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Background: Imatinib, a tyrosine kinase inhibitor, has been shown to restore blood-brain barrier integrity and reduce infarct size, haemorrhagic transformation and cerebral oedema in stroke models treated with tissue plasminogen activator. We evaluated the safety of imatinib, based on clinical and neuroradiological data, and its potential influence on neurological and functional outcomes.Methods: A phase II randomized trial was performed in patients with acute ischaemic stroke treated with intravenous thrombolysis. A total of 60 patients were randomly assigned to four groups [3 (active): 1 (control)]; the active treatment groups received oral imatinib for 6 days at three dose levels (400, 600 and 800 mg). Primary outcome was any adverse event; secondary outcomes were haemorrhagic transformation, cerebral oedema, neurological severity on the National Institutes of Health Stroke Scale (NIHSS) at 7 days and at 3 months and functional outcomes on the modified Rankin scale (mRS).Results: Four serious adverse events were reported, which resulted in three deaths (one in the control group and two in the 400-mg dose group; one patient in the latter group did not receive active treatment and the other received two doses). Nonserious adverse events were mostly mild, resulting in full recovery. Imatinib ameliorated neurological outcomes with an improvement of 0.6 NIHSS points per 100 mg imatinib (P = 0.02). For the 800-mg group, the mean unadjusted and adjusted NIHSS improvements were 4 (P = 0.037) and 5 points (P = 0.012), respectively, versus controls. Functional independence (mRS 0-2) increased by 18% versus controls (61 vs. 79; P = 0.296).Conclusion: This phase II study showed that imatinib is safe and tolerable and may reduce neurological disability in patients treated with intravenous thrombolysis after ischaemic stroke. A confirmatory randomized trial is currently underway. [ABSTRACT FROM AUTHOR]

The cause of multiple sclerosis (MS) is unknown. Recently reported abnormal T-cell responses to several myelin proteins and myelin basic protein (MBP) peptides in peripheral blood constitute one line of evidence that autoimmune mechanisms could be involved in the pathogenesis of the disease. Monosymptomatic unilateral optic neuritis (ON) is a common first manifestation of MS and important to examine for a possible restriction of the T-cell repertoire early in the disease. T-cell activities to MBP and the MBP amino acid sequences 63-68, 110-128 and 148-165 were examined by short-term cultures of mononuclear cells from cerebrospinal fluid (CSF) and blood in the presence of these antigens, and subsequent detection and counting of antigen-specific T cells that responded by interferon-gamma (IFN-γ) secretion. Most patients with MS and ON had MBP and MBP peptide-reactive T cells in CSF, amounting to mean values of between about 1 per 2000 and 1 per 7000 CSF cells and without immunodominance for any of the peptides. Numbers were 10-fold to 100-fold lower in the patients' blood. Values were similar in ON and MS, and no evidence was obtained for a more restricted T-cell repertoire in ON. The MBP peptide-recognizing T-cell repertoire was different in CSF than in blood in individual patients with ON and MS, thereby giving further evidence for an autonomy of the autoimmune T-cell response in the CSF compartment. No relations were observed between numbers of autoreactive T cells and presence of oligoclonal IgG bands in CSF or abnormalities on magnetic resonance imaging of the brain in ON or clinical variables of MS. The high numbers of MBP and MBP peptide-reactive T cells could play a role in the pathogenesis of ON via secretion of effector molecules, one of them being IFN-γ, as well as in the transfer of ON to MS. [ABSTRACT FROM AUTHOR]

A protein factor that stimulates CD8+ lymphocytes to produce and secrete IFN-γ has been purified from Trypanosoma brucei brucei (T.b. brucei). This was accomplished by raising monoclonal antibodies (MoAbs) against a fraction of T.b. brucei obtained by gel filtration, which contained high levels of material inducing rat mononuclear cells (MNC) to IEN-γ production. MoAbs from four hybridomas strongly inhibited trypanosome-induced IFN-γ production. One of them (MO1) was used for purification of the trypanosome-derived lymphocyte triggering factor (TLTF) by affinity chromatography. SDS electrophoresis of the purified TLTF displayed a band of 42-45 kDa MW. Gel filtration of homogenates of whole parasites yielded several peaks of IFN-γ-inducing activity with a lowest MW of 41 -46 kDa. Bioactivity of all peaks was blocked by MO1, suggesting that a single molecule, or a single epitope of additional molecules, is responsible for the different peaks with IFN-γ-inducing activity. IFN-γ released from MNC stimulates T.b. brucei growth. Blocking of TLTF in vitro with MOI inhibited MNC supported growth of the parasites. To study the in vivo relevance of TLTF in the course of experimental African trypanosomiasis, MOI was used to treat rats and mice at different times after infection. Treatments instituted at different time-points after infection suppressed parasite growth, abrogated the IFN-γ production by splenocytes induced by the infection and prolonged survival of the animals. The data support the hypothesis that TLTF and IFN-y have a crucial regulatory function in the parasite host interactions and that these molecules influence the disease course during experimental African trypanosomiasis. [ABSTRACT FROM AUTHOR]

We evaluated the B-cell response in cerebrospinal fluid (CSF) and blood by enumerating cells secreting antibodies to myelin-associated glycoprotein (MAG) and, for reference, to myelin basic protein (MBP), two myelin components which may constitute targets for autoimmune attack in multiple sclerosis (MS). Among 25 untreated MS patients, 12 had cells in CSF secreting anti- MAO IgG antibodies (mean value 1 per 1429 CSF cells) and three also had cells secreting anti- MAO antibodies of the IgM isotype but at lower levels. In CSF from 2 out of 10 MS patients examined, anti-MAO and anti-MBP IgO antibody-secreting cells were present concurrently. Antibody-secreting cells were less frequent in blood and bone marrow, reflecting compartmentalization to CSF. Anti-MAG antibody-secreting cells were found in CSF from only 1 out of 27 control patients. The intrathecal production of anti-MAG and anti-MBP antibodies may be important in the pathogenesis of MS. [ABSTRACT FROM AUTHOR]

The role of CD8+ T 'cytotoxic/suppressor' T cells in induced immunospecific tolerance and during recovery after actively induced disease was examined by means of elimination of CD8+ cells from Lewis rats using in vivo treatment by Ox8 monoclonal antibodies, in experimental allergic neuritis (EAN). Animals depleted of CD8+ T cells after recovery from EAN did not show any clinical signs of relapse. Other animals were pretreated with the peripheral nerve basic protein P2 and thereby rendered resistant to disease induction with a potentially neuritogenic emulsion. The elimination of CD8+ T cells did not result in EAN here either. Thus, the CD8+ T-cell population does not seem to participate in the suppression of this autoimmune disease under these experimental conditions. [ABSTRACT FROM AUTHOR]

Glucose-induced insulin release is decreased in the spontaneously diabetic GK rat, a nonobese rodent model of type 2 diabetes. Forskolin restores the impaired insulin release in both the isolated perfused pancreas and isolated islets from these rats (Abdel-Halim et al., Diabetes 45:934-940, 1996). We demonstrate here that the insulinotropic effect of forskolin in the GK rat is due to increased generation of cAMP and that it is associated with overexpression of adenylyl cyclase (AC)-III mRNA and gene mutations. The AC-III mRNA overexpression was demonstrated by in situ hybridization using oligonucleotide probes binding to different regions of the rat AC-III mRNA. It was associated with the presence of two point mutations identified at positions -28 bp (A --> G) and -358 bp (A --> C) of the promoter region of the AC-III gene and was demonstrable in both GK rat islets and peripheral blood cells. Transfection of COS cells with a luciferase reporter gene system revealed up to 25-fold increased promoter activity of GK AC-III promoter when compared with normal rat promoter (P < 0.0001). In conclusion, forskolin restores the impaired insulin release in islets of the GK rat through enhanced cAMP generation. This is linked to overexpression of AC-III mRNA in GK islets due to two functional point mutations in the promoter region of the AC-III gene. [ABSTRACT FROM AUTHOR]

Antibodies against peripheral nerve myelin have previously been demonstrated in serum from patients with peripheral neuropathy and IgM paraproteinaemia, and a causal relationship has been suggested. Using enzyme-linked immunosorbent assay (ELISA), anti-myelin antibodies were found in sera from eight of 16 patients with polyneuropathy and paraproteinaemia, but also in 17% of 109 patients with peripheral neuropathy lacking monoclonal immunoglobulin, including five of 10 patients with Charcot-Marie-Tooth disease, and in 16% of 142 blood donors. The antibodies were mostly of IgM class in the two neuropathy groups, while blood donors had mostly IgA antibodies, and a few subjects of each group had antimyelin antibodies of two different isotypes. Western blot confirmed the ELISA results in a majority of antibody positive sera and revealed a 25-30 kD myelin target antigen for sera from the three groups, and for some of the non-paraproteinaemic sera also a 100 kD myelin target antigen. Our results demonstrate that the presence of serum autoantibodies against peripheral nerve myelin does not necessarily indicate a pathological event. [ABSTRACT FROM AUTHOR]

T cell reactivities to the putative autoantigens myelin basic protein (MBP), MBP peptides with amino acid residues 110-128 and 148-165, and myetin proteolipid protein (PLP) were examined in patients with acute ischaemic cerebrovascular disease (CVD) and, for comparison, in patients with inflammatory neurological diseases and other neurological diseases. A quantitative measure of these T cell reactivities was obtained by assessing numbers of T cells among blood and cerebrospinal fluid (CSF) mononuclear cells that secreted IFN-γ in response to antigen in vitro. Higher numbers of T cells reactive with each of these four antigens were detected in peripheral blood from patients with CVD compared with patients of the two control groups. Among blood cells from the CVD patients, their average number was 2.3-4.2/105 mononuclear cells. MBP reactive T cells were several-fold enriched in the CSF of CVD patients. The findings strongly suggest that brain damage in context with acute CVD leads to an in vivo expansion of myelin reactive T cells. [ABSTRACT FROM AUTHOR]