Search PubMed⌕ Search

Biomedical subjects

H Wekerle

Publications and source records attributed to H Wekerle.

At least 55 records · Page 3Linked to original sources
PubMed1998

In vivo and in vitro immune variables in patients with narcolepsy and HLA-DR2 matched controls.

We investigated cytokine levels (interleukin [IL]-1beta, IL-1ra, IL-2, IL-6, tumor necrosis factor [TNF]-alpha, TNF-beta) in plasma and secreted by mitogen-stimulated blood monocytes and lymphocytes; T-cell subsets; and natural killer cell activity in patients with narcolepsy and in human leukocyte antigen (HLA)-DR2 matched controls. The only significant finding was higher IL-6 secretion by monocytes of patients than by those of the HLA-DR2-positive controls. In conclusion, we found no major abnormalities of T-cell function in patients with narcolepsy, but slight alterations of monocyte function deserving further investigation.

Adult↗
PubMed1997

Interferon gamma gene expression in sensory neurons: evidence for autocrine gene regulation.

We explored expression and possible function of interferon-gamma (IFN-gamma) in cultured fetal (E15) rat dorsal root ganglion neurons combining whole cell patch-clamp electrophysiology with single cell reverse transcriptase polymerase chain reaction and confocal laser immunocytochemistry. Morphologically, we located IFN-gamma protein in the cytoplasm of the neurons in culture as well as in situ during peri- and postnatal development. Transcripts for classic IFN-gamma and for its receptor were determined in probes of cytoplasm sampled from individual cultured neurons, which had been identified by patch clamp electrophysiology. In addition, the cultured neurons expressed both chains of the IFN-gamma receptor. Locally produced IFN-gamma acts back on its cellular source. Phosphorylation and nuclear translocation of the IFN-inducible transcriptional factor STAT1 as well as IFN-gamma-dependent expression of major histocompatibility complex class I molecules on the neuronal membrane were noted in untreated cultures. However, both processes were substantially blocked in the presence of antibodies neutralizing IFN-gamma. Our findings indicate a role of IFN-gamma in autocrine regulation of sensory neurons.

Animals↗
PubMed1997

Inflammation promotes survival and migration of the CG4 oligodendrocyte progenitors transplanted in the spinal cord of both inflammatory and demyelinated EAE rats.

Oligodendrocyte progenitor CG4 cells were labeled with bisbenzimide and transplanted in the lumbar spinal cord of rats 15 to 17 days prior to the induction of experimental autoimmune encephalomyelitis (EAE). EAE was induced by immunization with the encephalitogenic peptide of myelin basic protein (amino acids 68-88; C1) in adjuvant, either alone or in combination with a single injection of an anti-myelin oligodendrocyte glycoprotein (MOG) antibody to enhance central nervous system (CNS) demyelination. In control animals without EAE, the survival and migration capacity of CG4 cells was minimal. In striking contrast, both the survival and migration of this oligodendrocyte progenitor cell line were greatly enhanced in animals with EAE. In both disease models, large number of CG4 cells were still found in the spinal cord 50 days after transplantation, by which time they had migrated up to 6 cm from the transplantation site. Migrating CG4 cells were found in the subpial space, around the ependyma and blood vessels, and as well as in the grey and white matter of the CNS parenchyma. In all these locations, the CG4 cells were often associated with reactive astrocytes. These data strongly support the concept that inflammatory responses within the CNS promote, rather than inhibit, the survival and migration of transplanted oligodendrocyte progenitors in the adult CNS.

Animals↗
PubMed1997

Growth transformation of antigen-specific T cell lines from rhesus monkeys by herpesvirus saimiri.

This study aims in establishing the in vitro basis for a primate model to evaluate potential applications of H. saimiri-transformed T cells. T cell lines specific for myelin basic protein and streptolysin O were derived from rhesus monkeys and transformed to stable antigen-independent growth with strain C488 of H. saimiri. The transformed T cells from rhesus monkeys did not produce infectious virus and harbored the H. saimiri genome exclusively in an episomal form, whereas transformed T cells from the New World monkey Calltithrix jacchus released infectious virus. Transformed T cells from rhesus monkeys showed an unaltered surface expression of CD2 and CD3, of the activation markers CD25 and CD69, and of the costimulatory molecule CD80 (B7.1). Remarkably, both transformed and nontransformed T cell lines were largely double-positive for CD4 and CD8. In contrast to the parental cell lines, the transformed cells constitutively expressed major histocompatibility complex-DR antigens and were able to present antigen to each other. The transformed T cells from rhesus monkeys continued to express a functionally intact T cell receptor and responded to recognition of their antigen with enhanced proliferation and production of Th1-type cytokines. In conclusion, H. saimiri-transformed rhesus monkey T cells may open a way to primate models for adoptive immunotherapy and studies on the pathogenesis of autoaggressive T cells.

Animals↗
PubMed1997

Insulin-like growth factor-I treatment reduces immune cell responses in acute non-demyelinative experimental autoimmune encephalomyelitis.

To test the effects of insulin-like growth factor-I (IGF-I) on clinical deficits, lesion severity, and immune cell response in acute, non-demyelinative experimental autoimmune encephalomyelitis (EAE), we induced EAE in Lewis rats by passive transfer of an MBP-reactive T lymphocyte line. Four days after receiving 5 x 10(5) MBPL-1 T cells intravenously, ten pairs of rats had the same mild degree of tail and hind limb weakness. Ten were given 300 micrograms IGF-I i.v. twice daily for 6 days, and the other 10 received the same volume of 0.89% NaCl. Pairs of rats were sacrificed after 4 days and 6 days of IGF-I and placebo treatment and spinal cord sections were processed for immunostaining, in situ hybridization, and morphological examination. IGF-I treatment decreased clinical deficits, lesion numbers, and lesion areas significantly. Numbers of CD4-positive T cells, alpha/beta TCR-positive cells, and ED-1-positive macrophages were also significantly reduced by IGF-I treatment. Similar reductions were found in our second trial, when 11 days of placebo and IGF-I injections began the day after transfer. No demyelination was observed in either toluidine blue-stained semithin sections or sections immunostained with an antibody raised against myelin basic protein (MBP). We conclude that IGF-I-induced reductions in immune cell responses can occur in the absence of demyelination and are of major importance in decreasing clinical deficits and lesion severity in EAE. If IGF-I has similar effects in multiple sclerosis, we think that it will be useful therapeutically.

Animals↗
PubMed1997

Major histocompatibility complex (MHC) class I gene expression in single neurons of the central nervous system: differential regulation by interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha.

This study examined the effect of the pro-inflammatory cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) on the induction of MHC class I-related genes in functionally mature brain neurons derived from cultures of dissociated rat hippocampal tissue. Patch clamp electrophysiology combined with single cell RT-PCR demonstrated that approximately 50% of the untreated neurons contained mRNA for MHC class I heavy chains, while, with few exceptions, the cells failed to transcribe beta2-microglobulin and TAP1/TAP2 gene transcripts. No constitutive expression of MHC class I protein was detectable by confocal laser microscopy on the surface of neurons. All neurons transcribed the alpha-chain of the interferon-type II receptor (binding IFN-gamma) along with the p55 receptor for TNF-alpha. Sustained exposure to IFN-gamma resulted in transcription of beta2-microglobulin and TAP1/TAP2 genes and MHC class I surface expression in a minor part of the neurons, but did not alter their electrophysiological activities as assessed by whole cell electrophysiology. Suppression of neuronal electric activity by the sodium channel blocker tetrodotoxin drastically increased to almost 100% IFN-gamma-mediated induction of MHC class I chains, of both TAP transporters, and of membrane expression of MHC class I protein. The effect of tetrodotoxin is at least partly reverted by the neurotransmitter glutamate. In contrast to IFN-gamma, treatment with TNF-alpha did neither upregulate TAP1/TAP2 nor beta2-microglobulin gene expression, but induced MHC class I heavy chain gene transcription in all neurons. Consequently, no MHC class I molecules were detectable on the membranes of TNF-alpha-treated neurons.

Gene Expression Regulation↗
PubMed1997

Induction of experimental autoimmune encephalomyelitis by CD4+ T cells specific for an astrocyte protein, S100 beta.

S100 beta protein is a calcium binding protein that is not only expressed by astrocytes in the CNS, but also in many other tissues including the eye, thymus, spleen and lymph nodes. Despite this tissue distribution, which was expected to induce a firm state of self-tolerance to S100 beta, the Lewis rat mounts a strong T cell response to this autoantigen. The pathogenicity of this T cell response was demonstrated by the adoptive transfer of S100 beta-specific T cells which induced an inflammatory response in the CNS and eye of naive syngeneic recipients. The distribution of lesions in this novel model of EAE resembles that seen in some patients with MS, suggesting that the initial autoimmune insult in MS may be directed against a non-myelin antigen co-expressed in the CNS and extra-neural tissues.

Adoptive Transfer↗
PubMed1997

TNF-alpha receptor fusion protein prevents experimental auto-immune encephalomyelitis and demyelination in Lewis rats: an overview.

To explore the therapeutic use of TNF-alpha inhibitors in human inflammatory demyelinating diseases we examined the effect of a recombinant TNFRp55 protein constructed by fusing TNFRp55 extracellular domain cDNA to a human IgG1 heavy gene fragment containing the hinge and constant domains CH2 and CH3 (TNFRp55-IgG1) in diverse experimental model systems representing inflammation and inflammatory demyelination of encephalitogenic T cells in vivo. In EAE actively induced by immunization of Lewis rats with MBP, a single dose of TNFRp55-IgG1 protected the recipient animals from clinical signs. Interestingly, the treatment neither prevented the formation CNS infiltrations, nor did it alter the cellular composition of the infiltrates. In EAE transferred by MBP specific activated T line cells, a model of inflammatory (not demyelinating) brain disease, the inhibitor's therapeutic effect on clinical disease was also striking achieving almost complete protection even after repeated transfers of encephalitogenic T cells. Finally, the recombinant inhibitor was also protective in Lewis rats with demyelinating experimental autoimmune panencephalitis produced by combined transfer of panencephalitogenic T cells and demyelinating monoclonal antibody specific for MOG. In this system, the T cells are of low encephalitogenic activity, but open the blood-brain barrier for the demyelinating immunoglobulins. The fusion protein treatment, however, prevented the formation of inflammatory lesions and demyelination. The strong therapeutic effect of the recombinant chimeric TNF-alpha inhibitor in three models of myelin specific autoimmunity raises hopes as to TNF-alpha directed therapy of human diseases like MS.

Animals↗
PubMed1997

Multiple sclerosis: comparison of the human T-cell response to S100 beta and myelin basic protein reveals parallels to rat experimental autoimmune panencephalitis.

The adoptive transfer of autoreactive S100 beta-specific T cells induces experimental autoimmune panencephalomyelitis and uveoretinitis in the Lewis rat, mimicking the distribution of lesions seen in a subset of patients with multiple sclerosis. We studied the frequency and functional properties of the human T-cell response to S100 beta in eight patients (two relapsing-remitting multiple sclerosis, one chronic-progressive multiple sclerosis, two with multiple sclerosis and uveitis, two neuromyelitis optica, one panuveitis) and in seven healthy individuals, using bovine S100 beta for T-cell stimulation. Both in patients and controls, the frequency of S100 beta-specific T-cell responses was half of that obtained for myelin basic protein (MBP), and only 10% of that obtained using purified protein derivative (PPD). The stimulation indices obtained in response to S100 beta were also less than half those obtained with either MBP or PPD. However, four long-term S100 beta-specific T-cell lines were established and studied in more detail. The four T-cell lines all exhibited a CD4+, CD8-, T-cell receptor alpha beta + surface phenotype and secreted tumour necrosis factor-alpha, interferon-gamma, interleukin-10 and interleukin-4 upon antigenic stimulation, but they were heterogenous with respect to T-cell receptor usage; two T-cell lines expressed V beta 2, one V beta 6.7 and one V beta 13. Antigen-specificity was confirmed using bovine S100 beta beta and alpha beta-isoforms, as well as a recombinant rat S100 beta preparation. The response to S100 beta was shown to the HLA-(human leukocyte antigen-) DR-restricted for two of the S100 beta-specific T-cell lines. Human S100 beta-specific T-cell lines were cytotoxic, although to a lesser extent than MBP-specific T-cell lines derived from the same donors. The phenotypic and functional properties of human S100 beta-specific T-cell lines raise the possibility that these T cells are pathogenic, as they are in the rat. The low frequency and proliferative index of S100 beta-specific, as opposed to MBP-specific T-cell responses suggests that the T-cell response to this widely expressed calcium-binding protein is under more efficient regulatory control.

Adult↗
PubMed1997

The thymus and self-tolerance: co-existence of encephalitogenic S100 beta-specific T cells and their nominal autoantigen in the normal adult rat thymus.

The adoptive transfer of auto-reactive T cells specific for S100 beta protein mediates experimental autoimmune panencephalomyelitis, an inflammatory autoimmune disease of the nervous system and eye. However, unlike classical encephalitogenic autoantigens which are components of the myelin membrane and restricted to the nervous system, S100 beta is expressed by many different cell types in a wide variety of peripheral tissues. We now report that S100 beta is also expressed within the rat thymus from embryonic day 16 through to adulthood at which time point the protein is localized within stroma cells of the thymic medulla. However, despite the continued expression of this autoantigen within the thymic microenvironment it proved possible to isolate encephalitogenic, S100 beta-specific CD4+ alpha beta TCR T cell lines from the naive adult rat thymus. These T cell lines were highly specific for S100 beta, and following activation in vitro and adoptive transfer initiate an inflammatory response in the central nervous system and eye of naive syngeneic recipients. These observations provide additional evidence that clonal deletion of autoaggressive T cell clones in the thymus is leaky. In this case allowing potentially autoaggressive T cell clones specific for S100 beta, a non-myelin autoantigen expressed in the nervous system, thymus and many peripheral tissues, to become an intrinsic component of the normal immune repertoire.

Animals↗
PubMed1997

Encephalitogenic potential of myelin basic protein-specific T cells isolated from normal rhesus macaques.

Myelin basic protein (MBP)-specific T cells are implicated in the pathogenesis of multiple sclerosis and are targets of selective immunotherapies. However, autoantigen-specific T cells can also be isolated from healthy individuals. Their functional potential is unknown and obviously cannot be tested in humans. We approached this question in a closely related primate species, the rhesus monkey. CD4+ T cell lines specific for MBP were isolated from normal rhesus monkeys using the same primary limiting dilution technique that is now widely used to generate human autoreactive T cell clones in vitro. Three different epitopes were recognized by three rhesus T cell lines isolated from three different monkeys. Upon activation, all lines produced interferon-gamma, interleukin-2, tumor necrosis factor-alpha, and granulocyte/macrophage colony-stimulating factor but neither interleukin-4 nor transforming growth factor-beta. The MBP-specific T cells were injected intravenously without adjuvant into the nonirradiated autologous monkey. One of the three rhesus monkeys developed an encephalomyelitis with a pleocytosis in the spinal fluid and perivascular infiltrates in the leptomeninges, spinal nerve roots and cerebral cortex. The data demonstrate that the normal immune repertoire of a primate species contains MBP-specific CD4+ T cells that are able to induce an autoimmune encephalomyelitis upon transfer into the nonirradiated autologous recipient.

Animals↗
PubMed1997

Experimental autoimmune encephalomyelitis: the antigen specificity of T lymphocytes determines the topography of lesions in the central and peripheral nervous system.

Recent studies on autoimmune encephalomyelitis and neuritis reveal that many different antigens of the central (CNS) and peripheral nervous system may become targets of an encephalitogenic T-cell response. The aim of this study was to determine the influence of T-cell specificity on the pathology of autoimmune-mediated inflammation in the nervous system. Autoimmune encephalomyelitis was induced by the adoptive transfer of CD4+ T-line cells specific for either myelin basic protein, myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein, S100 beta, or glial fibrillary acidic protein. The severity of the inflammatory response was antigen- and dose-dependent. With the exception of MOG-specific T-line cells, all autoreactive T-cell lines induced inflammation in the CNS and peripheral nervous system. In the myelin-basic-protein-mediated model, the spinal cord was most severely affected with only minor inflammation in the forebrain. In contrast, both MOG- and myelin-associated-glycoprotein-specific T cells induced a far higher density of lesions in the periventricular and cerebellar white matter. S100 beta- and glial-fibrillary-acidic-protein-specific T cells mediated particularly severe inflammation in the gray matter. In addition to these topographic differences, antigen specificity also influenced the extent of both parenchymal inflammation and macrophage activation in the CNS. However, irrespective of the specificity or number of T cells transferred, the major neuropathologic correlate with disease severity was the absolute number of activated macrophages recruited into the CNS parenchyma (r = 0.9; p < 0.0001). This study suggests that differences in lesion distribution in multiple sclerosis patients may reflect differences in the antigen specificity of an encephalitogenic T-cell response.

Amino Acid Sequence↗
PubMed1996

Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis.

Polymyositis (PM) and dermatomyositis (DM) are the prototypical inflammatory diseases of skeletal muscle. In PM, CD8+ T cells invade and destroy muscle fibers, whereas humoral effector mechanisms prevail in DM. We studied the expression of the cytotoxic mediator perforin in inflammatory cells in PM and DM muscle by semiquantitative PCR, immunohistochemistry and confocal laser microscopy. Similar levels of perforin mRNA were expressed in PM and DM, and abundant perforin-expressing CD3+CD8+ and CD3+ CD4+ T cells were observed in both diseases. However, there was a striking difference in the intracellular localization of perforin. In DM, perforin was distributed randomly in the cytoplasm of the inflammatory T cells. In contrast, 43% of the CD8+ T cells that contacted a muscle fiber in PM showed perforin located vectorially towards the target muscle fiber. The results suggest (a) that the random distribution of perforin in the cytoplasm of muscle-infiltrating T cells observed in DM reflects nonspecific activation, and (b) that the vectorial orientation observed only in PM reflects the specific recognition via the T cell receptor of an antigen on the muscle fiber surface, pointing to a perforin- and secretion-dependent mechanism of muscle fiber injury.

Base Sequence↗
PubMed1996

Differential expression of fibroblast growth factor-2 and receptor by glial cells in experimental autoimmune encephalomyelitis (EAE)

To assess the expression pattern of basic fibroblast growth factor (FGF-2) and one of its receptors (FGFR-1/flg) during autoimmune inflammation of the CNS, FGF-2, and FGFR1/flg peptide and mRNA levels were examined by immunocytochemistry, by in situ hybridisation and by Northern blot analysis in T cell-mediated EAE of the Lewis rat. In naive control animals as well as in animals injected with non-encephalitogenic, PPD-reactive T lymphocytes, FGF-2 immunoreactivity was low and confined to blood vessels and to a few spinal cord neurons. In rats injected with encephalitogenic, MBP-reactive T lymphocytes, however, FGF-2-immunoreactive cells were detected from day 4 after T cell transfer onward, i.e., from the onset of clinical symptoms. The number of FGF-2 immunoreactive cells was highest between days 6 and 10 after T cell transfer. Increased FGF-2 peptide expression was paralleled by increased FGF-2 mRNA expression on macrophages/microglia in the spinal cord. By 21 days after T cell transfer, i.e. after complete recovery, FGF-2 peptide and mRNA expression had fully subsided. Based on morphological criteria and on double labeling with the macrophage/microglia-binding lectin GSI-B4 two cell types expressed FGF-2: 1) round macrophages within the core, and 2) activated microglia at the edges of white and grey matter perivascular lesions. Paralleling the temporal and spatial expression pattern of FGF-2, FGFR-1/flg immunoreactivity was induced on activated macrophages/microglia but also on reactive astrocytes bordering perivascular inflammatory lesions. In situ hybridisation analysis furthermore showed that macrophages/microglia expressed the FGFR-1/flg mRNA, and that receptor mRNA expression paralleled ligand mRNA expression. Macrophage/microglia-derived FGF-2 could serve two main functions in EAE: 1) regulate microglial activation in an autocrine fashion, and 2) help to target astrocyte-derived insulin-like growth factor-I (IGF-I) to potentially injured oligodendrocytes in demyelination.

Animals↗
PubMed1996

The myelin basic protein-specific T cell repertoire in (transgenic) Lewis rat/SCID mouse chimeras: preferential V beta 8.2 T cell receptor usage depends on an intact Lewis thymic microenvironment.

In the Lewis rat, myelin basic protein (MBP)-specific, encephalitogenic T cells preferentially recognize sequence 68-88, and use the V beta 8.2 gene to encode their T cell receptors. To analyze the structural prerequisites for the development of the MBP-specific T cell repertoire, we reconstituted severe-combined immunodeficient (SCID) mice with fetal (embryonic day 15-16) Lewis rat lymphoid tissue, and then isolated MBP-specific T cell lines from the adult chimeras after immunization. Two types of chimera were constructed: SCID mice reconstituted with rat fetal liver cells only, allowing T cell maturation within a chimeric SCID thymus consisting of mouse thymic epithelium and rat interdigitating dendritic cells, and SCID mice reconstituted with rat fetal liver cells and rat fetal thymus grafts, allowing T cell maturation within the chimeric SCID and the intact Lewis rat thymic microenvironment. Without exception, the T cell lines isolated from MBP-immunized SCID chimeras were restricted by MHC class II of the Lewis rat (RT1.B1), and none by I-Ad of the SCID mouse. Most of the T cell lines recognized the immunodominant MBP epitope 68-88. In striking contrast to intact Lewis rats, in SCID mice reconstituted by rat fetal liver only, MBP-specific T cell clones used a seemingly random repertoire of V beta genes without a bias for V beta 8.2. In chimeras containing fetal Lewis liver plus fetal thymus grafted under the kidney capsule, however, dominant utilization of V beta 8.2 was restored. The migration of liver-derived stem cells through rat thymus grafts was documented by combining fetal tissues from wild-type and transgenic Lewis rats. The results confirm that the recognition of the immunodominant epitope 68-88 by MBP-specific encephalitogenic T cells is a genetically determined feature of the Lewis rat T cell repertoire. They further suggest that the formation of the repertoire requires T cell differentiation in a syngeneic thymic microenvironment.

Amino Acid Sequence↗
PubMed1996

Antigen presentation by astrocytes primes rat T lymphocytes for apoptotic cell death. A model for T-cell apoptosis in vivo.

In this study we have characterized apoptotic cell death of autoreactive T cells resulting from their interaction with astrocytes and the modulatory effect of steroid hormones. Time kinetics of T-cell activation by interferon (IFN)-gamma-treated astrocytes from neonatal Lewis rats and by professional antigen presenting cells (APCs) from bulk suspensions of thymus or spleen were performed. [3H]Thymidine incorporation of neuritogenic P2- and encephalitogenic myelin basic protein (MBP)-specific T-cell lines declined after 48 h in culture with astrocytes. A similar suppressive effect was observed when T cells were cocultured with thymic APCs and astrocytes. This effect disappeared when astrocytes were separated by a transwell system. After 72 h of culture with astrocytes a mean of 17.5 +/- 12.4% T cells exhibited morphological signs of apoptosis. Apoptosis was identified by light microscopy, and confirmed by electron microscopy, by in situ tailing reaction and by agarose gel electrophoresis. Glucocorticosteroids and oestrogen specifically enhanced T-cell apoptosis within 8 h (69.8 +/- 23.1% and 69 +/- 17.1%, respectively) when added after 72 h to the astrocyte system, but not at earlier time points of T-cell activation or when thymic APCs were used. Glucocorticoid-mediated T-cell apoptosis was inhibited by the steroid-receptor antagonist RU 486. Pregnenolone, lipocortin-1, indomethacin and transforming growth factor-beta did not induce apoptosis in this system. The steroid effect was not associated with CD28, IL-2 receptor, or transferrin-receptor expression, which were equally upregulated on T cells activated by astrocytes or thymic APC as shown by fluorescence activated cell sorting (FACS) analysis. We conclude that astrocytes as CNS-specific APC may render T cells susceptible for induction of apoptotic cell death. Some steroid hormones can markedly enhance this process in vitro and may augment an additional effect of a systemic corticosteroid response in vivo during recovery from autoimmune encephalomyelitis.

Analysis of Variance↗
PubMed1996

Neuronal control of MHC class II inducibility in rat astrocytes and microglia.

We analysed the inducibility of major histocompatibility complex (MHC) class II molecules of astrocytes and microglia in organotypic hippocampus slice cultures of Lewis rats. Treatment with interferon-gamma (IFN-gamma) resulted in the induction of MHC class II molecules on microglia preferentially in the injured marginal zones of the slice culture, but only sporadically in areas containing intact neuronal architecture. In astrocytes, inducibility of MHC class II molecules was even more strictly controlled. IFN-gamma treatment induced MHC class II expression only in the slice culture zones containing degenerated neurons, and not in the presence of functional neurons. After suppression of spontaneous neuronal activity of the slice culture by the sodium channel blocker tetrodotoxin, MHC class II molecules on astrocytes could be induced by IFN-gamma in areas with intact neuronal architecture, and microglia cells exhibited a higher level of expression. These data suggest that loss of neurons could result in MHC class II inducibility of glial cells, and thus in increased immune reactivity of nervous tissue.

Animals↗