Biomedical subjects

U Payne

Publications and source records attributed to U Payne.

7 recordsLinked to original sources

PubMed2004

Cytokine correlates of clinical response patterns to infliximab treatment of ankylosing spondylitis.

OBJECTIVE: To identify clinical and immunological markers of response to treatment with infliximab in ankylosing spondylitis (AS). METHODS: Baseline and sequential cytokine levels (IL1, TNFalpha, IFNgamma, TGFbeta and IL10) were examined after 52 weeks of infliximab treatment 5 mg/kg in 22 patients. RESULTS: At week 52, 18 patients were responders and four non-responders according to ASAS group criteria. Clinical measures of disease activity between the two groups at baseline were similar, apart from a trend towards longer disease duration in non-responders (p = 0.08). Baseline CRP and TNFalpha levels were higher in responders than non-responders (p<0.01 and p<0.006, respectively). The two groups had similar baseline cytokine levels, apart from TNFalpha. Baseline CRP levels did not correlate significantly with baseline cytokine levels in responders, but a strong correlation was noted between baseline CRP and IL1, IFNgamma, and IL10 in non-responders. Apart from an early rise in TGFbeta and a decrease in IL10 in responders after the first infusion, sequential cytokine analysis for the first six months of treatment was not related to clinical disease activity measures. CONCLUSION: Although sequential cytokine analysis does not appear to be informative, baseline CRP and TNFalpha levels are useful markers of clinical response patterns in patients with AS treated with infliximab.

Adult↗

PubMed2003

Comparative immune responses to candidate arthritogenic bacteria do not confirm a dominant role for Klebsiella pneumonia in the pathogenesis of familial ankylosing spondylitis.

OBJECTIVE: Using humoral immune responses, Klebsiella pneumoniae has been implicated as a candidate microbial trigger in ankylosing spondylitis (AS) by several investigators but refuted by others. The objective of this case-control study was to compare the cellular (T-cell proliferation) and humoral (IgG and IgA, by ELISA) immune responses of affected individuals in multiplex AS families with those of unaffected family members and normal healthy controls in order to find out whether affected individuals exhibit a predominant immune response to K. pneumoniae. METHODS: Twenty-five families with two or more individuals affected with AS and 34 normal healthy controls matched with the affected family members for age, sex and ethnicity were enrolled in the study. All affected (n = 57) and unaffected (n = 37) family members had a detailed clinical evaluation. Peripheral blood was drawn to determine T-lymphocyte proliferation and the IgG and IgA (by ELISA analysis) immune responses to K. pneumoniae, Salmonella typhimurium, Yersinia enterocolitica and Chlamydia trachomatis. Immune responses to each of the four candidate organisms were compared in affected and unaffected individuals. Each individual was classified by the predominant antigenic immune response that they showed when comparison was made among the same concentrations of the four candidate microbial antigens. This stratification was then used (i) to compare immune responses in affected and unaffected family members and (ii) to compare clinical characteristics of affected family members. RESULTS: There was no difference in mean stimulation indices or antibody responses between affected and unaffected family members for each of the candidate organisms. In terms of predominant cellular immune responses to these organisms, there was no difference between affected and unaffected family members with respect to K. pneumoniae, C. trachomatis or Y. enterocolitica. However, a higher percentage of affected family members (25.9%) exhibited a predominant response to S. typhimurium compared with unaffected family members (5.9%, P < 0.02). In assessing antibody titres, K. pneumoniae was the predominant amongst these four organisms, but there was no difference between affected family members, unaffected family members and normal healthy controls. There was no relationship between immune responses and clinical characteristics. CONCLUSION: Our analysis of affected and unaffected family members in familial AS demonstrated no significant differences with respect to cellular or humoral immune responses to K. pneumoniae and three control microbes. In addition, K. pneumoniae did not exhibit a predominant immune response in affected individuals. Thus we find no supportive evidence to implicate a causal role for K. pneumoniae in familial AS.

Adult↗

PubMed2001

Clinical and imaging correlates of response to treatment with infliximab in patients with ankylosing spondylitis.

OBJECTIVES: Ankylosing spondylitis (AS) is a chronic disease leading to progressive spinal ankylosis and deformity. The aims of this study were to (1) determine whether infliximab is an effective treatment for AS patients who have failed conventional treatment; (2) identify any baseline clinical variables that can be associated with responsiveness to treatment; and (3) resolve whether the clinical response correlated with changes from baseline inflammatory changes on magnetic resonance imaging (MRI). METHODS: Twenty-one patients who met the modified New York criteria for AS (M:F 18:3) were enrolled in this open labeled study. The mean age was 37.9+/-7.9 years and mean disease duration was 8.69+/-6.58 years. Patients received infliximab at a dose of 5 mg/kg by intravenous infusion over 2 hours at 0, 2, 6, weeks. Nine functional variables were measured [i.e., Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI) etc.], 6 clinimetrics (chest expansion, finger to floor, etc.), and inflammatory markers in the peripheral blood at baseline and each subsequent visit. Primary response to treatment was defined as a > 20% response in 5/9 functional variables. A subset of 9 consecutive patients was selected for MRI scans before and after infusions. RESULTS: Eighteen patients were available for assessment at week 14 having received 3 infusions (wks 0, 2, 6). There was > 60% improvement in functional variables, i.e., BASDAI, BASFI, Health Assessment Questionnaire, fatigue, and spinal and total body pain. Clinimetric scores selectively improved, e.g., chest expansion (p < 0.021) by 14 weeks. ESR, CRP and haptoglobin all showed significant improvement at 6 weeks and were maintained to the 14 week assessment point. Imaging studies showed improvement in all patients studied including those with advanced disease. Three patients developed headache during the infusions. Infliximab was effective in all, but degree of response varied. Very good responders were distinguished from good responders by shorter duration of disease and better baseline clinimetric scores. CONCLUSIONS: Infliximab was an effective treatment for AS in a short term trial. Longterm control of symptoms and potential alteration in clinical course of disease will require longterm assessment.

Achilles Tendon↗

PubMed2000

Tumor necrosis factor receptor p55-deficient mice respond to acute Yersinia enterocolitica infection with less apoptosis and more effective host resistance.

Tumor necrosis factor (TNF) has generally been regarded as a protective cytokine in host defense against bacterial infections. In the present study, we evaluated the role of TNF in the acute phase of infection by Yersinia enterocolitica by using mice rendered genetically deficient in TNF receptor p55 (TNFRp55(-/-)). Unexpectedly, TNFRp55(-/-) mice showed more effective resistance to the bacteria, reflected in enhanced bacterial clearance and less tissue damage, than did control C57BL/6 mice. C57BL/6 mice showed evidence of extensive apoptosis in the spleen accompanied by a selective decrease in the CD4(+)-T-cell population of splenocytes, whereas TNFRp55(-/-) mice were spared these changes. The splenocytes from TNFRp55(-/-) mice also maintained a robust gamma interferon IFN-gamma response to mitogenic stimulation, while the comparable response in C57BL/6 mice was impaired. In addition, splenocytes harvested from infected mice demonstrated lower production of interleukin-10 IL-10 in TNFRp55(-/-) mice than in C57BL/6 mice. These findings suggest that Yersinia can induce TNFRp55-mediated apoptosis of splenocytes in the acute phase of the infection and that alteration of T-cell-generated cytokines can dramatically alter the early events in host defense against this pathogen.

Acute Disease↗

PubMed1999

Tumor necrosis factor receptor p55 controls the severity of arthritis in experimental Yersinia enterocolitica infection.

OBJECTIVE: To dissect the host defense mechanisms in relation to the development of Yersinia-associated arthritis by evaluating the impact of tumor necrosis factor receptor p55 (TNFRp55) deficiency on Yersinia enterocolitica infection. METHODS: TNFRp55-/- and C57BL/6 mice were inoculated intravenously with arthritogenic strain 8081 of Yenterocolitica serotype 0:8. Mice were observed daily for generating survival curves and monitoring arthritis. In subsequent sets of experiments, mice were sacrificed at day 14 after infection for examination of histopathology of joints, bacterial clearance, macrophage microbicidal activity, nitric oxide (NO) production, oxidative burst generation, and cytokine production. RESULTS: There was an 80% mortality rate in TNFRp55-/- mice compared with 25% in the controls at 8 weeks after inoculation with 70 colony-forming units of Y. enterocolitica 0:8. Histologic examination of joint tissues revealed that TNFRp55-/- mice developed more severe arthritis, including cartilage degradation and bony destruction, than controls at day 14 after infection. The more extensive joint pathology in TNFRp55-/- mice was correlated with the higher bacterial load in liver, spleen, and lungs, and with the increased levels of interleukin-10. TNFRp55-/- mice displayed impaired intracellular killing of bacteria by macrophages. This was associated with decreased NO production and impaired oxidative burst activity. CONCLUSION: This study demonstrates that TNF signaling through TNFRp55 controls the severity of Yersinia-induced arthritis and implicates TNF-mediated macrophage microbicidal activity as a central event in this process.

Animals↗

PubMed1990

Class I (H-2Kb) gene transfection reduces susceptibility of YAC-1 lymphoma targets to natural killer cells.

A "hybrid gene" (MTKb) comprised of the human metallothionein IIA promoter ligated to the genomic sequence of the major histocompatibility complex class I (H-2Kb) gene was subcloned into the expression vector pSV2neo and transfected into the natural killer (NK) cell-sensitive YAC-1 lymphoma. The Kb gene product was readily detectable on the cell surface of G418-resistant transfectants using both Kb-specific monoclonal antibodies and H-2b-specific cytolytic T cells. Unlike control pSV2neo transfectants, MTKb-pSV2neo transfectants were relatively resistant to lysis by NK cells from H-2a, H-2b, H-2k or H-2 (a x b)F1 haplotype mice. These data strongly suggest that the effects of MHC expression on susceptibility to NK cells can be mediated by a single and well-defined class I molecule, Kb.

Animals↗

PubMed1985

Natural killer cell-mediated lysis involves an hydroxyl radical-dependent step.

The role of oxygen radicals in lysis of K562 target cells by human natural killer (NK) cells was determined by addition of scavengers of these free radicals. Lysis was greatly reduced under hypoxic conditions. Superoxide dismutase and cytochrome c, scavengers of superoxide anions, and catalase and scavengers of hypochlorite had no effect on lysis. Of 15 hydroxyl radical scavengers tested, 13 inhibited lysis. These were not toxic, because cell morphology and spontaneous chromium release were not affected and preculture with scavengers was not inhibitory. These scavengers differed widely in structure, but degree of inhibition of lysis correlated with their rate constants (k) for reaction with hydroxyl radical (k vs log inhibitor concentration required to decrease lysis by 50%: r = -0.9202, p less than 0.001), showing that inhibition was due to inactivation of the hydroxyl radical. Target cell binding was not reduced at concentrations that inhibited lysis. Inhibitors of the lipoxygenase pathway also decreased lysis, suggesting this pathway to be the source of hydroxyl radicals. In view of the reported requirements for hydroxyl radical-mediated lipid peroxidation for optimal secretory activity in a number of cell types, it appears that the generation of hydroxyl radicals by NK cells is required for delivery of cytotoxic factors.

Arachidonic Acid↗