimumab in the 24-week study. Results: After 24 weeks of double-blind treatment, the mean change in mTSS was −0.2 for the adalimumab group (N = 144) and 1.0 for the placebo group (N = 152; p<0.001), and outcomes for all individual ACR component variables were significantly improved in adalimumab compared with placebo-treated patients. Compared with 24-week responses, inhibition of radiographic progression and improvements in joint disease were maintained in most patients during long-term, open-label adalimumab treatment. Also, improvements in skin disease were maintained, with >20% of patients achieving the strict criterion of psoriasis area and severity index 100. The nature and frequency of adverse events during long-term adalimumab treatment were consistent with the safety profile during short-term treatment. Conclusions: The clinical and radiographic efficacy of adalimumab demonstrated during short-term treatment was sustained during long-term treatment. Adalimumab has a favourable risk–benefit profile in patients with PsA. Trial registration number: NCT00195689.
Modulating fatty acid oxidation in heart failure
Authors: V. Lionetti, W. C. Stanley, F. A. Recchia
Journal: Cardiovascular Research (2011)

In the advanced stages of heart failure, many key enzymes involved in myocardial energy substrate metabolism display various degrees of down-regulation. The net effect of the altered metabolic phenotype consists of reduced cardiac fatty oxidation, increased glycolysis and glucose oxidation, and rigidity of the metabolic response to changes in workload. Is this metabolic shift an adaptive mechanism that protects the heart or a maladaptive process that accelerates structural and functional derangement? The question remains open; however, the metabolic remodelling of the failing heart has induced a number of investigators to test the hypothesis that pharmacological modulation of myocardial substrate utilization might prove therapeutically advantageous. The present review addresses the effects of indirect and direct modulators of fatty acid (FA) oxidation, which are the best pharmacological agents available to date for 'metabolic therapy' of failing hearts. Evidence for the efficacy of therapeutic strategies based on modulators of FA metabolism is mixed, pointing to the possibility that the molecular/biochemical alterations induced by these pharmacological agents are more complex than originally thought. Much remains to be understood; however, the beneficial effects of molecules such as perhexiline and trimetazidine in small clinical trials indicate that this promising therapeutic strategy is worthy of further pursuit.
The effect of inhaled heparin on bronchial reactivity to sodium metabisulphite and methacholine in patients with asthma
Authors: I Pavord, T Mudassar, J Bennett, P Wilding, A Knox
Journal: European Respiratory Journal (1996)

Inhaled heparin inhibits the early response to allergen and exercise-induced asthma, probably by inhibiting mast cell mediator release. Recent animal studies suggest that heparin might also inhibit cholinergic neurotransmission in asthma by restoring inhibitory M2 receptor function. We have tested the hypothesis that heparin inhibits neurally-mediated bronchoconstriction in asthma by examining the effect of inhaled heparin on bronchial reactivity to sodium metabisulphite. We also examined the effect of inhaled heparin on methacholine-induced bronchoconstriction to exclude a direct effect on airway smooth muscle. Eleven patients with mild asthma inhaled nebulized heparin (1,000 U.kg-1) or placebo (normal saline) in a randomized, double-blind fashion, 10 min before a challenge with sodium metabisulphite. Nine patients were also challenged with methacholine after the same dose of heparin or placebo. Inhaled heparin did not significantly change forced expiratory volume in one second (FEV1), nor did it alter the provocative dose of sodium metabisulphite or methacholine required to cause a 20% fall in FEV1 (PD20). Geometric mean sodium metabisulphite PD20 was 2.54 and 2.15 mumol after placebo and heparin, respectively (mean difference -0.24 doubling doses; 95% confidence interval (95% CI) -0.64-0.17). Geometric mean methacholine PD20 was 1.00 and 1.51 mumol after placebo and heparin, respectively (mean difference 0.6 doubling doses; 95% CI -0.25-1.5). Thus, heparin inhaled at doses sufficient to inhibit allergen and exercise-induced bronchoconstriction has no effect on the response to sodium metabisulphite and methacholine challenge in asthma. This argues against an inhibitory effect on neural pathways or airway smooth muscle.
Type I interferon drives tumor necrosis factor–induced lethal shock
Authors: Liesbeth Huys, Filip Van Hauwermeiren, Lien Dejager, Eline Dejonckheere, Stefan Lienenklaus, Siegfried Weiss, Georges Leclercq, Claude Libert
Journal: The Journal of Experimental Medicine (2009)

Tumor necrosis factor (TNF) is reputed to have very powerful antitumor effects, but it is also a strong proinflammatory cytokine. Injection of TNF in humans and mice leads to a systemic inflammatory response syndrome with major effects on liver and bowels. TNF is also a central mediator in several inflammatory diseases. We report that type I interferons (IFNs) are essential mediators of the lethal response to TNF. Mice deficient in the IFN-α receptor 1 (IFNAR-1) or in IFN-β are remarkably resistant to TNF-induced hypothermia and death. After TNF injection, IFNAR-1−/− mice produced less IL-6, had less bowel damage, and had less apoptosis of enterocytes and hepatocytes compared with wild-type (WT) mice. Extensive gene expression analysis in livers of WT and IFNAR-1−/− mice revealed a large deficiency in the response to TNF in the knockout mice, especially of IFN-stimulated response element–dependent genes, many of which encode chemokines. In livers of IFNAR-1−/− mice, fewer infiltrating white blood cells (WBCs) were detected by immunohistochemistry. Deficiency of type I IFN signaling provided sufficient protection for potentially safer therapeutic use of TNF in tumor-bearing mice. Our data illustrate that type I IFNs act as essential mediators in TNF-induced lethal inflammatory shock, possibly by enhancing cell death and inducing chemokines and WBC infiltration in tissues.