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H Link

Publications and source records attributed to H Link.

At least 127 records · Page 7Linked to original sources
PubMed1999

Induction of neutralizing autoantibodies to interferon-gamma in patients with polyneuropathy.

We previously demonstrated the induction of IFN-gamma in polyneuropathy patients associated with monoclonal gammopathy, but not in patients with presumably non-immunological types of neuropathy. We herein examined mechanism involving release of neutralizing autoantibodies (Aabs) to IFN-gamma in sera from those patients. In contrast to polyneuropathy patients with monoclonal gammopathy, patients with polyneuropathy of presumably non-immunological types showed increased production of neutralizing Aabs specific for IFN-gamma. These results demonstrate a role for autoimmunity in cytokine regulation. However, their association to the clinical manifestations of the disease requires further investigations, which are necessary for future consideration in therapeutic strategies.

Adult↗
PubMed1998

Cytokine and chemokine mRNA expressing cells in muscle tissues of experimental autoimmune myasthenia gravis.

In-situ hybridization with labeled oligonucleotide probes was applied to explore cytokine and chemokine mRNA expression in sections of striated muscle, the target organ in experimental autoimmune myasthenia gravis (EAMG), induced in Lewis rats by immunization with acetylcholine receptor (AChR) and complete Freund's adjuvant (CFA). A transient burst of TNF-alpha, IL-1beta and IL-6 mRNA expressing cells was detected during the early phase of EAMG. This cytokine pattern was related to muscular infiltration of macrophages. Levels of IL-4, IL-10, IFN-gamma, cytolysin and TGF-beta mRNA expressing cells were low and observed mainly during the early phase of EAMG. C-C chemokine RANTES, MCP, MIP-1alpha and MIP-2 mRNA expressing cells were not detected over the course of EAMG. The low and transient expression of cytokines in EAMG muscle tissues suggests that the immune effector responses are unlikely operated by infiltrating cells in muscle. Muscular infiltrations in EAMG are unlikely due to local accumulation of C-C chemokines.

Animals↗
PubMed1998

No evidence for elevated numbers of mononuclear cells expressing MCP-1 and RANTES mRNA in blood and CSF in multiple sclerosis.

The perivascular accumulation of mononuclear cells (MNC) in brain white matter is critical in the development of active lesions in multiple sclerosis (MS). Chemokines contribute to leukocyte recruitment by increasing the adhesiveness of integrins expressed on leukocytes and by promoting migration through endothelium and extracellular matrix. By using an in situ hybridization technique, it was possible to enumerate blood and CSF MNC expressing mRNA for the two CC chemokines monocyte chemoattractant protein-1 (MCP-1) and RANTES (regulated upon activation, normal T cells, expressed and secreted) in MS patients and controls. No differences in numbers of blood MNC expressing MCP-1 or RANTES could be found in MS patients compared to healthy individuals or patients with acute aseptic meningoencephalitis (AM). High numbers of CSF MNC expressing MCP-1 and RANTES were found in some MS patients, but also in patients with AM. This shows that elevated numbers of MCP-1 and RANTES mRNA expressing CSF MNC are not specific for the inflammatory process in MS. We conclude that there is no evidence for a systemic dysregulation of the CC chemokines MCP-1 and RANTES in MS.

Adult↗
PubMed1998

Astrocytes induce hyporesponses of myelin basic protein-reactive T and B cell function.

We have isolated infiltrating mononuclear cells (inMNC) and lymph node MNC (lnMNC) from Lewis rats with actively induced experimental allergic encephalomyelitis (EAE), and compared their responses to myelin basic protein (MBP). MBP-induced proliferation and MBP-specific IgG secreting cells were lower in inMNC compared to lnMNC, while MBP-reactive IFN-gamma secreting cells in inMNC were higher. Using an in vitro culture system, we observed that astrocytes derived from newborn Lewis rats not only suppressed T cell proliferation and IFN-gamma production but also reduced MBP-specific IgG production by B cells. Astrocyte-derived soluble factor (s), rather than direct cell-to-cell interactions, seems to be responsible for the inhibitory effect. Supernatants from IFN-gamma-stimulated astrocytes exhibited stronger suppressive effects than supernatants from unstimulated astrocytes, whereas supernatants from microglia did not cause downregulation of T and B cell functions. These results indicate that astrocytes are major effector cells in inhibiting functions of MBP-reactive T and B cells. Astrocytes down-regulated expression of ICAM-1 and MHC class II in lnMNC, but did not induce apoptosis of lnMNC. The results in the present study do not exclude the possibility that astrocytes induce T cell apoptosis in a cognate fashion. Taken together, the inhibitory properties of astrocytes may contribute to the confinement of inflammatory lesions in multiple sclerosis and EAE. Our report compares immunoreactivities of inMNC and lnMNC in EAE and elucidates the role of astrocytes in the inactivation of MBP-reactive T and B cells.

Animals↗
PubMed1998

Incidence of optic neuritis in Stockholm, Sweden 1990-1995: I. Age, sex, birth and ethnic-group related patterns.

We studied the incidence of monosymptomatic optic neuritis (MON) in Stockholm county, Sweden and its variation with person-related factors. Patients with suspected or diagnosed MON between January 1, 1990 and December 31, 1995 were referred from ophthalmologists and neurologists to a research registry. The diagnosis was based on accepted clinical criteria only, and verified by an ophthalmologist who examined all the patients. Data were collected by interview using a structured questionnaire. The crude mean annual incidence, based on 147 patients, 118 females and 29 males, diagnosed with MON, was 1.46 per 100,000 person-years, 2.28 for females and 0.59 for males. The corresponding age-adjusted incidences were 1.40, 2.28 and 0.53. The age-specific incidence curve for both sexes suggested a bimodal distribution with peaks at 30-34 years and 45-49 years. The smoothed cumulative incidences in 1 year birth cohorts showed a notchy profile, related to bimodality. The incidence among residents born out of the Nordic countries was low, 0.28 per 100,000. Patients with onset of MON before 40 years of age had a significantly higher frequency of mononuclear pleocytosis in cerebrospinal fluid and shorter duration to conversion to multiple sclerosis. In summary, MON occurred in Stockholm at a relatively low frequency, particularly among males. The presence of particular birth date and birth place related patterns might be etiologically relevant.

Adult↗
PubMed1998

Linomide-mediated protection of oligodendrocytes is associated with inhibition of nitric oxide production and IL-1beta expression in Lewis rat glial cells.

Linomide is a synthetic immunomodulator that down-regulates autoimmune response without inducing systemic immunosuppression. Linomide effectively inhibits severe experimental autoimmune diseases, like experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis (MS). Here we report that Linomide suppresses nitric oxide (NO) production by microglia and astrocytes derived from newborn rats and prevented oligodendrocyte damage. Linomide strongly inhibited interleukin (IL) 1 betamRNA expression on glial cells, suggesting a potential mechanism for inhibition of NO production by Linomide. These results demonstrate that Linomide-mediated inhibition of NO production by glial cells could explain the preventive and therapeutic effects of Linomide in EAE and perhaps also MS. However, Linomide at higher dose [correction of doss] (10(-5) M) resulted in direct oligodendrocyte damage.

Adjuvants, Immunologic↗
PubMed1998

Treatment with P2 protein peptide 57-81 by nasal route is effective in Lewis rat experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) is a CD4+ T cell-mediated autoimmune disorder of the peripheral nervous system (PNS) that can be actively induced in susceptible animal species and strains by active immunization with PNS myelin + Freund's complete adjuvant (FCA). EAN represents an animal model for studying the immunopathogenesis and treatment of Guillain-Barré syndrome (GBS), which is a major inflammatory demyelinating disease of the PNS in humans. Here, we report that treatment by nasal administration of the neuritogenic peptide 57-81 of the PNS myelin component, P2 protein, dose-dependently suppressed EAN severity and shortened clinical EAN. Clinical EAN relapse induced by rechallenge with BPM + FCA was also prevented in EAN rats receiving high dose P2 peptide. P2 peptide induced suppression of EAN was associated with PNS antigen specific T cell hyporesponsiveness reflected by lymphocyte proliferation, numbers of PNS antigen-reactive IFN-gamma secreting and IFN-gamma mRNA expressing lymph node cells, but elevated levels of PNS antigen reactive TGF-beta mRNA secreting cells. Reduced CD4+ T cell and macrophage infiltrations within the PNS were also observed. Based on these observations, nasal autoantigen administration should be further evaluated, considering its possible future use in GBS.

Administration, Intranasal↗
PubMed1998

Safety and cost effectiveness of a 10 x 10(9)/L trigger for prophylactic platelet transfusions compared with the traditional 20 x 10(9)/L trigger: a prospective comparative trial in 105 patients with acute myeloid leukemia.

In 105 consecutive patients with de novo acute myeloid leukemia (French-American-British M3 excluded), we compared prospectively the risk of bleeding complications, the number of platelet and red blood cell transfusions administered, and the costs of transfusions using two different prophylactic platelet transfusion protocols. Two hundred sixteen cycles of induction or consolidation chemotherapy and 3,843 days of thrombocytopenia less than 25 x 10(9)/L were evaluated. At the start of the study, each of the 17 participating centers decided whether they would use a 10 x 10(9)/L prophylactic platelet transfusion trigger (group A/8 centers) or a 20 x 10(9)/L trigger (group B/9 centers). Bleeding complications (World Health Organization grade 2-4) during treatment cycles were comparable in the two groups: 20 of 110 (18%) in group A and 18 of 106 (17%) in group B (P = .8). Serious bleeding events (grade 3-4) were generally not related to the patient's platelet count but were the consequence of local lesions and plasma coagulation factor deficiencies due to sepsis. Eighty-six percent of the serious bleeding episodes occurred during induction chemotherapy. No patient died of a bleeding complication. There were no significant differences in the number of red blood cell transfusions administered between the two groups, but there were significant differences in the number of platelet transfusions administered per treatment cycle: pooled random donor platelet concentrates averaged 15.4 versus 25.4 (P < .01) and apheresis platelets averaged 3.0 versus 4.8 (P < .05) for group A versus group B, respectively. This resulted in the cost of platelet therapy being one third lower in group A compared with group B without any associated increase in bleeding risk.

Acute Disease↗
PubMed1998

IFN-gamma production of adult rat astrocytes triggered by TNF-alpha.

IFN-gamma plays an important role in modulating inflammatory responses within the CNS. The cell type responsible for IFN-gamma production within the CNS is less well defined. We examined the production and regulation of IFN-gamma by adult rat astrocytes. IFN-gamma was hardly detectable in cultured astrocytes, while addition of TNF-alpha dose-dependently induced IFN-gamma production by astrocytes. No IFN-gamma production by astrocytes could be induced by LPS, IL-10 or TGF-beta 1. TNF-alpha-induced IFN-gamma production by astrocytes was inhibited by treatment of astrocytes with TGF-beta 1, but not IL-10. TNF-alpha induced IFN-gamma production by astrocytes was confirmed by using immunocytochemical staining. The data suggest that astrocyte-derived IFN-gamma induced by TNF-alpha may participate in local immune reactions of the brain in an autocrine and paracrine fashion.

Animals↗
PubMed1998

Synthetic peptides fail to induce nasal tolerance to experimental autoimmune myasthenia gravis.

Nasal administration of Torpedo acetylcholine receptor (AChR) to Lewis rats prior to induction of experimental autoimmune myasthenia gravis (EAMG) is highly efficient in prevention of clinical weakness, and suppression of AChR-specific T and B cell responses. To identify possible antigenic determinants within the receptor which can modulate EAMG and anti-AChR response, we evaluated the effects of nasal administration of alpha 61-76, alpha 100-116, alpha 146-162, delta 354-367, and alpha 261-277 of Torpedo AChR at different doses on the tolerance induction against EAMG irrespective if given at lower, the same or higher doses than whole Torpedo AChR protein, that was confirmed to be highly efficient as tolerogen to EAMG. None of these peptides, neither administrated alone nor in combination, induced tolerance to EAMG. Peptide administration did not affect the levels or affinities of anti-AChR antibodies when compared with non-tolerized control EAMG rats, while administration of whole AChR protein affected both variables. The results may indicate that the T and B cell heterogeneity of AChR epitopes makes it difficult to induce tolerance using synthetic peptide.

Animals↗
PubMed1998

Immune regulation within the central nervous system.

The brain constitutes an environment that is specifically designed to accommodate, regulate and shape immune responses. On one hand, the central nervous system (CNS) has traditionally been regarded as an immunologically privileged organ, owing to local tissue barrier and immunosuppressive microenvironment. On the other hand, activated microglia and astrocytes express MHC and adhesion/costimulatory molecules, release reactive oxygen intermediates and cytokines, and participate in local immune regulation. Bidirectional interactions between immune and neuroglial components occur in response to infectious and traumatic lesions. Glial cells may facilitate and amplify immune effector mechanisms within the CNS. Cytokines and chemokines within the CNS constitute a specialized CNS-cytokine network, and regulate the development and recovery from autoimmune diseases within the CNS. The interactions between glial cells and lymphoid cells are constituents of a complex immune regulatory system within the CNS. New data on the cross-talk between the CNS and the immune systems are envisaged, and followed by an attempt to create a synthesis of current knowledge.

Animals↗
PubMed1998

Suppression of acute and protracted-relapsing experimental allergic encephalomyelitis by nasal administration of low-dose IL-10 in rats.

In this study we report for the first time that nasal administration of the Th2 cell-related cytokine interleukin-10 (IL-10), at concentrations of 1.5 microg/rat and 15 microg/rat, suppressed clinical signs of acute experimental allergic encephalomyelitis (EAE) in Lewis rats and prevented the development and relapse of protracted-relapsing EAE (PR-EAE) in DA rats. In contrast, subcutaneous injection of IL-10 (15 microg/rat) did not inhibit acute EAE. The IL-10-mediated suppression of EAE was associated with decreased myelin antigen-specific T-cell proliferative responses and IFN-gamma secretion in both acute and PR-EAE. In sections of spinal cords derived from rats nasally pretreated with IL-10, there were no infiltrating CD4+ T cells or macrophages, which are considered as major encephalitogenic or inflammatory cells. Most interestingly, nasally administered IL-10 also inhibited MHC class II expression in microglia, indicating that IL-10 administration by the nasal route prevents the activation of microglia. Administration of cytokines via the nasal route offers an exciting alternative in the prevention and treatment of autoimmune diseases.

Acute Disease↗
PubMed1998

Cytokine production and the pathogenesis of experimental autoimmune neuritis and Guillain-Barré syndrome.

Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré syndrome, GBS) and its animal model experimental autoimmune neuritis (EAN) are prototypes of T cell-mediated autoimmune diseases affecting the peripheral nervous system (PNS). Perivascular accumulation of macrophages and T lymphocytes in the PNS, and high levels systemically of PNS myelin antigen-reactive T cells are characteristic features of both diseases, thereby suggesting a pathogenic role for immunoregulatory cytokines. Here we summarise recent studies that have clearly documented that Th1/Th2/Th3 cytokines are differently upregulated during various clinical phases of EAN and GBS. The observations indicate that the role of cytokines in immune regulation and autoimmune disease is more complex than a simple Th1-Th2 dichotomy would suggest. New treatments may be searched for that counteract this complex cytokine imbalance. Treatments with antibodies that selectively target certain pro-inflammatory cytokines, as well as with immunomodulatory preparations that promote cytokines that beneficially influence the disease course should be in focus of future therapeutic trials.

Animals↗
PubMed1998

Cerebrospinal fluid mononuclear cell counts influence CSF HIV-1 RNA levels.

This study evaluated the relation between cerebrospinal fluid (CSF) mononuclear cells (MNC) and CSF HIV-1 RNA levels. HIV-1 RNA levels in plasma and CSF were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) in 58 consecutive patients with neurologic symptoms and late HIV-1 infection. The majority of the patients had no central nervous system (CNS) complication (n = 36), 11 had AIDS dementia complex (ADC) and 11 had CNS opportunistic infection (CNS OI). CSF cell counts were analyzed using a method that also evaluated hypocellular CSF (i.e., from 0.1 x 10(6) cells/L). A strong correlation was found between CSF MNC and CD4+ lymphocyte counts in blood (r = 0.58; p < .0001). HIV-1 RNA was detected in all plasma samples and in 38 of 58 (66%) of the cell-free CSF samples. CSF HIV-1 RNA was less frequently detected in patients with hypocellular CSF than in patients with normocellular or pleocytic CSF (13 of 28 patients [46%] versus 10 of 14 patients [71%] versus 15 of 16 patients [94%], respectively). The levels of CSF HIV-1 RNA correlated with the CSF MNC count (r = 0.61; p < .0001). The correlation also remained strong within the clinical subgroups of CNS asymptomatic patients (r = 0.55; p < .001) and ADC patients (r = 0.79; p < .001), but not among CNS OI patients (r = 0.19). Patients with CNS OI were found to have higher CSF HIV-1 RNA levels than the patients without evidence of CNS complication. Thus, a close relation was found between CSF HIV-1 RNA levels and CSF MNC counts. These data support the hypothesis that a substantial part of the virus in the CSF of HIV-1-infected patients is locally produced by CSF MNC.

AIDS Dementia Complex↗
PubMed1998

Nasal administration of multiple antigens suppresses experimental autoimmune myasthenia gravis, encephalomyelitis and neuritis.

Oral tolerization with acetylcholine receptor (AChR) and myelin basic protein (MBP) prior to immunization with AChR+MBP+ complete Freund's adjuvant (CFA) alleviated clinical signs of experimental autoimmune myasthenia gravis (EAMG)+experimental allergic encephalomyelitis (EAE) and AChR- or MBP-specific T and B cell responses. Tolerance induced via the nasal route needs much less tolerogen and may still be as effective as oral tolerance induction. We now immunized Lewis rats with AChR+MBP+bovine peripheral nerve myelin (BPM)+CFA, which resulted in a multiphasic clinical picture with a combination of clinical signs of the EAMG+EAE+experimental allergic neuritis (EAN), accompanied by massive macrophage infiltrations in sections of muscle, spinal cord and sciatic nerve, and strong T and B cell responses to AChR, MBP and BPM in lymphoid organs. Nasal administration of microg doses of AChR+MBP+BPM prior to immunization with a mixture of these antigens+CFA effectively suppressed the incidence and severity of clinical disease, reduced macrophage infiltrations in sections of muscle, spinal cord and sciatic nerve, and down-regulated autoreactive T cell responses to the three antigens in lymphoid organs. Numbers of AChR-, MBP-, BPM-reactive Th1 type of cytokine interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha mRNA expression in lymph node cells were markedly suppressed, while transforming growth factor-beta (TGF-beta) mRNA expression was upregulated from nasally tolerized rats, suggesting an active suppression mechanism may act partly in the induction of tolerance. The results implicate the possibility to establish multiple autoantigen-based vaccination for the prevention of autoimmune diseases in humans.

Administration, Intranasal↗