Biomedical subjects

Halina Offner

Publications and source records attributed to Halina Offner.

43 records · Page 3Linked to original sources

PubMed2002

Identification of Bphs, an autoimmune disease locus, as histamine receptor H1.

Bphs controls Bordetella pertussis toxin (PTX)-induced vasoactive amine sensitization elicited by histamine (VAASH) and has an established role in autoimmunity. We report that congenic mapping links Bphs to the histamine H1 receptor gene (Hrh1/H1R) and that H1R differs at three amino acid residues in VAASH-susceptible and -resistant mice. Hrh1-/- mice are protected from VAASH, which can be restored by genetic complementation with a susceptible Bphs/Hrh1 allele, and experimental allergic encephalomyelitis and autoimmune orchitis due to immune deviation. Thus, natural alleles of Hrh1 control both the autoimmune T cell and vascular responses regulated by histamine after PTX sensitization.

Alleles↗

PubMed2002

Effects of cytokine deficiency on chemokine expression in CNS of mice with EAE.

Although both cytokines and chemokines have been implicated in the pathogenesis of clinical and histological EAE, their interactions in vivo have not yet been clearly established. To address this issue, we evaluated expression of chemokines and receptors in the CNS of wild-type control and cytokine deficient mice at the peak of EAE induced with MOG-35-55 peptide in CFA. Our results demonstrate that: 1) expression of most chemokines/receptors was drastically inhibited in TNF-alpha deficient mice, and was reflective of delayed onset and reduced severity of EAE; 2) distinct patterns of chemokine expression occurred in various other cytokine knockout mice that did not significantly affect expression of clinical EAE; 3) there was a strong association between expression of MIP-1alpha, MIP-2 and MCP-1 in CNS and overall severity of EAE in wild-type and cytokine knockout mice; and 4) among CNS infiltrating cells at the peak of EAE, macrophages and CD8+ T cells were the primary cellular source of most of the chemokines. Of note, we present evidence that TNF-alpha may be involved in regulating RANTES and MIP-1alpha, and that IL-4 may be involved in regulating MCP-1. Our results not only identify the cellular source of chemokines in CNS, but also implicate MIP-1alpha, MIP-2, and MCP-1 in controlling CNS inflammation and severity of EAE.

Animals↗

PubMed2002

Estrogen inhibits systemic T cell expression of TNF-alpha and recruitment of TNF-alpha(+) T cells and macrophages into the CNS of mice developing experimental encephalomyelitis.

Estrogen treatment has been found to have suppressive activity in several models of autoimmunity. To investigate the mechanism of 17 beta-estradiol (E2) suppression of experimental autoimmune encephalomyelitis, we evaluated E2 effects on TNF-alpha expression in the central nervous system (CNS) and spleen of C57BL/6 mice immunized with MOG 35-55/CFA. Kinetic analysis demonstrated that E2 treatment drastically decreased the recruitment of total inflammatory cells as well as TNF-alpha(+) macrophages and T cells into the CNS at disease onset. In contrast, E2 had only moderate effects on the relatively high constitutive TNF-alpha expression by resident CNS microglial cells. E2 treatment also had profound inhibitory effects on expression of TNF-alpha by splenic CD4(+) T cells, including those responsive to MOG 35-55 peptide. We propose that the mechanism of E2 protection may involve both systemic inhibition of TNF-alpha expression and local (CNS) recruitment of inflammatory cells, with modest effects on TNF-alpha expression by resident CNS microglial cells.

Animals↗

PubMed2002

A synthetic androstene derivative and a natural androstene metabolite inhibit relapsing-remitting EAE.

Experimental allergic encephalomyelitis (EAE), a Th1 polarized demyelinating disease of the central nervous system (CNS), shares many pathological and clinical similarities with multiple sclerosis (MS), and thus represents an attractive animal model for this disease. The goal of this study was to evaluate the suppressive effects of fluasterone (HE2500), a synthetic androstene derivative, and androstenetriol (HE2200), a natural androstene hormone on EAE. SJL mice were immunized with proteolipid protein (PLP) 139-151 peptide/CFA to induce EAE. Starting on day -7, animals were given daily injections (s.c.) of derivatives (3.0 mg) in vehicle, or vehicle alone for 33 days. Both HE2500 and HE2200 significantly delayed the onset, reduced the peak clinical score and cumulative disease index of EAE, and prevented or significantly attenuated relapses. Lower doses or other routes of administration were less effective. Moreover, T cells from treated mice had significantly reduced PLP 139-151-specific T cell proliferation responses and reduced numbers of TNF-alpha- and IFN-gamma-producing cells in the CNS. Daily treatment of B10.PL mice with HE2500, starting on day 0, completely prevented the development of disease in these animals. Finally, SJL mice treated with HE2500 at EAE onset showed significantly reduced mean clinical scores. Thus, these compounds, which have been reported to have a few androgenic or estrogenic side effects, appear to have a potent inhibitory activity in EAE. These observations suggest that HE2500 and/or HE2200 limit the production of autoimmune Th1 associated cytokines, and ultimately may be beneficial for patients with MS or other autoimmune diseases.

Androstenes↗

PubMed2002

Inhibitory effects of incomplete Freund's adjuvant on experimental autoimmune encephalomyelitis.

Freund's incomplete adjuvant (IFA), an aqueous/oil emulsion that is widely used in combination with antigenic proteins and peptides to induce tolerance, is considered to be immunologically inert. However, sporadic reports indicate that IFA may itself have inhibitory properties on induction of adjuvant induced arthritis and spontaneous diabetes. In the current study, the effects of IFA/saline were evaluated on the induction of experimental autoimmune encephalomyelitis (EAE) in three different strains of mice. IFA/saline given i.p. in two doses of > 100 microl 10 days apart were found to inhibit EAE induction to varying degrees in all three strains of mice in a dose dependent fashion. The IFA/saline injections inhibited both mitogen and antigen-induced T cell proliferation, induced elevated secretion of IFN-gamma and IL-10 by neuroantigen specific T cells, and reduced expression of cytokines, chemokines, and chemokine receptors of CNS-infiltrating mononuclear cells. These data demonstrate for the first time a direct inhibitory effect of IFA/saline on EAE, and re-emphasize the need to properly control experiments using IFA to induce antigen-specific tolerance.

Animals↗

PubMed2002

Evaluation of the effects of 17beta-estradiol (17beta-e2) on gene expression in experimental autoimmune encephalomyelitis using DNA microarray.

The aim of this study was to identify immune-related genes affected by treatment with 17beta-estradiol (17beta-E2) that contribute to protection of T cell antigen receptor double transgenic mice from experimental autoimmune encephalomyelitis (EAE). The Affymetrix microarray system was used to screen more than 12,000 genes from E2-treated mice protected from EAE vs. control mice with severe EAE. In general, E2 treatment affected about 10% of the genes tested, but only 18 cytokine, chemokine/receptor, adhesion molecule, or activation genes were up- or down-regulated more than 2.4-fold by E2 treatment. Down-regulated genes included TNFalpha (an important proinflammatory cytokine in EAE); peptidoglycan recognition proteins (Pgrp); regulated on activation, normal T cell expressed and secreted (RANTES); and neural cell adhesion molecule (MCP-1). Up-regulated genes included cytotoxic T lymphocyte antigen-4 (CTLA-4; known to inhibit T cell activation), TGFbeta3, IL-18, and two interferon-gamma-induced genes, the chemokines: monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1beta (MIP-1beta), vascular cell adhesion molecule (VCAM), and disintegrin metalloprotease (thought to regulate TNFalpha production). These results implicate a limited set of known and previously unsuspected E2-sensitive genes that may be crucial for inhibition of EAE and potentially the human disease, multiple sclerosis.

Animals↗

PubMedDate not supplied

Congruent effects of estrogen and T-cell receptor peptide therapy on regulatory T cells in EAE and MS.

Both estrogen (E2) and T-cell receptor (TCR) peptides have beneficial effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and possibly multiple sclerosis (MS) that involve distinct but congruent mechanisms. Of interest, these two approaches share an ability to enhance expression of the FoxP3 gene and associated activity of regulatory T (Treg) cells. E2 increases the number and activity of FoxP3(+) T cells through Esr-1 signaling during TCR activation of CD4(+)CD25(-) T cells. In contrast, TCR peptide therapy appears to increase the frequency of regulatory FoxP3(+) T cells specific for self-TCR determinants expressed by targeted pathogenic T cells. The combined effects on Treg expansion and activation induced by these distinct immunoregulatory approaches may account for their potent effects on clinical EAE and argue for a similar combined therapeutic approach for MS.

Animals↗