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Biomedical subjects

J Killestein

Publications and source records attributed to J Killestein.

At least 19 recordsLinked to original sources
PubMed2005

Sex differences in proinflammatory cytokine profiles of progressive patients in multiple sclerosis.

The objective of this article is to evaluate the presence of sex differences in expression of cytokines in both CD4+ and CD8+ T cells derived from peripheral blood of untreated multiple sclerosis (MS) patients. The predominance of females in MS and other autoimmune diseases may be related to their differential responses in many immunological settings. Recent data show beneficial effect of sex hormones on proinflammatory cytokine levels and on magnetic resonance imaging in MS. Better understanding of gender differences is warranted. In this study 124 MS subjects (M:F; 56:68) and 34 healthy controls (M:F; 12:22) were included. Stimulated peripheral blood-derived CD4+ and CD8+ T cells were analysed for interferon-gamma, interleukin (IL)-2, tumour necrosis factor alpha, IL-4, IL- 10 and IL- 13 production. There were no significant differences for these cytokines between male and female MS subjects in the whole group. Compared to males, female patients had higher proinflammatory cytokine levels in the progressive phase of the disease. In conclusion, the data presented indicate that cytokine production and sex differences in cytokine production might differ between disease phases, probably related to underlying disease mechanisms.

Adult↗
PubMed2004

[Medicinal cannabis for diseases of the nervous system: no convincing evidence of effectiveness].

--In 1996, the Netherlands Health Council issued a negative recommendation regarding the use of medication on the basis of cannabis (marihuana). However, interest in medicinal cannabis has certainly not waned since. --The neurological diseases for which cannabis could presently be used therapeutically are: multiple sclerosis, chronic (neuropathic) pain and the syndrome of Gilles de la Tourette. --Since September 2003, the Dutch Ministry of Health, Welfare and Sport delivers medicinal cannabis to Dutch pharmacies, so that now for the first time, medicinal cannabis can be given to patients on a prescription basis within the framework of the Opium Law. The result of this is that doctors and patients now assume that this is a medication for which the efficacy and safety have been established. --The question arises whether new scientific data have become available since 1996 that provide scientific support for the current Governmental policy. --In a recent clinical trial that has aroused much discussion, patients with multiple sclerosis and problematic spasticity were treated with oral cannabis or a placebo. There was no significant effect of treatment on the primary outcome measure, i.e. objectively determined spasticity. Nevertheless, it was concluded that the mobility was improved and that the pain was subjectively decreased. --Until now, convincing scientific evidence that cannabinoids are effective in neurological conditions is still lacking. --However, it is also not possible to conclude definitely that cannabinoids are ineffective; still, this is no basis for official stimulation of their use.

Cannabis↗
PubMed2004

Osteopontin levels and increased disease activity in relapsing-remitting multiple sclerosis patients.

Osteopontin (OPN) has been identified as the most prominent cytokine-encoding gene expressed within multiple sclerosis (MS) lesions. Recently, we demonstrated that OPN plasma levels were elevated in active relapsing-remitting (RR) MS patients. In this longitudinal study, a trend was observed for OPN serum levels in relation to clinical exacerbations. Moreover, OPN protein levels were significantly elevated 1 month prior to increase of gadolinium (Gd)-enhancing lesion number, whereas no relation was observed between OPN levels and increase in Gd-enhancing lesion volume. Although no robust relation between OPN and disease activity was observed, these data suggest that OPN levels are elevated prior to increased disease activity in RR MS patients.

Adult↗
PubMed2004

Multiple sclerosis following treatment with a cannabinoid receptor-1 antagonist.

Laboratory research including animal models of human disease suggests that cannabinoids might have therapeutic potential in multiple sclerosis (MS). We have recently seen a 46-year-old woman who developed MS after starting treatment with a cannabinoid receptor antagonist for obesity. The occurrence of MS several months after starting a cannabinoid receptor antagonist suggests that the cannabinoid system might indeed be relevant to disease pathogenesis in MS.

Appetite Depressants↗
PubMed2003

Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis.

Cannabinoids can modulate the function of immune cells. We here present the first human in vivo study measuring immune function in 16 MS patients treated with oral cannabinoids. A modest increase of TNF-alpha in LPS-stimulated whole blood was found during cannabis plant-extract treatment (p=0.037), with no change in other cytokines. In the subgroup of patients with high adverse event scores, we found an increase in plasma IL-12p40 (p=0.002). The results suggest pro-inflammatory disease-modifying potential of cannabinoids in MS.

Adjuvants, Immunologic↗
PubMed2002

Safety, tolerability, and efficacy of orally administered cannabinoids in MS.

The authors conducted a randomized, double-blind, placebo-controlled, twofold crossover study in 16 patients with MS who presented with severe spasticity to investigate safety, tolerability, and efficacy of oral Delta(9)-Tetrahydrocannabinol (THC) and Cannabis sativa plant extract. Both drugs were safe, but adverse events were more common with plant-extract treatment. Compared with placebo, neither THC nor plant-extract treatment reduced spasticity. Both THC and plant-extract treatment worsened the participant's global impression.

Administration, Oral↗
PubMed2002

Seasonal variation in immune measurements and MRI markers of disease activity in MS.

BACKGROUND: The exact mechanisms by which T cells contribute to MS progression are not known. Recently, the results of cross-sectional studies suggested seasonal variation of both interferon (IFN)-gamma production and the number of active MRI lesions in MS. OBJECTIVE: To investigate whether seasonal fluctuations of IFN-gamma and active MRI lesions could be confirmed and whether any correlations could be detected. METHODS: Data were analyzed from a group of 28 MS patients in whom detailed longitudinal monitoring of both immune function and MRI measurements had taken place. RESULTS: Significant seasonal variation was observed in T-cell activation as measured by the ability of T cells to secrete the pro-inflammatory cytokines tumor necrosis factor-alpha and IFN-gamma. Maximum values were found in samples obtained during autumn. Even though clear fluctuations were observed, no significant seasonal variation could be detected in the number of active MRI lesions. Fluctuations of in vitro IFN-gamma secretion correlated weakly with changes in active MRI lesions. CONCLUSIONS: The finding of seasonal variation of immune function in serially MRI-monitored MS patients suggests an environmental role in T-cell activation.

Adult↗
PubMed2002

Baseline T cell reactivity in multiple sclerosis is correlated to efficacy of interferon-beta.

BACKGROUND: Measuring proliferative responses of T lymphocytes is a simple, reproducible and widely used assay of immune competence. Evidence suggests a role of T cell reactivity in autoimmune diseases. Interferon (IFN)-beta blocks in vitro proliferation of human T cells. OBJECTIVES: To assess (i) the relation between T cell proliferation and disease characteristics of MS patients, (ii) differences in T cell proliferation between subgroups and HC, and (iii) the predictive value of T cell proliferation for efficacy of IFN-beta. METHODS: Proliferative responses were measured in phytohaemagglutinin (PHA), anti-CD2/CD28 and anti-CD3 stimulated whole blood of 189 MS patients and 249 healthy controls (HC). Forty-eight patients started treatment with IFN-beta. Based on EDSS progression, number of relapses and steroid interventions, patients were classified as either clinical responder or nonresponder to IFN-beta. RESULTS: Significant differences between MS subgroups and HC were found in T cell responses upon both PHA stimulation (RR>HC: p=0.001 and SP>HC: p=0.001) and CD2/CD28 stimulation (RR>HC, SP>HC and PP>HC: all p values <0.001). No significant differences were found between the MS subgroups. A probability of 88% (95% CI, 71-95%) for a favorable response to IFN-beta was found with increased baseline proliferative T cell responses to PHA; a probability of only 16% (95% CI, 7-33%) with decreased values. CONCLUSION: Our results suggest that the level of T cell proliferation in whole blood predicts efficacy of IFN-beta in MS.

Adult↗
PubMed2002

Chemokine receptor expression on T cells is related to new lesion development in multiple sclerosis.

The expression of chemokine receptors CCR5 and CXCR3 on CD4 and CD8 positive T cells in blood, measured by flow cytometry, was studied in 124 patients with different clinical subtypes of multiple sclerosis (MS) and 22 healthy controls. In a subgroup of patients (n=69) from whom MRI was available, chemokine receptor expression was correlated to the annualised changes in T1 and T2 lesion load. It was found that CCR5 and CXCR3 on both cell types might have impact on annualised increase in T2 lesion load, but not on T1 lesion load. Our results suggest that chemokines may play a more important role in the development of new lesions in MS than in the long-term outcome of those lesions.

Adult↗
PubMed2001

Cytokine and IL-12 receptor mRNA discriminate between different clinical subtypes in multiple sclerosis.

Little is known about the involvement of cytokines in the pathogenesis of primary progressive (PP) multiple sclerosis (MS). We evaluated in this cross-sectional study whether IL-18, IL-12p35, IL-12p40, TNF-alpha, IFN-gamma, IL-10, IL-4, TGF-beta, IL-12Rbeta1, and IL-12Rbeta2 mRNA expression in unstimulated white blood cells showed significant differences between relapsing-remitting (RR), secondary progressive (SP) and PP MS patients, and healthy controls. All clinical subtypes showed unique mRNA expression patterns as compared to the controls. Both RR and SP patients displayed increased levels of IL-12p40, IL-18, and TGF-beta mRNA compared to controls, whereas PP patients showed only increased IL-18 mRNA levels. Both in PP and SP patients, IFN-gamma and IL-10 mRNA were decreased compared to RR patients and controls. PP patients were unique in that they showed decreased IL-12Rbeta1 mRNA. In conclusion, our data show that the assessment of cytokine (receptor) mRNA profiles is useful to discriminate between the different clinical subtypes and suggest that different cytokines are involved in the pathogenesis of PP MS as compared to RR and SP MS.

Adult↗
PubMed2001

TNFalpha production by CD4(+) T cells predicts long-term increase in lesion load on MRI in MS.

Reliable laboratory prognostic factors for MS are still lacking. The predictive value of markers of T-cell activation for long-term disease progression was investigated. Flow cytometry measurements were correlated to changes in Expanded Disability Status Scale and MR T2 lesion load over 36 months in 14 patients with secondary progressive MS. A correlation was found between the percentage of tumor necrosis factor-alpha-producing CD4(+) T cells at baseline and the change in T2 lesion load during 3-year follow-up (r = 0.79, adjusted r(2) = 0.59, p = 0.001).

Adult↗
PubMed2001

Active MRI lesion appearance in MS patients is preceded by fluctuations in circulating T-helper 1 and 2 cells.

BACKGROUND: The role of T cell subpopulations and their ability to produce immunoregulatory cytokines has been extensively studied in multiple sclerosis (MS). However, the exact mechanisms by which T cells and cytokines contribute to disease activity remain to be clarified. OBJECTIVES: To analyze the longitudinal relation between markers of T cell activation and differentiation and disease activity in MS patients. METHODS: During a period of 9 months, clinical disease activity was scored, monthly MRI scans were performed, and blood was taken for immune measurements in a group of 13 untreated clinically definite MS patients. RESULTS: Disease activity, as measured by the occurrence of active MRI lesions, is associated with a significant transient decrease in both T cells producing interferon-gamma (IFN-gamma) and T cells producing interleukin (IL)-4. CONCLUSIONS: Our results suggest that MRI-documented disease activity is associated with a transient decrease in circulating cytokine producing T cells, possibly due to the migration of activated T cells into the CNS.

Adult↗
PubMed2001

Intracellular cytokine profile in T-cell subsets of multiple sclerosis patients: different features in primary progressive disease.

OBJECTIVE: To evaluate the expression of cytokines in both CD4+ and CD8+ T cells derived from peripheral blood of untreated multiple sclerosis (MS) patients with either relapsing-remitting (RR), secondary progressive (SP) or primary progressive (PP) MS and healthy controls (HC). BACKGROUND: MS is an immune-mediated disease and cytokines hove been hypothesized to contribute significantly to disease progression. Compared to the relapse-onset (RR, SP) form of the disease, PPMS patients have different clinical, immunological and pathological features. Surprisingly, the ability of their circulating T cells to produce immunoregulatory cytokines has not been extensively studied so far. METHODS: Seventy-two MS patients (24 RR, 26 SP, 22 PP) and 34 HC were studied. Stimulated peripheral blood derived CD4+ and CD8+ T MS patients express significantly more CD4+ and CD8+ T cells were analyzed for IFN-gamma, IL-2, TNF-alpha, IL-4, IL-10 and IL-13 production. RESULTS: cells producing IFN-gamma compared to HC. Compared to the other forms of the disease, PPMS patients display a significant decrease in CD4+ T cells producing IL-2, IL-13 and TNF-alpha and a significant increase in CD8+ T cells producing IL-4 and IL-10. CONCLUSIONS: The data presented here demonstrate that patients with PPMS express less pro- and more anti-inflammatory cytokine producing T cells compared to the relapse-onset form of the disease, confirming the view on PPMS as a distinct disease entity.

Adult↗