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Biomedical subjects

J P Erälinna

Publications and source records attributed to J P Erälinna.

9 recordsLinked to original sources
PubMed2006

MxA protein induction in MS patients treated with intramuscular IFNbeta-1a.

MxA protein production in peripheral blood leukocytes is a valuable marker to evaluate biologic effects of interferon-beta (IFNbeta) therapy in multiple sclerosis (MS) patients. The three IFNbeta preparations available in the treatment of MS differ with respect to antigenicity and biologic activity. We studied prospectively the induction of MxA protein and the development of binding (BAb) and neutralising antibodies (NAb) in nine relapsing-remitting MS (RRMS) patients during one year of intramuscular IFNbeta -1a (Avonex) treatment. Another nine RRMS patient treated with Avonex for 1-3.5 years were also included. The results were compared with our earlier published data of subcutaneous IFNbeta-1a (Rebif). None of these 18 patients developed NAb but three of the long-term patients developed BAb. The baseline MxA protein levels rose but the induction was weaker compared to Rebif. The stimulation index (MxA after/before IFNbeta-1a injection) remained elevated. Weekly intramuscular dosing of IFNbeta-1a provides a sustained effect on lymphocytes but differences in leukocyte stimulation may underlie some of the differences between IFNbeta therapies.

Adjuvants, Immunologic↗
PubMed2005

The efficacy of glatiramer acetate in beta-interferon-intolerant MS patients.

OBJECTIVES: Glatiramer acetate (GA) is routinely used in multiple sclerosis (MS) patients who cannot tolerate or fail to respond to beta-interferon (IFN-beta). The aim of this study was to assess the efficacy and tolerability of GA in these patients. METHODS: Fifteen relapsing-remitting MS patients who had discontinued IFN-beta therapy due to side effects were included in this open, 1-year prospective study. Neurologic examinations and laboratory assessments were performed every 3 months. The induction of MxA protein production was also evaluated. RESULTS: Eleven of fifteen patients (73%) tolerated GA well whereas four patients (27%) discontinued treatment due to side effects. The relapse rate reduced from 1.86 per year to 0.91 per year. Neither laboratory abnormalities nor MxA protein induction was found. CONCLUSION: GA can be considered as a good treatment alternative to IFN-beta-intolerant MS patients. However, some patients were not able to use available immunomodulative treatments, which emphasizes the need for new therapeutic options. The lack of MxA protein induction confirms the different mechanisms of action of GA and IFN-beta.

Adjuvants, Immunologic↗
PubMed2001

Expression of interleukin-4 but not of interleukin-10 from a replicative herpes simplex virus type 1 viral vector precludes experimental allergic encephalomyelitis.

We have used interleukin (IL)-4 and -10-producing HSV-1 gamma(1)34.5 deletion viruses in gene therapy of a BALB/c model of experimental allergic encephalomyelitis (EAE), a T cell-mediated demyelinating disease of the central nervous system. It is known that in EAE of mice the Th2-type cytokines are down-regulated and the Th1-type cytokines up-regulated during the onset and relapse of the disease. Therefore, we tested two HSV-1 recombinants expressing the Th2-type cytokines IL-4 and IL-10. The recombinant viruses were injected intracranially (i.c.) in BALB/c mice 6 days after induction of EAE. As control groups we used mice without any infection, mice infected with backbone virus R3659 and mock-infected mice. Weights and symptoms of the mice were recorded daily and the tissue specimens were collected at specific time-points. The results indicate that the intracranial infection with IL-4-producing virus (1) precludes EAE symptoms, (2) protects the spinal cord from massive leukocyte infiltrations and (3) prevents demyelination and axonal loss. The IL-10-expressing virus R8308 did not have a similar favorable effect on the recovery of the mice as did the IL-4 virus R8306.

Animals↗
PubMed1998

Selective downregulation of Th1 response by Linomide reduces autoimmunity but increases susceptibility to viral infection in BALB/c and SJL mice.

Susceptibility to autoimmunity has been associated with polarization of Th1/Th2 balance in immune system towards the Th1-type of reactivity. We report here that orally administered quinoline-3-carboxamide (Linomide) selectively downregulates Th1 response in BALB/c and SJL mice, leading to reduction of autoimmunity in the BALB/c and SJL models of experimental allergic encephalomyelitis (EAE). This was shown by prevention of EAE in Th1 responding SJL mice and partial downregulation of EAE in Th2-prone BALB/c mice. In a BALB/c model of EAE, in which infection with Semliki Forest A7 virus (SFV-A7) is used for enhancement of autoimmunity, clinical signs of EAE were reduced while mortality due to viral infection in the CNS was enhanced. Selective downregulation of the Th1 response by Linomide also rendered initially resistant SJL mice susceptible to SFV-A7 CNS infection. This was shown by immunohistochemical detection of extensive deposits of viral antigen in numerous perivascular foci within the CNS and abolished virus antigen-specific lymphocyte reactivity in Linomide-treated SJL mice. In addition, analysis of spleen cell cytokine mRNA production profile revealed decreased number of IFN-gamma producing cells in both SJL and BALB/c mice, reduced number of IL-12p40 producing cells in SJL and increased number of 12p40 producing cells in BALB/c mice along with slightly increased IL-4 production in both strains of mice. These results indicate that oral treatment with Linomide induces selective downregulation of Th1 reactivity causing reduction of autoimmunity and increased susceptibility to SFV-A7 CNS infection. Selective downregulation of Th1 response is a desired effect in the treatment of autoimmune diseases but our results suggest that the benefits have to be balanced against the possible loss in immunoprotection against pathogens.

Adjuvants, Immunologic↗
PubMed1996

Physical state of the neuroantigen in adjuvant emulsions determines encephalitogenic status in the BALB/c mouse.

A novel form of adjuvant-neuroantigen formulation was established which was highly encephalitogenic in previously resistant BALB/c mice. The antigen formulation contained mouse whole spinal cord homogenate (MSCH), mycobacteria, and mineral oil, identically to the conventional preparation, but emulsification was completed by sonication instead of extrusion. Sonication of MSCH alone did not render a conventionally prepared emulsion encephalitogenic. The novel adjuvant formulation showed reduced water-oil droplet size, and the neuroantigen was located on the surface of the droplets as well as in the intermicellar space, while in the extruded formulation the material was buried in the droplet interior. Mice inoculated with the sonicated emulsion showed strong brain and spinal cord infiltration of lymphoid cells. The sonicated emulsion was highly encephalitogenic in all six BALB/c substrains tested. The results suggest that availability of the neuroantigen is of critical importance for the development of clinical EAE in the BALB/c mouse.

Adjuvants, Immunologic↗
PubMed1996

Blood-brain barrier breakdown and increased intercellular adhesion molecule (ICAM-1/CD54) expression after Semliki Forest (A7) virus infection facilitates the development of experimental allergic encephalomyelitis.

This report describes two mechanisms by which virus infection can facilitate demyelinating autoimmune inflammation in the murine CNS. In the BALB/c mouse model of experimental allergic encephalomyelitis (EAE), peripheral infection with an avirulent strain (A7) of Semliki Forest virus (SFV) increased the morbidity to EAE by infecting endothelial cells and damaging the blood-brain barrier (BBB). An influx of hematogenous CD18+ (LFA-1+ and MAC-1+) cells into the CNS compartment was followed by a local increase in intercellular adhesion molecule 1 (ICAM-1) expression on the vascular endothelium. Although SFV A7 infection without EAE induction caused multifocal cerebral vascular endothelial cell infection and BBB damage followed by cellular infiltration and transient increase of ICAM-1, inflammation and demyelination of CNS white matter with classical clinical signs of EAE was observed only in EAE-induced BALB/c mice, whereas the control mice remained neurologically healthy. The upregulation of ICAM-1 after virus infection was detected after the CD18+ (LFA-1+ and MAC-1+) cells had infiltrated the CNS both after EAE induction and also in nonsensitized control mice. The observed increase in ICAM-1 expression was transient in nonsensitized SFV A7 infected mice just as in the cellular infiltrates in the CNS, but EAE induction resulted in prolongation in both the cellular infiltrates and upregulation of ICAM-1. Thus, SFV A7 infection causes BBB damage and prolongs increased ICAM-1 expression on brain endothelium. This results in increased and more rapid morbidity to EAE in mice which have been sensitized with neuroantigen. However, SFV A7-infected mice without neuroantigen sensitization remain neurologically healthy.

Alphavirus Infections↗
PubMed1994

Facilitation of experimental allergic encephalomyelitis by irradiation and virus infection: role of inflammatory cells.

Infection with an avirulent strain of Semliki Forest virus (SFV-A7) facilitates the development of experimental allergic encephalomyelitis (EAE) in a genetically resistant BALB/c mouse strain. Irradiation which is necessary for EAE induction caused a decrease in the total number of lymphocytes and an increase in CD4+/CD8+ T cell ratio in the spleen of BALB/c mice. EAE induction increased the ratio further until clinical and histological signs of EAE appeared. Entry of perivascular CD4+ and CD8+ cells preceded the onset of clinical signs and the appearance of MAC-1+ cells in the central nervous system (CNS). In the acute phase of EAE, cellular infiltrates, which were sparse, consisted mainly of MAC-1+ cells and a few CD4+ and CD8+ cells. Inflammatory cells gradually disappeared during the recovery phase. SFV-A7 infection after irradiation and EAE induction did not significantly change the CD4+/CD8+ ratio in the spleen or in the CNS infiltrates but enhanced the entry of inflammatory cell into the CNS. Similar perivascular cell influx was also seen in untreated mice infected with SFV-A7. We conclude that observed rapid reduction of splenic mononuclear cells and increase of the CD4+/CD8+ T cell ratio caused by irradiation prior EAE induction are early crucial events in disease induction in this resistant strain of mice. SFV-A7 infection, which further facilitates the development of EAE, does not induce immunoregulatory changes but provides its effect by enhancing the entry of inflammatory cells into the CNS. The combination of these two mechanisms thus effectively breaks the natural resistance against EAE in this genetically resistant mouse strain.

Animals↗
PubMed1994

Semliki Forest virus infects mouse brain endothelial cells and causes blood-brain barrier damage.

Induction of experimental allergic encephalomyelitis is facilitated in a genetically resistant BALB/c mouse strain by a nonpathogenic strain of a neurotropic alphavirus, Semliki Forest virus (SFV-A7). One possible explanation for this enhancement is virus infection of endothelial cells (EC), causing increased permeability of the blood-brain barrier. We have now sought evidence for virus infection of EC in vivo by immunocytochemistry and in situ hybridization. SFV-A7 antigens and RNA were detected in vascular EC and perivascular neurons in cerebellar and spinal cord white matter. Expression of viral antigens was followed by fibrinogen leakage from the blood vessels into brain parenchyma. This was shown by immunoperoxidase staining detecting fibrinogen extravascularly in central nervous system sections of infected mice. Simultaneously, expression of ICAM-1 (intercellular adhesion molecule 1) was induced on brain EC. SFV-A7 replicated in mouse brain microvascular EC in vitro and caused lysis of the cells. SFV-A7 did not induce ICAM-1 expression of mouse brain microvascular EC in vitro, while ICAM-1 was readily induced by gamma interferon and interleukin 1 beta. The observed increase of ICAM-1 expression on EC is immune mediated and not a direct effect of the virus infection. We conclude that SFV-A7 infection causes cerebral microvascular damage which contributes to the facilitation of experimental allergic encephalomyelitis in BALB/c mice.

Animals↗