Biomedical subjects

T Olsson

Publications and source records attributed to T Olsson.

At least 217 records · Page 12Linked to original sources

PubMed1994

Increased transforming growth factor-beta, interleukin-4, and interferon-gamma in multiple sclerosis.

The inflammatory nature of multiple sclerosis (MS) implicates the participation of immunoregulatory cytokines, including the T-helper type 1 (Th1) cell-associated interferon-gamma (IFN-gamma), the Th2 cell-related interleukin-4 (IL-4), and the immune response-downregulating cytokine transforming growth factor-beta (TGF-beta), but proof for their involvement in MS has been lacking. By adopting in situ hybridization with complementary DNA oligonucleotide probes for human IFN-gamma IL-4, and TGF-beta, the expression of mRNA for these cytokines was detected in mononuclear cells (MNC) from blood and cerebrospinal fluids. Strongly elevated levels of MNC expressing all three cytokines were found in peripheral blood and at even higher frequencies in cerebrospinal fluid from untreated patients with MS and optic neuritis, i.e., a common first manifestation of MS, compared with patients with other neurological diseases and healthy subjects. In MS and optic neuritis, IL-4 mRNA expressing cells predominated, followed by TGF-beta- and IFN-gamma-positive cells. Control patients with myasthenia gravis had similarly elevated levels of IFN-gamma and TGF-beta and TGF-beta mRNA expressing blood MNC but lower numbers of IL-4-positive cells. No or slight disability of MS was associated with high levels of TGF-beta mRNA expressing cells, while MS patients with moderate or severe disability had high levels of IFN-gamma-positive cells. IFN-gamma and TGF-beta may have opposing effects in MS, and treatments inhibiting IFN-gamma and/or promoting TGF-beta might ameliorate MS.

Adult↗

PubMed1994

Multiple sclerosis:cerebrospinal fluid.

Examination of cerebrospinal fluid (CSF) in the context of multiple sclerosis (MS), is valuable for several reasons. First, routine diagnostic evaluation of CSF cell counts and various forms of immunoglobulin determination are important to differentiate MS from other diseases. Second, because MS most probably is an organ-specific inflammatory disease and CSF is often the closest one can get to the target organ, examination of this fluid may allow basic studies on the immunopathogenesis of the disease, and indications of different aspects of inflammation should be considered when evaluating treatments aimed at reducing central nervous system inflammation. This article describes measurements taken at the cellular level in blood and CSF, of myelin-antigen autoreactive B- and T-cell responses, as well as cytokine production. Patients with MS display greatly increased numbers of cells in the CSF that produce antibodies against a variety of myelin antigens, such as myelin basic protein, proteolipid protein, and myelin-oligodendrocyte glycoprotein. Such antibodies may promote demyelination, and autoreactive B cells may enhance antigen presentation to T cells. There is also an increased number of T cells in MS, which in response to a broad range of myelin antigens and peptides, produce cytokines. The production of interferon-gamma, belonging to the T helper-1 type of cells, may have a disease up-regulatory role, while production of other cytokines, such as transforming growth factor beta, may counteract disease. Accurate measurements of cellular production of cytokines will be important in the design and monitoring of immunotherapy.

Autoantigens↗

PubMed1994

Neuronal interferon-gamma immunoreactive molecule: bioactivities and purification.

An interferon (IFN)-gamma immunoreactive molecule, localized to small neurons in peripheral sensory ganglia (N-IFN-gamma), has been detected with two mouse monoclonal antibodies (DB1 and DB16) directed against different epitopes of rat IFN-gamma. To define N-IFN-gamma with regard to its protein characteristics and bioactivities, DB1 and DB16 were used to purify N-IFN-gamma from rat trigeminal ganglia in a two-step sequential antibody-affinity procedure. Sodium dodecylsulfate polyacrylamide gel electrophoresis (PAGE) and silver staining of purified N-IFN-gamma displayed three bands with an approximate molecular mass of 66, 62 and 54 kDa. The N-IFN-gamma bioactivity was confined to the protein stained on gel when native material was run on PAGE. Biological effects of pure N-IFN-gamma were examined and compared with those of lymphocyte-derived recombinant IFN-gamma. N-IFN-gamma had antiviral effects in vitro and induced major histocompatibility complex class I and II antigens on macrophages and in cells in skeletal muscle cell cultures. N-IFN-gamma also stimulated myoblast proliferation and affected cholinergic receptor distribution on myotubes similar to recombinant IFN-gamma. Both molecules potently stimulated Trypanosoma brucei brucei growth. These data suggest that, although N-IFN-gamma is a protein distinct from lymphocyte-derived IFN-gamma, the two molecules have enough structural similarities to allow for antibody recognition of at least two epitopes, and action on similar target structures on both parasite and mammalian cells.

Animals↗

PubMed1994

Induction of interferon-gamma, interleukin-4, and transforming growth factor-beta in rats orally tolerized against experimental autoimmune myasthenia gravis.

Oral administration of nicotinic acetylcholine receptor (AChR) to Lewis rats prior to myasthenogenic immunization with Torpedo AChR+complete Freund's adjuvant (CFA) results in the prevention of experimental autoimmune myasthenia gravis (EAMG) and the suppression of AChR-specific B cell responses and counteracts the development of AChR-reactive interferon-gamma (IFN-gamma) secreting T cells. To study the involvement of the T helper type 1 (Th1) cell-related lymphokine IFN-gamma, the Th2 cell-related interleukin-4 (IL-4), and transforming growth factor beta (TGF-beta) that suppresses the synthesis of IFN-gamma and IL-4, we used in situ hybridization with complementary DNA oligonucleotide probes to enumerate mononuclear cells (MNC) expressing mRNA for the cytokines IFN-gamma, IL-4, and TGF-beta. Upon in vivo recognition of AChR, popliteal, inguinal, and mesenteric lymph nodes, spleen and thymus of rats with EAMG contained higher levels of IFN-gamma, IL-4, and TGF-beta mRNA-expressing cells compared to CFA-injected control rats, implicating the involvement in EAMG of AChR-reactive Th1 and Th2 cells in parallel. TGF-beta was also upregulated in EAMG. Oral tolerance to EAMG was characterized by suppression of the levels of MNC expressing IFN-gamma and IL-4, but augmentation of cells expressing TGF-beta. The results suggest that IFN-gamma, IL-4, and TGF-beta are involved in the development of EAMG, and that TGF-beta is important in the induction of oral tolerance to EAMG.

Animals↗

PubMed1994

Co-induction of neuronal interferon-gamma and nitric oxide synthase in rat motor neurons after axotomy: a role in nerve repair or death?

Induction of an interferon-gamma-like molecule, previously isolated from neurons (N-IFN-gamma), and of the neuronal isoform I of the synthetic enzyme of the free radical nitric oxide, nitric oxide synthase I, as well as of NADPH-diaphorase, were examined in axotomized dorsal motor vagal and hypoglossal neurons. Unilateral transection of the vagal and hypoglossal nerves was performed in the same rat and an induction of N-IFN-gamma and nitric oxide synthase I immunostaining as well as NADPH-diaphorase histochemical positivity was observed in the ipsilateral motoneurons after 2-4 days. The immuno- and enzyme-histochemical positivities were much stronger in the dorsal motor vagal neurons than in hypoglossal neurons. Two and 4 weeks after axotomy N-IFN-gamma immunoreactivity and NADPH-diaphorase positivity persisted in the former, but started to decrease in the latter neurons. Previous data have shown that 23 weeks after nerve transection the majority of the dorsal motor vagal neurons are lost, while the majority of the hypoglossal neurons survive. The high and persistent expression of N-IFN-gamma and nitric oxide synthase I after axotomy in the dorsal motor vagal neurons, that are largely destined to die, indicates that the co-induction of these two molecules may be implicated in the pathogenesis of neuronal degeneration.

Amino Acid Oxidoreductases↗

PubMed1994

gamma delta+ T cells are increased in patients with Parkinson's disease.

The etiology of Parkinson's disease is mainly unknown. Immune abnormalities have been reported, including the occurrence of autoantibodies against neuronal structures and abnormal T cell functions. gamma delta+ T cells represent a recently recognized T cell subpopulation which is considered to play a role in immune responses in infections and autoimmunity. We examined by three-colour flow cytometry the proportions of gamma delta+ T cells in blood and cerebrospinal fluid (CSF) from patients with Parkinson's disease. Increased proportions of gamma delta+ T cells were found in CSF in Parkinson's disease compared to other neurological diseases (OND) and tension headache. In peripheral blood, patients with Parkinson's disease had higher numbers of gamma delta+ T cells compared to OND patients. No differences between gamma delta+ T cells in CSF compared to blood were demonstrable in the individual patient groups. CD25 was not expressed on gamma delta+ T cells in blood of the majority of cases, but 50% of patients with Parkinson's disease and 30% with OND and tension headache had CD25+ gamma delta+ T cells in CSF arguing for a preferential activation of gamma delta+ T cells in the CSF compartment. Whether the elevated gamma delta+ T cell population in Parkinson's disease reflects previously unrecognized inflammation or may occur also in non-inflammatory disorders remains to be elucidated.

Aged↗

PubMed1994

Estrogen induces a potent suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice.

We have earlier described a chronic relapsing experimental autoimmune encephalomyelitis (EAE) in B10.RIII mice induced with a peptide of myelin basic protein (MBP), mimicking the course of multiple sclerosis in man. We now show that estrogens ameliorate chronic EAE. Castration of female mice led to an earlier disease onset (day 9 +/- 2 postimmunization (p.i.) in castrated mice vs. day 16 +/- 4 p.i. in normal mice). Long-term treatment with high levels of 17 beta-estradiol (E2) given as Silastic implants led to a dramatically delayed onset of disease in both castrated and normal female mice (mean onset day was day 39 +/- 14 and day 50 +/- 3, respectively). Treatment of castrated females by injections of E2, at a concentration which induces the serum levels seen at late stage pregnancy, delayed the onset approximately 1 week (mean onset 21 +/- 8). In contrast, treatment with estriol (E3), which was also given at doses corresponding to those levels seen during pregnancy, delayed the disease onset for a longer time (mean onset day 31 +/- 5). Five times higher doses of E2, compared with those seen during pregnancy, were required to obtain similar effects as the low E3 dose. The same mouse strain (B10.RIII) is also susceptible to induction of collagen-induced arthritis (CIA). We show here that also CIA is suppressed by the same treatments with E2 and E3, suggesting that similar estrogen-mediated mechanisms may operate to suppress these T-cell-dependent autoimmune disease models.

Animals↗

PubMed1994

Optic neuritis is associated with myelin basic protein and proteolipid protein reactive cells producing interferon-gamma, interleukin-4 and transforming growth factor-beta.

Studies on patients with monosymptomatic optic neuritis (ON) should give opportunities to identify features typical for early multiple sclerosis (MS). There are increased T and B cell responses to the myelin components myelin basic protein (MBP) and proteolipid protein (PLP) in both ON and MS, but there is little information on the types of cytokines produced by such cells. We describe the use of in situ hybridization with complementary DNA oligonucleotide probes to detect and enumerate mononuclear cells expressing mRNA for the cytokines interferon-gamma (IFN-gamma) which augments cell-mediated immunity; interleukin-4 (IL-4) which promotes the B cell response; and transforming growth factor beta (TGF-beta) that in many cases downregulates immune responses. Expression of these cytokines was studied in mononuclear cells from peripheral blood and cerebrospinal fluid (CSF) from patients with ON and MS after in vitro exposure to MBP and PLP, and in absence of antigen. There were elevated levels of cells that in response to MBP and PLP expressed IFN-gamma, IL-4 and TGF-beta mRNA in blood and further enriched in CSF in both ON and MS, compared to patients with other neurological diseases. The results suggest that IFN-gamma, IL-4 as well as TGF-beta are involved in both ON and MS, and that the cytokine profile in early MS as reflected by ON is not different from that in clinically definite MS.

Adult↗

PubMed1994

V delta 1 gene usage, interleukin-2 receptors and adhesion molecules on gamma delta+ T cells in inflammatory diseases of the nervous system.

This study investigates the expression of T cell receptor V delta 1 chain, interleukin-2 receptor alpha-chain (CD25) and adhesion molecules ICAM-1 (CD54), LFA-1 (CD11a/18) and CD44 on gamma delta+ T cells by three-color flow cytometry on cerebrospinal fluid (CSF) and blood cells in patients with multiple sclerosis (MS), other inflammatory neurological diseases (OIND) and other neurological diseases (OND). Of gamma delta + T cells in CSF and blood, 20-40% belonged to the 'epithelial' V delta 1 subtype. MS patients had the lowest levels in both CSF and blood, but the differences between the patient groups were not significant. The activation markers CD25 and CD54 were expressed by only a small proportion of gamma delta+ T cells and in a minority of patients. Although the occurrence of CD25+ and CD54+ gamma delta+ T cells was somewhat higher in CSF than in blood and in inflammatory diseases than in controls, the small numbers of CD25+ and CD54+ gamma delta+ T cells preclude establishing differences amongst compartments and patient groups. The adhesion molecules CD11a/18 and CD44 were constitutively expressed on all T cells. Therefore, we compared the relative antigen density per cell as measured by the relative fluorescence index (RFI) between CSF and blood, between the patient groups and between gamma delta+ and total T cells. The only difference encountered was a slightly higher expression of adhesion molecules on gamma delta+ compared to total T cells, with preference to MS patients. In conclusion, the V delta 1+ subtype of gamma delta+ T cells does not dominate in the CSF compartment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Trypanosoma brucei and the nervous system.

African sleeping sickness, characterized by a peculiar pain syndrome and prominent neuropsychiatric symptoms, is caused by the parasite Trypanosoma brucei (T.b.). In experimental T.b. infections, a molecule released from the trypanosomes has been isolated that binds to the CD8 molecule of T cells, whereby T cells are activated to secrete interferon gamma. This cytokine binds to the parasites and triggers them to proliferate, establishing a peculiar bidirectional activating signal system. The hypothesis is presented that the molecules involved in these bidirectional signals might also interact with neurons, thus causing brain dysfunctions. Studies on the molecular interactions between parasites and the nervous system in sleeping sickness might reveal basic mechanisms underlying other neuropsychiatric diseases.

Animals↗

PubMed1994

Glucocorticoid receptor and NGFI-A gene expression are induced in the hippocampus after environmental enrichment in adult rats.

Environmental manipulation alters hippocampal glucocorticoid receptor (GR) expression in neonatal rats, but effects in adults have not been documented. Chronic environmental enrichment (EE) increases nerve-growth factor (NGF) concentrations in the adult rat hippocampus. Here we demonstrate that EE induces GR, but not mineralocorticoid receptor (MR) gene expression in specific hippocampal subfields (CA1 and CA2). This is accompanied by increased expression of mRNA encoding the (NGF-induced) immediate early gene NGFI-A in CA2, whereas expression of NGFI-B mRNA decreased in CA1 and CA2. The nature of any relationship between NGF, the transcription factors and GR remains to be determined, but the results demonstrate that chronic environmental manipulations alter hippocampal GR gene expression in adult rats.

Animals↗

PubMed1994

Cellular mRNA expression of interferon-gamma, IL-4 and transforming growth factor-beta (TGF-beta) by rat mononuclear cells stimulated with peripheral nerve myelin antigens in experimental allergic neuritis.

Experimental allergic neuritis (EAN) serves as a useful model for inflammation in the peripheral nervous system. To study the potential role of important immunoregulatory and effector cytokines in EAN, we examined the expression of mRNA for interferon-gamma (IFN-gamma), IL-4 and TGF-beta by in situ hybridization in lymph node and splenic cells cultured with bovine peripheral nerve myelin (BPM), P2 and P0 during the course of EAN in Lewis rats. Levels of IFN-gamma mRNA-expressing mononuclear cells (MNC) from lymph nodes and spleens roughly correlated with clinical status, consistent with a disease-promoting role for IFN-gamma. BPM, P0 and P2-reactive IFN-gamma mRNA-expressing T cells appeared in lymph nodes and spleen before onset of the disease, whereas a significant TGF-beta response to BPM, P2 and P0 was observed at lower levels than the IFN-gamma response and at onset of recovery, consistent with a disease down-regulating role of TGF-beta. IL-4 mRNA-expressing cells were found at levels similar to TGF-beta mRNA-expressing cells, and with the latest peak of the three cytokines examined. This result suggests that IL-4 may also suppress IFN-gamma expression at late recovery phase of EAN.

Animals↗

PubMed1994

Peptide specificity of anti-myelin basic protein antibodies in patients with acute optic neuritis and the HLA system.

Multiple sclerosis (MS) may be an autoimmune disease, partially caused by autoreactivity to myelin basic protein (MBP) and other central nervous system proteins. Acute optic neuritis (ON) is a frequent first symptom of MS. The role of the HLA system in anti-MBP antibody production in ON was investigated employing a restriction fragment length polymorphism system for genomic HLA-DQ and -DR typing and an immunospot assay for the detection of individual cells secreting antibodies to three different synthetic MBP peptides. Thirty-two out of 40 patients (80%) with ON had cells in cerebrospinal fluid secreting anti-MBP peptide antibodies while this occurred in 10/19 patients with other neurological diseases (53%; mainly in patients with inflammatory diseases in the central nervous system). This difference was statistically significant (P = 0.03). None of the three examined peptides were immunodominant in any patient group. It was found, however, that presence of HLA DR15, which is associated with MS, may be associated further with predominant production of antibodies to the MBP amino acids 63-88 in patients with ON (P = 0.002, corrected for multiple comparisons).

Adult↗

PubMed1994

Th1-like cell responses to peripheral nerve myelin components over the course of experimental allergic neuritis in Lewis rats.

Experimental allergic neuritis (EAN) is a T cell-mediated animal model of Guillain-Barré syndrome characterized by inflammation and demyelination of peripheral nerves. EAN can be induced by immunization of rats with bovine peripheral nerve myelin (BPM) or the myelin proteins P2 or P0, but the extent of T cell responses over the course of EAN is incompletely defined. We studied the T cell responses to these proteins and the glycolipid GM1 by enumerating T helper type 1 (Th1)-like cells secreting interferon-gamma (IFN-gamma) after short-term culture of mononuclear cells (MNC) in presence of antigen. Already 7 days post immunization (p.i.) with BPM and before onset of clinical EAN, lymph nodes contained elevated levels of P2 responsive T cells. At the height of EAN on day 14 p.i. and during recovery, T cell levels responding to BPM, P0 and GM1 were also elevated. The same temporal profiles and specificities were registered for antigen reactive spleen MNC. The results implicate that Th1-like cells with multiple specificities including the glycolipid GM1 occur at increased levels in lymphoid organs in EAN rats, and that IFN-gamma may be an important effector molecule in the induction of nerve damage.

Animals↗

PubMed1994

Organ-specific autoantigens induce interferon-gamma and interleukin-4 mRNA expression in mononuclear cells in multiple sclerosis and myasthenia gravis.

T cells recognizing the myelin components myelin basic protein (MBP) and proteolipid protein (PLP) are increased in multiple sclerosis (MS), and there are elevated numbers of T cells recognizing the nicotinic acetylcholine receptor (AChR) in myasthenia gravis (MG). However, the cytokine repertoires in these diseases are largely unknown. We adopted in situ hybridization with radiolabeled complementary DNA oligonucleotide probes to enumerate mononuclear cells that expressed the T-helper type 1 (Th1) cell-related interferon-gamma (IFN-gamma) and Th2-associated interleukin-4 (IL-4) after short-term culture in the presence of autoantigen. High numbers of IFN-gamma and IL-4 mRNA-expressing cells in response to MBP and PLP were detected in patients with untreated MS, and to AChR in MG. The levels of IFN-gamma and IL-4 mRNA-positive cells in MS after culture in the presence of AChR, and in MG after culture in the presence of MBP or PLP, did not differ from those detected after culture without antigen. The CSF of MS patients contained four- to eightfold more myelin protein-reactive IFN-gamma and IL-4 expressing cells. The findings imply that MS and MG are associated with mixed Th1- and Th2-like cell responses directed to organ-specific target antigens.

Adult↗

PubMed1994

Influence of K+ channel openers on interferon-gamma dependent immune response in experimental allergic neuritis (EAN).

We examined the influence of the K+ channel opening drugs BRL 38227, pinacidil and diazoxide on cellular immune response and clinical course of experimental allergic neuritis (EAN) actively induced in Lewis rats by bovine peripheral myelin (BPM). T cell functions of EAN lymph node cells were assessed by measurement of proliferation and by counting of interferon-gamma secreting cells (IFN-gamma sc) in response to the specific antigen BPM and the T cell mitogen phytohemagglutinin (PHA). BRL 38227 and diazoxide at concentrations of 10(-5)M-10(-6)M and pinacidil at concentrations of 10(-5)M-10(-7)M enhanced the proliferative response to both BPM and PHA. The number of IFN-gamma sc was suppressed by the K+ channel openers in the same concentration range. There was a tendency of stronger suppression of cultures with high numbers of BPM-reactive IFN-gamma sc than of cultures with low numbers of BPM-reactive IFN-gamma sc. The applied K+ channel openers are primarily acting on ATP-sensitive K+ channels, which have not been found in T cells so far. The drugs may, therefore, exert non-selective effects on conventional voltage- and/or Ca(++)-dependent channels of T cells. A first trial with in vivo administration of 2.5 mg/kg x day of the drugs resulted in more severe neurological deficits in the early phase of EAN with BRL 38227, whereas pinacidil and diazoxide had no significant effects.

Animals↗

PubMed1994

A new approach for the pathogenesis of human African trypanosomiasis.

From Trypanosoma brucei brucei, a molecule has been isolated which triggers the production of IFN-gamma by CD8+ T-cells. IFN-gamma modulates events in the hosts immune- and nervous system and provides a growth stimulus for the parasites. Furthermore, a molecule with IFN-gamma-like immunoreactivity has been detected in rat dorsal root ganglion cells and certain neurons in the brain. This neuron-derived IFN-gamma-like molecule differs in molecular weight from lymphocyte-derived IFN-gamma but shares important biological activities with the latter, which includes a growth stimulus for trypanosomes. Trypanosomes localized to sensory ganglia and infected rats develop a severe thermal hyperalgesia. Intrathecal injection of IFN-gamma causes in rats a sustained phase of nociceptive flexor reflex facilitation, which can be partially blocked by nitro-L-arginin-ester, an inhibitor of nitric oxide synthase, indicating that nociceptive effects of the IFN-gamma is mediated by activation of the L-arginin-nitric oxide pathway.

Animals↗

PubMed1993

Environmental influences on the central nervous system and their implications for the aging rat.

Two methods of providing environmental stimulation that were introduced in the 1950s have guided much research on neurobehavioural plasticity. These are neonatal handling and environmental enrichment. Neonatal handling has been shown to permanently affect behaviour and endocrine responses. Recently this manipulation has been shown to have important influences on the aging individual, protecting the hippocampus from age-related dysfunction and neuronal loss. These effects are mediated, in part, by keeping glucocorticoid levels low. This has been characterised by, among other things, elevated expression of glucocorticoid receptors in the hippocampus. Earlier studies have failed to present convincing evidence for differences in hormonal variables between animals housed in enriched and impoverished environments, and have not consistently reported changes in the hippocampus. Recent data from our laboratories have shown that adult animals housed in enriched environments had, like neonatally-handled rats, higher expression of the gene encoding glucocorticoid receptors in the hippocampus. Taken together with the induction of NGF and NGFIA gene expression in the hippocampus of enriched animals, these results implicate genes encoding transcription factors and glucocorticoid receptors in the cascade of events leading to environmentally induced cerebral changes. In addition, these results suggest that environmental enrichment in adulthood, like neonatal handling, may have the potential to protect the aging hippocampus from glucocorticoid neurotoxicity.

Aging↗