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R Liblau

Publications and source records attributed to R Liblau.

At least 37 records · Page 2Linked to original sources
PubMed1998

A viral peptide with limited homology to a self peptide can induce clinical signs of experimental autoimmune encephalomyelitis.

Molecular mimicry has been suggested as a mode of autoreactive T cell stimulation in autoimmune diseases. Myelin basic protein (MBP) peptide 1-11 induces experimental autoimmune encephalomyelitis (EAE) in susceptible strains of mice. Here we show that a herpesvirus Saimiri (HVS) peptide, AAQRRPSRPFA, with a limited homology to MBP1-11 peptide, ASQKRPSQRHG (underlined letters showing homology), can stimulate a panel of MBP-11-specific T cell hybridomas and more importantly cause EAE in mice. We demonstrate that this is due to cross-recognition of these two peptides by TCRs. Results presented in this communication are the first demonstration that a viral peptide with homology at just 5 amino acids with a self peptide can induce clinical signs of EAE in mice. These findings have important implications in understanding the breakdown of T cell tolerance to self Ags in autoimmune diseases by means of cross-reactivity with unrelated peptides.

Animals↗
PubMed1998

Systemic autoimmune features and multiple sclerosis: a 5-year follow-up study.

OBJECTIVES: To evaluate in patients with multiple sclerosis (MS) the occurrence of clinical systemic signs and biological autoimmune abnormalities, including positive titers of antinuclear antibodies and antiphospholipid antibodies, suggestive of autoimmune diseases that may affect the central nervous system. Also, to compare the clinical and magnetic resonance imaging features and evolution of MS in patients with and without autoimmune abnormalities. DESIGN AND PATIENTS: Prospective study of 161 patients fulfilling the criteria of having probable or definite MS hospitalized in our institution between November 1990 and June 1992. RESULTS: Among the 161 patients, 84 (52.1%) had at least 1 clinical and/or biological general sign suggestive of an autoimmune disease; 64 were followed up for 4 to 5 years. The diagnosis of MS was confirmed in 50 patients and is still pending in 14 of them. No significant difference was found between patients with MS who were free of autoimmune features and those with autoimmune abnormalities (MS plus) concerning the age of disease onset, the presenting symptoms and signs, symptoms found on neurologic examination, and the course of the disease. For all patients with confirmed MS, general signs were found in 13.3%, positive titers of antinuclear antibodies in 26%, and positive titers of antiphospholipid antibodies in 6.2%. CONCLUSIONS: Patients with MS with autoimmune features, including those with titers of antinuclear antibodies of 1:100 or less and/or antiphospholipid antibodies, are not different than others with MS, and therefore should not be excluded from clinical trials.

Adolescent↗
PubMed1998

Imaging antigen recognition by naive CD4+ T cells: compulsory cytoskeletal alterations for the triggering of an intracellular calcium response.

Antigen recognition was analyzed at the single-cell level by using for the first time T cells which were not altered by in vitro selection, transfection or immortalization. The first consequence of antigen recognition by ex vivo naive CD4+ T cells from T cell receptor (TCR)-transgenic mice is the formation of a "contact zone" with the B cell presenting the antigen. The T cell intracellular calcium (Ca2+) response begins after a delay of 30 s on average, following the formation of the contact zone. The T cell response is entirely inhibited by either protein tyrosine kinase or actin polymerization inhibitors but, surprisingly, it is insensitive to inhibitors of phosphoinositide 3-kinase. Moreover, inhibition of microtubule polymerization and use of Ca2+-free medium do not prevent the beginning of the T cell response, but do reduce the stability of the contact zone and/or the amplitude of the Ca2+ plateau. The critical involvement of the cytoskeleton in antigen recognition on B cells introduces a checkpoint in T cell activation: the initial TCR engagement triggers a Ca2+ response only after an amplification step corresponding to a cytoskeleton-controlled increase in the number of engaged TCR.

Actins↗
PubMed1998

Role of co-stimulation in CD8+ T cell activation.

The two-signal model states that activation of naive T cells requires a signal 1 stimulus through the TCR and a co-stimulatory signal 2. By contrast, signal 1 alone is sufficient for pre-activated T cells. Recently, however, it has been shown that under certain conditions T cells can bypass the requirement for co-stimulation. For example, CD28-deficient mice, when immunized with lymphocytic choriomeningitis virus, mount a vigorous cytotoxic T lymphocyte response and clear the virus. As a continuous effort to unravel the mechanisms of T cell activation, we previously reported activation of hybridoma T cells by recombinant single-chain MHC molecules in the absence of antigen-presenting cells. In such reconstitution experiments, since the signals delivered to the T cells are well controlled, the contribution of any known or unknown signals can be ruled out. In the present study, we analyzed the requirements for activation of naive T cells by using splenocytes from TCR transgenic mice as a source of responding cells. We observed that naive CD8+ T cells are fully activated by signal 1 alone, but that co-stimulation lowers their activation threshold. Previously activated T cells are fully responsive, even when the first stimulation was performed in the absence of co-stimulation. They display a low activation threshold and are insensitive to co-stimulation. The physiological relevance of this finding and its consequences for immunotherapy as well as for our understanding of self-tolerance are discussed.

Amino Acid Sequence↗
PubMed1998

T cell receptor V beta 5 and V beta 17 clonal diversity in cerebrospinal fluid and peripheral blood lymphocytes of multiple sclerosis patients.

To better characterize the cellular immune response taking place in the MS central nervous system, we investigated the blood and CSF T cell receptor (TCR) V beta 5 and V beta 17 repertoire in HLA-typed patients with recently diagnosed MS or other neurological diseases (OND). Using a RT-PCR based technique, we analysed directly ex vivo the CDR3 size of TCR beta chains utilizing V beta 5 (eight patients with MS and one with OND) or V beta 17 (eight patients with MS and six with OND) gene segments on paired blood-CSF samples. Globally, the analysis of V beta 5-J beta and V beta 17-J beta repertoire showed a less diverse pattern in the CSF samples than in the corresponding peripheral blood lymphocytes both in MS and in OND patients. However, we did not detect any recurrent clonal expansion within the V beta 5+ T cells in MS patients, underlining the potential limits of V beta 5-based immunotherapy in MS. We found an expanded T cell population using the same V beta 17-J beta 1.6 combination with identical CDR3 length in the CSF of three MS patients and none of the control patients. These results suggest selective expansion of T cells expressing this segment gene in the MS central nervous system.

Adult↗
PubMed1998

Lack of association between human leukocyte antigens and the anti-Hu syndrome in patients with small-cell lung cancer.

We compared the human leukocyte antigen alleles found in a group of 17 patients with small-cell lung cancer (SCLC), paraneoplastic neurologic syndromes (PNS), and high titers of anti-Hu autoantibodies with those in 30 patients with SCLC but no PNS and no anti-Hu antibodies (control group). There was no difference between the two groups, suggesting that specific haplotypes are not required for the development of the "anti-Hu syndrome."

Alleles↗
PubMed1998

A systematic study of oligodendrocyte growth factors as candidates for genetic susceptibility to MS. French Multiple Sclerosis Genetics Group.

OBJECTIVE: To test 23 genes coding for growth factors and their receptors as candidates for MS genetic susceptibility in 84 multiplex families of French origin by linkage analysis. BACKGROUND: Epidemiologic studies have indicated that genetic susceptibility in MS exists. To identify MS susceptibility genes, association and linkage studies were performed with candidate genes suggested by the pathology of MS. The most consistent result was genetic association and linkage of MS to human leukocyte antigen (HLA) DR15. Recent advances in the knowledge of MS pathology have suggested that the oligodendrocyte, the myelin-forming cell in the CNS, and its growth factors might play a crucial role in MS. METHODS: Fifty-two polymorphic markers within or flanking 23 candidate genes were used. Data were analyzed with the maximum likelihood score (MLS) approach. We also searched for a genetic interaction with HLA. RESULTS: Negative results were obtained for all candidate genes. The lower limits of the relative risk (Xs) possibly excluded for any candidate gene ranged from 1.3 to 2.8. Positive MLS values (up to 0.93) were observed for transforming growth factor beta 3 (TGFbeta3) in HLA DR15-associated families, suggesting a possible role for this growth factor in interaction with HLA. CONCLUSIONS: Oligodendrocyte growth factors do not play a significant role in MS genetic susceptibility, at least in the tested sample. TGFbeta3, the only gene highlighted by this study, deserves further analysis.

Adult↗
PubMed1998

Prevention of diabetes in NOD mice by a mutated I-Ab transgene.

Susceptibility to the human autoimmune disease IDDM is strongly associated with those haplotypes of the major histocompatibility complex (MHC) carrying DQB1 alleles that do not encode aspartic acid at codon 57. Similarly, in a spontaneous animal model of this disease, the NOD mouse, the genes of the MHC play an important role in the development of diabetes. The DQB1 homolog in NOD mice, I-Ab(g7), encodes a histidine at codon 56 and a serine at codon 57, while all other known I-Ab alleles encode proline and aspartic acid, respectively, at these positions. We therefore mutated the NOD I-Ab allele to encode proline at position 56 and aspartic acid at position 57 and introduced this allele onto the NOD genetic background to study the effect of these substitutions on susceptibility to diabetes. No transgenic mice developed diabetes by 8 months of age, and transgenic mice had markedly reduced lymphocytic infiltration in the pancreas compared with nontransgenic littermates. Furthermore, splenocytes from transgenic mice failed to proliferate or secrete gamma-interferon in response to a panel of beta-cell autoantigens, although the mice did produce beta-cell specific antibodies. Interestingly, the proportion of IgG1 and IgE relative to IgG2a comprising these autoantibodies was much greater in transgenic mice compared with nontransgenic control mice. Finally, T-cells from transgenic mice inhibited the adoptive transfer of diabetes to irradiated recipients. This inhibition was partially reversed by treatment of the recipients with a combination of anti-interleukin (IL)-4 and anti-IL-10 monoclonal antibodies. Thus, a transgenic class II MHC allele encoding aspartic acid at B57 prevents diabetes, in part, by promoting the production of IL-4 and IL-10, which interfere with the effector phase of the diabetic process.

Animals↗
PubMed1998

The pathophysiology of paraneoplastic neurological syndromes.

Paraneoplastic neurological diseases are a group of neurological disorders associated with neoplastic tumors but not due to tumoral extension, metabolic, infectious, vascular or toxic complications of these tumors or their treatment. In the majority of paraneoplastic neurological disorders, circulating autoantibodies directed against neurons have been found in the serum and/or the CSF suggesting, and in some cases implicating, autoimmunity in the pathophysiology of these diseases. The finding of autoimmune phenomena during the course of paraneoplastic neurological disorders is of importance: from a practical point of view, since the detection of anti-neuronal autoantibodies is of great diagnostic help and should lead to the thorough search of the associated tumor often at an early stage of its development; from a theoretical point of view, these disorders represent a peculiar type of molecular mimicry. Tumoral neontigens having structural homology or identity with neuronal autoantigens elicit autoreactivity. The immunological effector mechanisms involved in the pathophysiology of paraneoplastic syndromes appear to differ according to the disease: autoantibodies are pathogenic in Lambert-Eaton syndrome whereas, in paraneoplastic cerebellar degeneration and in the Hu syndrome, the cellular immune response might play a greater role.

Encephalomyelitis↗
PubMed1998

[Experimental autoimmune encephalomyelitis].

Experimental autoimmune encephalomyelitis is an induced inflammatory and demyelinating disease of the central nervous system widely used as an animal model for multiple sclerosis. New insights into its pathophysiology have been possible due to recent immunological concepts. New therapeutical approaches have been designed and tested in experimental autoimmune encephalomyelitis and are now entering the clinical setting.

Animals↗
PubMed1997

Enrichment of antigen-specific T lymphocytes by panning on immobilized MHC-peptide complexes.

Numerous studies have focused on characterizing and monitoring antigen-specific T cells during the course of an immune response. Mostly indirect methods were used to circumvent the low frequency of T cell precursors and the inherent complexity of T cell receptor (TcR)-MHC-peptide interactions. Here, we took advantage of peptide-specific adhesion induced by immobilized MHC-peptide complexes. We describe a simple technique which allows enrichment in antigen-specific T lymphocytes among a heterogeneous CD8+ T cell population. Enrichment of T cells according to their specificity should facilitate their characterization and provide an attractive tool for immunotherapy.

Animals↗
PubMed1997

Systemic antigen in the treatment of T-cell-mediated autoimmune diseases.

Systemic injection of antigen is one of the approaches that reproducibly induces effective antigen-specific hyporesponsiveness. Here, Roland Liblau and colleagues discuss the cellular and molecular bases of such tolerance, review the current use of this therapeutic strategy in experimental organ-specific autoimmune diseases and analyse what steps are necessary to make this approach suitable for clinical use.

Animals↗
PubMed1997

Gene transfer to the central nervous system by transplantation of cerebral endothelial cells.

A cerebral endothelial immortalized cell line was used in transplantation experiments to deliver gene products to the adult rat brain. Survival of grafted cells was observed for at least 1 year, without any sign of tumor formation. When genetically modified to express bacterial beta-galactosidase and transplanted into the striatum, these cells were shown, by light and electron microscope analysis, to integrate into the host brain parenchyma and microvasculature. Following implantation into the striatum and nucleus basalis of adult rats, endothelial cells engineered to secrete mouse beta-nerve growth factor (NGF) induced the formation of a dense network of low-affinity NGF receptor-expressing fibers near the implantation sites. This biological response was observed from 3 to 8 weeks after engraftment. The present study establishes the cerebral endothelial cell as an efficient vector for gene transfer to the central nervous system.

Animals↗
PubMed1997

Experimental autoimmune encephalomyelitis in IL-4-deficient mice.

Experimental autoimmune encephalomyelitis (EAE) in an inflammatory demyelinating disease which usually follows a monophasic course. Autoreactive Th1 CD4+ T cells are responsible for the lesions, whereas autoreactive Th2 CD4+ T cells can, upon adoptive transfer, suppress the disease process. However, the role of IL-4 and Th2 cells in the spontaneous remission of EAE and in the prevention of relapses is not known. We have addressed these issues using IL-4-deficient mice in which the differentiation of Th2 CD4+ T cells is severely compromised. The clinical course of actively induced EAE was compared in IL-4+/+, IL-4+ /- and IL-4-/- mice on the PL/J genetic background. No significant differences were noted between groups for the frequency, severity and duration of EAE, and the frequency of relapses. Our results indicate that IL-4, despite its well-documented regulatory role in EAE, is not necessary for the spontaneous remission of disease or for the prevention of relapses. Therefore, in the absence of IL-4, overlapping or compensatory immunoregulatory mechanisms can restrict an inflammatory response within the central nervous system.

Animals↗
PubMed1997

Schwann cell transplantation and myelin repair of the CNS.

Studies with experimental models of dysmyelination and demyelination have shown that rodent Schwann cells including a Schwann cell line, transplanted in the central nervous system compete with host oligodendrocytes to remyelinate denuded central axons of the spinal cord. The myelin produced by transplanted SC around these central nervous system axons is structurally normal and restores, secure nerve conduction. In the presence of a favorable substrate, transplanted Schwann cells migrate over considerable distances (several mm) and are recruited by a demyelinated lesion which they will partially repair Thus Schwann cells, which can also support axonal growth, may be instrumental in central nervous system repair. In addition, the possibility of obtaining large quantities of human and non-human primate Schwann cells, makes it possible to consider autologous Schwann cell transplantation as a potential therapy for demyelinating or traumatic diseases. The various differences which may exist between rodents and humans, however, require further investigation of this possibility in a non-human primate model of demyelination. These experiments should provide not only insights on the potential of autologous transplantation in primates but also a better understanding of the process of central remyelination.

Animals↗
PubMed1996

CD8(+) T cell-mediated spontaneous diabetes in neonatal mice.

Transgenic mice that express the influenza virus hemagglutinin (HA) on pancreatic islet beta cells (ins-HA) demonstrate tolerance of HA even after immunization with influenza virus. Surprisingly, when Ins-HA mice were mated with a transgenic mouse expressing a TCR specific for an epitope of HA that is restricted by MHC class I H-2Kd (Clone-4 TCR), the resulting double transgenic (Ins-HA x Clone-4 TCR)F1 neonates developed spontaneous autoimmune diabetes immediately after birth and died within 10 days. This represents a unique situation in which all safeguards within the immune system that normally maintain tolerance of self-antigens in the neonate are insufficient.

Animals↗