Bystander modulation of chemokine receptor expression on peripheral blood T lymphocytes mediated by glatiramer therapy

Background: Glatiramer acetate therapy is thought to be effective for multiple sclerosis (MS) by promoting TH2 cytokine deviation, possibly in the brain, but the exact mechanism and site of action are incompletely understood. Determining the site of action and effect of glatiramer on cell trafficking is of major importance in designing rational combination therapy clinical trials. Objective: To determine whether glatiramer therapy will also act in the peripheral blood through bystander modulation of chemokine receptor (CKR) expression and cytokine production on T lymphocytes. Design: Before-and-after trial. Setting: A university MS specialty center. Patients: Ten patients with relapsing-remitting MS. Interventions: Treatment with glatiramer for 12 months and serial phlebotomy. Main Outcome Measures: Cytokine production, CKR expression, and cell migration. Results: The glatiramer-reactive T cells were TH2 cytokine biased, consistent with previous studies. We found a significant reduction in the expression of the TH1 inflammation associated with the CKRs CXCR3, CXCR6, and CCR5 on glatiramer- and myelin-reactive T cells generated from patients with MS receiving glatiramer therapy vs baseline. Conversely, expression of the lymph node-homing CKR, CCR7, was markedly enhanced on the glatiramer-reactive T cells derived from patients with MS undergoing glatiramer therapy. There was a reduction in the percentage of CD4+ glatiramer-reactive T cells and an increase in the number of CD8+ glatiramer-reactive T cells. Conclusions: Glatiramer may suppress autoreactive CD4+ effector memory T cells and enhance CD8+ regulatory responses, and bystander modulation of CKRs may occur in the periphery. ©2005 American Medical Association. All rights reserved.Link_to_subscribed_fulltex

Randomised placebo-controlled trial on the effectiveness of nasal salmon calcitonin in the treatment of lumbar spinal stenosis

This is a double blind randomised controlled trial to assess the effectiveness of nasal salmon calcitonin in the treatment of lumbar spinal stenosis. The trial compared the outcome of salmon calcitonin nasal spray to placebo nasal spray in patients with MRI confirmed lumbar spinal stenosis. Lumbar spinal stenosis is one of the commonest conditions encountered by spine surgeons. It more frequently affects elderly patients and lumbar decompression has been used to treat the condition with variable success. Non operative measures have been investigated, but their success ranges from 15% to 43% in patients followed up for 1–5 years (Simotas in Clin Orthop 1(384):153–161, 2001). Salmon calcitonin injections have been investigated in previous trials and may have a treatment effect. Nasal salmon calcitonin has become available and if effective would have advantages over injections. Forty patients with symptoms of neurogenic claudication and MRI proven lumbar spinal stenosis were randomly assigned either nasal salmon calcitonin or placebo nasal spray to use for 4 weeks. This was followed by a ‘washout’ period of 6 weeks, and subsequent treatment with 6 weeks of nasal salmon calcitonin. Standard spine outcome measures including Oswestry disability index (ODI), low back outcome score, visual analogue score and shuttle walking test were administered at baseline, 4, 10 and 16 weeks. Twenty patients received nasal salmon calcitonin and twenty patients received placebo nasal spray. At 4 weeks post treatment there was no statistically significant difference in the outcome measures between the two groups. The change in ODI was a mean 1.3 points for the calcitonin group and 0.6 points for the placebo group (P = 0.51), the mean change in visual analogue score for leg pain was 10 mm in the calcitonin group and 0 mm in the placebo group (P = 0.51). There was no significant difference in walking distance between the two groups, with a mean improvement in walking distance of 21 m in the calcitonin group and 8 m in the placebo group (P = 0.78). At the end of the trial the ODI had improved by a mean of 3.7 points in the calcitonin group and 3.8 points in the placebo group (P = 0.44). This randomised placebo controlled trial has not shown any treatment effect in patients with lumbar spinal stenosis treated with nasal salmon calcitonin

Use of Magnetic Resonance Imaging as Well as Clinical Disease Activity in the Clinical Classification of Multiple Sclerosis and Assessment of Its Course: A Report from an International CMSC Consensus Conference, March 5-7, 2010

It has recently been suggested that the Lublin-Reingold clinical classification of multiple sclerosis (MS) be modified to include the use of magnetic resonance imaging (MRI). An international consensus conference sponsored by the Consortium of Multiple Sclerosis Centers (CMSC) was held from March 5 to 7, 2010, to review the available evidence on the need for such modification of the Lublin-Reingold criteria and whether the addition of MRI or other biomarkers might lead to a better understanding of MS pathophysiology and disease course over time. The conference participants concluded that evidence of new MRI gadolinium-enhancing (Gd+) T1-weighted lesions and unequivocally new or enlarging T2-weighted lesions (subclinical activity, subclinical relapses) should be added to the clinical classification of MS in distinguishing relapsing inflammatory from progressive forms of the disease. The consensus was that these changes to the classification system would provide more rigorous definitions and categorization of MS course, leading to better insights as to the evolution and treatment of MS

Involvement of interleukin-1β, nerve growth factor and prostaglandin E(2) in endotoxin-induced localized inflammatory hyperalgesia

1. Intraplantar endotoxin (ET) injection (1.25 μg) into the hind paw of rats resulted in a localized inflammatory hyperalgesia, as assessed by paw pressure (PP), paw immersion (PI), tail flick (TF) and hot plate (HP) tests. 2. ET injection resulted in a significant elevation in the levels of interleukin-1β (IL-1β) and nerve growth factor (NGF) in the injected foot as compared with the non-injected foot. This increase was attenuated by intraperitoneal injections of dexamethasone (200 and 400 μg kg(−1)) and to a lesser extent by indomethacin (2 and 8 mg kg(−1)). 3. The tripeptide Lys-D-Pro-Val, which is known to antagonize IL-1β and prostaglandin E(2) (PGE(2)) reversed mechanical hyperalgesia, as assessed by the PP test, and reduced significantly thermal hyperalgesia, as assessed by the HP and TF tests. 4. IL-1ra reversed both mechanical (PP) and thermal (PI) nociceptive thresholds tested on the injected leg and significantly reduced thermal hyperalgesia, as assessed by the HP and TF tests. 5. A sheep, anti-mouse NGF antiserum reversed mechanical hyperalgesia (PP test) but had little or no effect on thermal hyperalgesia (PI, HP and TF tests). 6. Our results indicate the importance of IL-1β, NGF and prostaglandin E(2) (PGE(2)) in the development of ET induced hyperalgesia and the possible existence of different mechanisms underlying thermal and mechanical as well as central and peripheral hyperalgesia

Modulation of ultraviolet-induced hyperalgesia and cytokine upregulation by interleukins 10 and 13

1. Exposure to midrange ultraviolet radiation (UVB) is known to produce skin inflammation similar to sunburn. The aim of this study was to characterize the hyperalgesia and cytokine upregulation induced by UVB and their modulation by antiinflammatory cytokines. 2. Acute exposure of the dorsal skin of mice to UVB (200, 250 and 300 mJ cm(2)) resulted in a dose-dependent decrease in the latencies of the hot plate and tail flick tests, without evident signs of skin lesions. 3. The observed hyperalgesia displayed a biphasic temporal evolution with an acute phase (3–6 h) and a late (48–96 h) phase. 4. Exposure to UVB (300 mJ cm(2)) elicited significant upregulation of interleukin (IL)-1β, tumour necrosis factor (TNF)-α and nerve growth factor (NGF), determined by ELISA in the exposed skin. This upregulation was more important during the acute phase of hyperalgesia. 5. Daily treatment of mice, with i.p. injections of either IL-10 or IL-13 (1.5, 7.5 and 15 ng in 100 μl saline) produced a dose-dependent attenuation of the UVB-induced hyperalgesia. 6. Treatment with the highest doses of either IL-10 or IL-13, produced significant attenuation of the levels of the cytokines and NGF by UVB, with relatively more pronounced effects by IL-13. 7. Acute exposure to moderate amounts of UVB results in a systemic hyperalgesia related to the upregulation of cytokine and NGF levels, since both were prevented by treatment with antiinflammatory cytokines