Cerebrospinal Fluid TNF-alpha Research Articles

Increased levels of IL-23 and osteopontin in serum and cerebrospinal fluid of multiple sclerosis patients

Osteopontin (OPN) and interleukin-23 (IL-23) are pro-inflammatory cytokines proposed to play central roles to the development of multiple sclerosis (MS). The aim of this study was to evaluate levels of OPN, IL-23 and other inflammatory cytokines and investigate their relationships in serum and cerebrospinal fluid (CSF) in patients with MS. Fifty one MS patients and 48 patients with non-inflammatory neurological diseases (NIND) were recruited from clinic. The levels of OPN, IL-23, IL-17, IL-6, and tumor necrosis factor-alpha (TNF-alpha) in serum and CSF were determined in each participant. Compared with NIND group, MS patients had significantly elevated levels of OPN, IL-23, IL-17 and TNF-alpha in CSF, and elevated levels of IL-23, IL-17 and TNF-alpha in serum (All P<0.001). In MS patients, OPN and IL-23 were positively correlated with IL-17 (r=0.302, P=0.019; r=0.417, P=0.001, respectively); and IL-23 was positively correlated with EDSS (r=0.329, P=0.019). Both OPN and IL-23 may play pivotal role in development of MS and might be specific markers and therapeutic targets for MS.

Tumor necrosis factor-alfa and interleukin-4 in cerbrospinal fluid and plasma in different clinical forms of multiple sclerosis

Multiple sclerosis (MS) is an immune-mediated central nervous system disease characterized by inflammation, demyelination and axonal degeneration. Cytokines are proven mediators of immunological process in MS. The aim of this study was to investigate whether there is a difference in the production of the tumor necrosis factor alpha (TNF-alpha) and interleukin-4 (IL-4) in cerebrospinal fluid (CSF) and plasma in the MS patients and the controls (other neurological non-inflammatory diseases) and to determine a possible difference in these cytokines in plasma and CSF in different clinical forms of MS. This study involved 60 consecutive MS patients--48 patients with relapsing-remitting MS (RRMS) and 12 patients with secondary progressive MS (SPMS). The control group consisted of 20, age and sex matched, non-immunological, neurological patients. According to the clinical presentation of MS at the time of this investigation, 34 (56.7%) patients had relapse (RRMS), 14 (23.3%) were in remission (RRMS), while the rest of the patients, 12 (20.0%), were SPMS. TNF-alpha and IL-4 concentrations were measured in the same time in CSF and plasma in the MS patients and the controls. Extended disability status score (EDSS), albumin ratio and IgG index were determined in all MS patients. The MS patients had significantly higher CSF and plasma levels of TNF-alpha than the controls (p < 0.001 for both samples). IL-4 CSF levels were significantly lower in the MS patients than in the controls (p < 0.001), however plasma levels were similar. The patients in relapse (RRMS) and with progressive disease (SPMS) had higher concentrations of CSF TNF-alpha levels than the patients in remission (p < 0.001). IL-4 CSF levels in relapse (RRMS) and SPMS groups were lower than in the patients in remission. The patients in remission had an unmeasurable plasma TNF-alpha level and the patients with SPMS had significantly lower IL-4 levels in plasma than the patients in relapse and remission (p < 0.001). The only significant correlation between cytokine level with either EDSS, or albumin ratio, or IgG index, was found between CSF TNF-alpha levels and albumin ratio in the patients with relapse (R square = 0.431, p < 0.001). According to the obtained data MS relapse was characterized by high concentrations of TNF-alpha in CSF and plasma and low concentrations of IL-4 in CSF. Remission was characterized by high concentrations of IL-4 and low concentrations of TNF-alpha both in CSF and plasma. SPMS was characterized with lower concentrations of TNF-alpha and IL-4 compared to relapse, both in CSF and plasma.

6-Mercaptopurine exerts an immunomodulatory and neuroprotective effect on permanent focal cerebral occlusion in rats.

A bursting cascade of inflammation imposes progressive neurological deterioration after experimental stroke has been demonstrated. In our study, 6-mercaptopurine (6-mp) has been successful in alleviating cerebral infarct in a rodent permanent middle cerebral artery occlusion (pMCAO) model. The present study was aimed to examine the effect of 6-mp on cytokine levels in experimental stroke. The rodent pMCAO model was employed. A dose of 2 mg/kg 6-mp or vehicle (0.1 mol/L PBS) was administered intraperitoneally 30 min after the induction of pMCAO. Neurological score, serum, and cerebrospinal fluid (CSF) cytokines such as IL-1beta, IL-6, and TNF-alpha and infarct volume were determined 48 h after pMCAO. Cerebral infarction volume was significantly decreased in animals treated with 6-mp (74.3%, p < 0.01), and the ratio of tissue edema was also decreased in 6-mp-treated groups (71%). Animals receiving 6-mp thus showed a significant decrease in IL-1 and TNF-alpha (18/43% and 48/64% in CSF/serum, respectively) when compared with the pMCAO groups (p < 0.01). This study demonstrates that 6-mp interposes the production of IL-1 and TNF-alpha in CSF and serum, attenuates ischemic brain injury, and thus alleviates neurological deficits in the pMCAO animals. These findings also offer first evidence that 6-mp may attenuate TNF-alpha-related neuron apoptosis and also support the notion that 6-mp and other anti-inflammatory agents could potentially have therapeutic uses in cases of cerebral infarct.

Multiple Therapeutic Effects of Adjunctive Baicalin Therapy in Experimental Bacterial Meningitis

This study aimed to examine effects of adjunctive baicalin therapy to ampicillin for experimental bacterial meningitis in rabbits. After Escherichia Coli inoculation, mean leukocyte counts, concentrations of protein, tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and lactate in cerebrospinal fluid (CSF), brain water content and mean arterial and intracranial pressures substantially increased in the meningitis group. Ampicillin alone for 5 h markedly exacerbated the enhanced leukocyte counts and protein concentration, and showed no significant effect on the elevated CSF TNF-alpha, IL-1 and lactate concentration, mean arterial and intracranial pressures, and brain water content. Baicalin (7-D-glucuronic acid-5,6-dihydroxyflavone, C(21)H(18)O(11)) completely counteracted ampicillin-induced exacerbation, and further alleviated the enhanced mean leukocyte counts and protein concentration when combined with ampicillin. Adjunctive baicalin also significantly ameliorated the elevated CSF TNF-alpha, IL-1 and lactate concentration, mean arterial and intracranial pressures, and brain water content. Baicillin, as an adjunctive treatment exerted multiple therapeutic effects in experimental bacterial meningitis.

Interleukin-6 Is Elevated in the Cerebrospinal Fluid of Suicide Attempters and Related to Symptom Severity

Depressive disorders are associated with immune system alterations that can be detected in the blood. Cytokine concentrations in cerebrospinal fluid (CSF) and their relationship to aspects of suicidality have previously not been investigated. We measured interleukin-1beta, interleukin-6 (IL-6), interleukin-8, and tumor necrosis factor-alpha (TNF-alpha) in CSF and plasma of suicide attempters (n = 63) and healthy control subjects (n = 47). Patients were classified according to diagnosis and violent or nonviolent suicide attempt. We evaluated suicidal ideation and depressive symptoms using the Suicide Assessment Scale and the Montgomery-Asberg Depression Rating Scale (MADRS). We also analyzed the relation between cytokines and monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in CSF, as well as the integrity of the blood-brain barrier as reflected by the CSF:serum albumin ratio. IL-6 in CSF was significantly higher in suicide attempters than in healthy control subjects. Patients who performed violent suicide attempts displayed the highest IL-6. Furthermore, there was a significant positive correlation between MADRS scores and CSF IL-6 levels in all patients. IL-6 and TNF-alpha correlated significantly with 5-HIAA and HVA in CSF, but not with MHPG. Cytokine levels in plasma and CSF were not associated, and patients with increased blood-brain barrier permeability did not exhibit elevated cytokine levels. We propose a role for CSF IL-6 in the symptomatology of suicidal behavior, possibly through mechanisms involving alterations of dopamine and serotonin metabolism.

The Effects of β-Adrenoceptor Antagonists on Proinflammatory Cytokine Concentrations After Subarachnoid Hemorrhage in Rats

Proinflammatory cytokines increase in cerebrospinal fluid (CSF) after subarachnoid hemorrhage (SAH). Recent evidence suggested that beta-adrenoceptor antagonist could reduce proinflammatory cytokines. We conducted the present study to examine whether beta-adrenoceptor antagonists would reduce proinflammatory cytokine concentrations after SAH in rats. In Experiment 1, to investigate the time course of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), rats were randomized into groups: 1, 3, 6, and 12 h after SAH or sham operation. CSF and blood samples were obtained at each time point. In Experiment 2, to investigate the effects of beta-adrenoceptor antagonists on the IL-6 and TNF-alpha concentrations, rats were randomized into groups: 1) control group: SAH + normal saline, 2) propranolol group: SAH + propranolol, 3) metoprolol group: SAH + metoprolol, and 4) butoxamine group: SAH + butoxamine (beta(2)-adrenoceptor antagonist). CSF and blood samples were obtained 6 h after SAH. IL-6 and TNF-alpha concentrations in samples were measured. In Experiment 1, CSF IL-6 concentrations in the SAH groups increased markedly and peaked at 6 h after SAH, whereas CSF TNF-alpha concentrations in the SAH groups were consistently low. In Experiment 2, CSF IL-6 concentrations in the propranolol and butoxamine groups were significantly lower compared with those in the control group (P < 0.01 and P < 0.05 for each group). Plasma IL-6, CSF TNF-alpha, and plasma TNF-alpha concentrations were comparable in all four groups. CSF IL-6 concentrations increased in the acute stage of SAH and beta-adrenoceptor antagonists with a beta(2)-adrenoceptor blocking action suppressed this elevation of IL-6 concentrations after SAH in rats.

Effect of infliximab in progressive Neuro-Behçet's syndrome

Recent studies have shown the beneficial effect of infliximab in ocular manifestation of Behçet's disease. The current studies examined the efficacy of infliximab in progressive neuro-Behçet's syndrome (NB) refractory to methotrexate (MTX). Five male patients with progressive NB with sustained elevation of cerebrospinal fluid (CSF) IL-6 (over 20 pg/ml) despite administration of MTX and steroid, were given intravenous infusion of 5 mg/kg infliximab at weeks 0, 2, 6, and 14 with MTX (10-17.5 mg/week) and prednisolone (<10 mg/day) at the same doses. The clinical responses were judged by neuropsychiatric findings, revised Wechsler adult intelligence scale (WAIS-R), and brain magnetic resonance imaging (MRI) scans at 24 weeks. In all the 5 patients, CSF IL-6 were markedly decreased by 1/2-1/37 on the next day of the first infusion and remained below 20 pg/ml before the last infusion at 14 weeks, whereas CSF TNF-alpha were not significantly changed at any time point. At 24 weeks from the initial infusion, none of the 5 patients showed exacerbation (3 patients significantly improved). Nor did the atrophy in midbrain, pons and medulla on brain MRI scans show significant progression. These results suggest that infliximab might have a beneficial effect in the treatment of progressive NB by reducing CSF IL-6 levels but not TNF-alpha. Since infliximab has been shown to have cytotoxic effects on monocytes/macrophages, the rapid fall of CSF IL-6 after the infusion suggest that infliximab might directly act on such inflammatory cells producing IL-6.

Proinflammatory cytokine levels in the serum and cerebrospinal fluid of tuberculous meningitis patients

The pathophysiology underlying tuberculous meningitis (TBM), the most prominent extra pulmonary tuberculosis and a serious public health problem in developing countries is still unclear. Whereas, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) are cytokines involved in cell-mediated immune response. TNF-alpha and IFN-gamma production has earlier been shown to be associated with tissue necrosis. To see whether these cytokines have any role to play in the pathophysiology of TBM, we measured the levels of serum and cerebrospinal fluid (CSF) TNF-alpha and IFN-gamma in 31 consecutive patients of TBM by ELISA. There was a remarkable rise (P<0.001) in the levels of serum and CSF TNF-alpha and IFN-gamma levels in TBM patients with respect to 20 age and sex-matched control subjects. Furthermore, TNF-alpha and IFN-gamma levels showed a positive correlation with the severity of the disease at the end of 6 months of antibiotic therapy. Elevated TNF-alpha and IFN-gamma levels, especially in CSF, despite of these patients undergoing multidrug therapy suggests the persistence of central nervous system inflammation. We also found an associated rise (P<0.001) in the nitric oxide (NO) levels of serum and CSF but there was no correlation between NO levels and the severity of TBM. The continuous release of cytokines despite these patients undergoing anti-tubercular therapy suggests that TBM severity may result mainly from the immune response rather than the organism itself.

Factors influencing the anti-inflammatory effect of dexamethasone therapy in experimental pneumococcal meningitis.

Dexamethasone (DXM) interferes with the production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) and can thereby diminish the secondary inflammatory response that follows initiation of antibacterial therapy. A beneficial effect on the outcome of Haemophilus meningitis in children has been proven, but until recently the effect of DXM therapy in pneumococcal meningitis was uncertain. The aim of the present study was to evaluate factors that might influence the modulatory effect of DXM on the antibiotic-induced inflammatory response in a rabbit model of pneumococcal meningitis. DXM (1 mg/kg) was given intravenously 30 min before or 1 h after administration of a pneumococcal cell wall extract, or the first dose of ampicillin. In meningitis induced by cell wall extract, DXM therapy prevented the increase in cerebrospinal fluid (CSF) leucocyte and lactate concentrations, but only if given 30 min before the cell wall extract. In meningitis caused by live organisms, initiation of ampicillin therapy resulted in an increase in CSF TNF-alpha and lactate concentrations only in animals with initial CSF bacterial concentrations > or =5.6 log10 cfu/mL. In those animals, DXM therapy prevented significant elevations in CSF TNF-alpha [median change -184 pg/mL, -114 pg/mL versus +683 pg/mL with DXM (30 min before or 1 h after ampicillin) versus controls (no DXM), respectively, P=0.02] and lactate concentrations [median change -10.6 mmol/L, -1.5 mmol/L versus +14.3 mmol/L with DXM (30 min before or 1 h after ampicillin) versus controls (no DXM), respectively, P=0.01]. These effects were independent of the timing of DXM administration. In this model of experimental pneumococcal meningitis, an antibiotic-induced secondary inflammatory response in the CSF was demonstrated only in animals with high initial CSF bacterial concentrations (> or =5.6 log10 cfu/mL). These effects were modulated by DXM therapy whether it was given 30 min before or 1 h after the first dose of ampicillin.

Early TNF-alpha levels correlate with ischaemic stroke severity.

The study aimed to evaluate the levels of an important proinflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) in cerebrospinal fluid (CSF) and serum in acute stroke and to study the relation between those and the neurological stroke severity and functional disability. The investigations comprised 23 ischaemic stroke patients. CSF and blood samples were obtained 24 h after the onset of stroke, and stored until analysis. Patients were examined according to Scandinavian Stroke Scale (SSS) and to Barthel Index (BI). The patients displayed statistically significant high levels of TNF-alpha in CSF and sera within the first 24 h of stroke. These correlated significantly with SSS and BI scores calculated within the same interval, and 1 and 2 weeks later. Our results suggest the involvement of TNF-alpha in mechanisms of early stroke-induced inflammation and a predictive value of the initial TNF-alpha levels for the outcome of stroke.

Tumour necrosis factor-alpha is increased in the cerebrospinal fluid and serum of ischaemic stroke patients and correlates with the volume of evolving brain infarct

A growing body of evidence suggests the involvement of inflammatory mediators, including cytokines, in the development of ischaemic brain lesions. The aim of the present study was to investigate whether tumour necrosis factor-alpha (TNF-alpha), the proinflammatory cytokine, contributes to early pathophysiological mechanisms leading to brain damage as a consequence of acute stroke. We have studied TNF-alpha levels in cerebrospinal fluid (CSF) and serum in 23 stroke patients within the first 24 hours after ischaemic stroke, confirmed by computerized tomography of the brain (CT). The control group consisted of 15 patients with the diagnosis of tension headache and neurasthenia. In stroke patients the levels of TNF-alpha both in CSF and serum were significantly higher in comparison with the control group. The positive correlation between the levels of TNF-alpha in CSF and serum of the studied patients has been observed. Furthermore, a positive correlation between both TNF-alpha levels in CSF and serum and the volume of evolving brain infarct have been shown.

Are elevated cerebrospinal fluid levels of IL-6 in sudden unexplained deaths, infectious deaths and deaths due to heart/lung disease in infants and children due to hypoxia?

Many SIDS cases probably die after periods of hypoxia and it has been shown that hypoxia may stimulate IL-6 production. The purpose of this paper was to examine if there were any correlations between hypoxanthine in vitreous humour and IL-6 in CSF. The concentration of IL-6, IL-1beta and TNFalpha in cerebrospinal fluid of 50 Sudden Infant Death syndrome (SIDS) cases, 9 borderline SIDS cases, 18 infectious deaths, 8 violent deaths and 22 cases with heart/lung disease were measured by ELISA. The hypoxanthine (Hx) vitreous humour concentrations in the same groups were determined by high performance liquid chromatography. The IL-6 levels in cases of infectious death, heart/lung disease and borderline cases were significantly higher than in the SIDS cases (p < 0.01). The Hx levels were in the same range in cases of SIDS, borderline SIDS and infectious death, and they were significantly higher than the levels in cases of violent death and heart/lung disease (p < 0.01). There was no correlation between hypoxanthine and IL-6 in any of the groups. In the cases studied IL-6 elevation is probably not induced by hypoxia, but is rather a result of immunological stimulation.

The effect of interleukin-10 on meningeal inflammation in experimental bacterial meningitis.

Interleukin-10 (IL-10) is a cytokine with antiinflammatory effects. In a rabbit model of meningitis, IL-10 was given intracisternally or intravenously to evaluate the impact on inflammation induced by lipooligosaccharide (LOS), Haemophilus influenzae type b (Hib), or Listeria monocytogenes. Intracisternal IL-10 in concentrations >1 microg significantly reduced tumor necrosis factor-alpha (TNF-alpha) and lactate values in cerebrospinal fluid (CSF). Intravenous IL-10 (1 mg/kg) in two doses after intracisternal LOS significantly reduced CSF TNF-alpha and lactate. When Hib was used, animals were treated with ceftriaxone and dexamethasone with or without IL-10 (1 mg/kg). TNF-alpha was significantly reduced in animals treated with IL-10, dexamethasone, or both compared with levels in rabbits receiving ceftriaxone alone. Comparable results were obtained when L. monocytogenes was inoculated and animals were treated with ampicillin with or without IL-10, dexamethasone, or nothing. In conclusion, IL-10 modulates CSF TNF-alpha concentrations in experimental LOS, Hib, or L. monocytogenes meningitis. The maximal inhibitory effect was seen when IL-10 and dexamethasone were combined.

Tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 concentrations in cerebrospinal fluid predict ventriculoperitoneal shunt infection.

To determine the diagnostic value of cerebrospinal fluid tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and IL-6 released into the cerebrospinal fluid of patients with ventriculoperitoneal shunt infection. Prospective, observational study. University teaching hospital. Sixty-four patients requiring cerebrospinal fluid aspiration for suspected ventriculoperitoneal shunt malfunction. Cerebrospinal fluid samples were obtained by shunt aspiration at the time of patient presentation. TNF-alpha and IL-1 beta concentrations were measured by enzyme-linked immunosorbent assay, and IL-6 activity by bioassay. The sensitivity, specificity, predictive values, and overall efficiency for each cytokine were determined based on the cerebrospinal fluid culture results. Ten patients had positive cerebrospinal fluid cultures, eight of which yielded Staphylococcus species, and one each Acinetobacter and Pseudomonas. Cerebrospinal fluid TNF-alpha, IL-1 beta, IL-6, protein, and leukocyte concentrations were significantly increased in patients with shunt infection. Cerebrospinal fluid IL-6 activity had the highest diagnostic accuracy of the cytokines evaluated, with sensitivity of 80% and specificity of 98%. The presence of cerebrospinal fluid inflammatory cytokines strongly suggests ventriculoperitoneal shunt infection. Detection of these cytokines in the cerebrospinal fluid could be used for earlier diagnosis of bacterial infection.

Tumour necrosis factor alpha is elevated in serum and cerebrospinal fluid in multiple sclerosis and inflammatory neuropathies.

Tumour necrosis factor alpha (TNFalpha) is a peptide that is derived from T lymphocytes and macrophages and is used as a marker of activated cellular immune responses. TNFalpha was measured in paired sera and cerebrospinal fluid (CSF) from 30 patients with multiple sclerosis (MS) with worsening disability, 54 patients with other neurological diseases, and 20 normal subjects. A sensitive enzyme-linked immunosorbent assay was used to determine the TNFalpha levels. We found significantly elevated serum and CSF levels in 12 (40%) and 6 (20%) MS patients, respectively, compared with healthy controls (P < 0.007 and P < 0.05). Among the 18 patients with neuropathy, we also found high serum and CSF TNFalpha values in 3 (17%) and 5 (28%) patients, respectively (P < 0.04 and P < 0.002). Our study shows that TNFalpha is probably involved in the pathogenetic mechanisms of MS and other inflammatory neurological diseases.

Concentrations of interferon gamma, tumor necrosis factor alpha, and interleukin-1 beta in the cerebrospinal fluid of children treated for tuberculous meningitis.

Concentrations of interferon gamma (IFN-gamma) in the lumbar cerebrospinal fluid (CSF) of 30 children (mean age, 27 months) being treated for stage III (16 children) and stage II (14 children) tuberculosis meningitis (TBM) were determined by ELISA. Nine children with stage III TBM and six with stage II TBM received prednisone (4 mg/kg). Concentrations of IFN-gamma in 73 CSF specimens (18 from the first week of therapy, 20 from the second, 19 from the third, and 16 from the fourth) were determined. The mean concentrations were 780 pg/mL in the first week of therapy and 554 pg/mL, 529 pg/mL, and 269 pg/mL in the second, third, and fourth weeks, respectively. Tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) concentrations in 56 specimens from 23 of these same children were determined by ELISA. The mean CSF TNF-alpha concentration in 12 specimens obtained during the first week of therapy was 17 pg/mL, and the mean was 11 pg/mL during each of the subsequent weeks (14 specimens were evaluated in the second week and 15 specimens in the third and fourth weeks of therapy). Mean IL-1beta concentrations in these same groups of specimens were 52 pg/mL, 43 pg/mL, 42 pg/mL, and 18 pg/mL. No correlation could be shown between cytokine concentration and stage of disease, and no differences existed between those who did and those who did not receive prednisone. A significant decline in IL-1beta concentrations was shown during the 4-week period, but none in TNF-alpha or IFN-gamma concentrations was noted. Persistently high CSF INF-gamma concentrations in cases of TBM (as in cases of aseptic meningitis but not bacterial meningitis) at the time of diagnosis suggest an immune response fundamentally different from that in bacterial meningitis.

Immunological fluctuations during intrathecal immunotherapy in three patients affected by CNS tumours disseminating via CSF.

The immunological therapy of cancer has been proposed in a number of neoplasms (Borden, Sondel, 1989; Foon, 1989; Rosenberg, 1992) and has recently been adopted in the treatment of Central Nervous System (CNS) tumors in combination with conventional surgical and radiotherapeutical approach. In this context, loco-regional administration of immunomodulating agents (for instance in post-surgical cavity) allows to achieve much higher in situ concentrations than by systemic route. Since these treatments have potential adverse effects, careful assessment of clinical and immunological parameters in phase I trials is needed. CNS tumors disseminating via Cerebrospinal Fluid (CSF) pathways offer a stimulating opportunity for intrathecal immunotherapy. In this context, alpha-IFN and IL2 (alone or in combination with LAK cells) have been employed either loco-regionally or intrathecally (Merchant, Mc Vicar, Merchant & Young, 1992; Schiller, Hank, Storer, Borchert, Moore, Albertini, Bechhofer, Wesley, Brown, Bastin & Sondel, 1993). The rationale for the use of both these substances includes the known anti-tumor action of alpha-IFN (Mahaley, Urso, Whaley, Blue, Williams, Guaspari & Selker, 1985; Nagai, 1988) and the ability of r-IL2 to generate activated cells effective in lysing tumor cell targets (Hayes, Moore, Pierz, Chen, Da Rosso, Nirenberg & Allen, 1993). We treated 3 patients (2 affected by disseminating cerebellar medulloblastoma, 1 by disseminating thalamic glioblastoma) by intrathecal r-IL2 via recervoir. In the first 2 patients, this treatment was preceded by alpha-IFN (also intrathecally). Monitoring of immunological effects of the treatment schedule involved kinetics of CSF and serum TNF-alpha, IL2s and IL2R during the first day of r-IL2 treatment, as well as on day +2 and +4 of both r-IL2 cycles, and assessment of CSF cells, protein and CSF and PB NK cell activity and CD3-CD56+ cells during the course of all treatment cycles. We also assessed clinical and neuroradiological effects of immunotherapy.

Cerebrospinal fluid cytokines in AIDS dementia complex.

We evaluated cerebrospinal fluid (CSF) and serum concentrations of interleukin-1-alpha (IL-1-alpha), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) in 30 patients with AIDS dementia complex (ADC), and in 20 HIV-seronegative subjects with other neurological diseases (OND). CSF TNF-alpha, IL-1-alpha and IL-6 were more frequently detectable in ADC patients than in OND subjects. These cytokines were also detectable in CSF of ADC patients with minimal symptoms. In contrast, the majority of both ADC and OND patients did not contain detectable serum levels of cytokines. Our data support the notion of intrathecal synthesis of cytokines in ADC patients and raise the possibility that activated macrophages may play a significant role in the pathogenesis of ADC.

Tumor cell dissemination triggers an intrathecal immune response in neoplastic meningitis.

The intrathecal immune response in neoplastic meningitis (NM) was studied by quantitation of immune parameters such as immunoglobulin G (IgG); IgM; interleukins (IL) 1, 2, 4, and 6; soluble IL-2 receptors (sIL-2R); interferon gamma (IFNy); tumor necrosis factor-alpha (TNF alpha); and three tumor markers, carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), and fibronectin (FN), in 47 paired cerebrospinal fluid (CSF) and serum samples from patients with NM from different carcinomas, malignant melanoma, and lymphoma. Elevated IgG and IgM indices, CSF oligoclonal Ig bands, and CSF IL-6 indicated an intrathecal immune activation in most patients with NM. Results for IL-1, IL-2, and IL-4 were always negative. sIL-2R and IFNy were detected occasionally but not associated with specific malignant neoplasms. CSF TNF alpha was detected only in NM from cases of malignant melanoma. None of the immune parameters proved useful for the differentiation of NM from autoimmune or inflammatory conditions. Immune parameters were not correlated with tumor markers CEA, AFP, or FN. Results for AFP were positive only in a case of glioblastoma. CEA was a useful and specific diagnostic parameter in carcinomatous NM. CSF FN levels frequently were elevated but are not specific for NM.

Association between Tumor Necrosis Factor-α and Disease Progression in Patients with Multiple Sclerosis

Cachectin, or tumor necrosis factor-alpha (TNF-alpha), is a principal mediator of the inflammatory response and may be important in the pathogenesis and progression of multiple sclerosis, an inflammatory disease of the central nervous system. In a 24-month prospective study, we used a sensitive enzyme-linked immunosorbent assay to determine levels of TNF-alpha in cerebrospinal fluid and serum in 32 patients with chronic progressive multiple sclerosis and in 20 with stable multiple sclerosis and 85 with other neurologic diseases. An attempt was made to relate TNF-alpha levels with the degree of disability of the patients with multiple sclerosis and with their neurologic deterioration during the 24 months of observation. High levels of TNF-alpha were found in the cerebrospinal fluid of 53 percent of the patients with chronic progressive multiple sclerosis and in none of those with stable multiple sclerosis (P less than 0.001). TNF-alpha was detected in the cerebrospinal fluid of 7 percent of the controls (P less than 0.01) with other neurologic disease. In patients with chronic progressive multiple sclerosis, mean TNF-alpha levels were significantly higher in the cerebrospinal fluid than in corresponding serum samples (52.41 vs. 11.88 U per milliliter; range, 2 to 178 vs. 2 to 39; P less than 0.001). In these patients, cerebrospinal fluid levels of TNF-alpha correlated with the degree of disability (r = 0.834, P less than 0.001) and the rate of neurologic deterioration (r = 0.741, P less than 0.001) before the start of the study. Cerebrospinal fluid levels also correlated with the increase in neurologic disability after 24 months of observation (r = 0.873, P less than 0.001). These data provide evidence of intrathecal synthesis of TNF-alpha in multiple sclerosis and suggest that the level of TNF-alpha in cerebrospinal fluid correlates with the severity and progression of the disease. Our results suggest that TNF-alpha may reflect histologic disease activity in multiple sclerosis and could be used to monitor outcomes or responses to therapy.