Characterization of the immune response to a secondary encephalitogenic epitope of basic protein in Lewis rats. II. Biased T cell receptor V beta expression predominates in spinal cord infiltrating T cells.

The immune response of Lewis rat lymph node T cells to guinea pig myelin basic protein (GP-BP) in experimental allergic encephalomyelitis is directed primarily against a region of basic protein encompassed by residues 72-89. T cells that respond to this epitope are restricted by the RT1.B class II molecule of the MHC and use V beta 8.

Characterization of the immune response to a secondary encephalitogenic epitope of basic protein in Lewis rats. I. T cell receptor peptide regulation of T cell clones expressing cross-reactive V beta genes.

In Lewis rats, immunization with myelin basic protein induces two distinct encephalitogenic T cell populations, those responding to the immunodominant 72-89 epitope and those specific for a secondary epitope including residues 87-99. The 72-89 specific T cells were I-A restricted and preferentially expressed V beta 8.2 in their TCR.

Common sequence on distinct V beta genes defines a protective idiotope in experimental encephalomyelitis.

Synthetic TCR peptides expressed by encephalitogenic T cells can induce both cellular and humoral responses that protect against experimental encephalomyelitis. In the Lewis rat, encephalitogenic T cells predominantly express V beta 8.2, and a peptide in the CDR2 region representing residues 39-59 could both protect against and treat experimental autoimmune encephalitis (EAE).

Human CD8+ T cell clone regulates autologous CD4+ myelin basic protein specific T cells.

Normal human CD8+ T cell clones were co-isolated from the same culture wells as CD4+ T effector cell clones specific for myelin basic protein (MBP). Microcultures from which the CD8+ clones were isolated initially proliferated weakly to whole MBP and to an MBP peptide spanning residues 90-170. This pattern of response was similar to strongly proliferating wells that yielded CD4+ T cell clones specific for the 90-170 peptide.

Analysis of T cell receptor beta chains in Lewis rats with experimental allergic encephalomyelitis: conserved complementarity determining region 3.

This study explores the usage of T cell antigen receptor (TCR) beta chain elements in Lewis rats with experimentally induced allergic encephalomyelitis (EAE). TCRs from 15 different T cell clones and hybridomas derived from animals immunized with myelin basic protein (MBP), and all having specificity for the 21-mer encephalitogenic fragment MBP 68-88, utilized V beta 8.2.

Location of a new encephalitogenic epitope (residues 43 to 64) in proteolipid protein that induces relapsing experimental autoimmune encephalomyelitis in PL/J and (SJL x PL)F1 mice.

Synthetic peptides of proteolipid protein (PLP) were screened for their ability to induce experimental autoimmune encephalomyelitis (EAE) in SJL/J, PL/J, and (SJL x PL)F1 mice, and T cell lines were selected by stimulation of lymph node cells with PLP peptides. PLP 141-151 was found to be less encephalitogenic in SJL/J mice than PLP 139-151, due to deletion of two amino acids from the amino-terminal end. PLP 139-151 immunization induced relapsing EAE in SJL/J and F1 mice but not PL/J mice.

Preferential T-cell receptor beta-chain variable gene use in myelin basic protein-reactive T-cell clones from patients with multiple sclerosis.

Multiple sclerosis is an autoimmune disease in which T lymphocytes reactive to myelin basic protein (BP) could play a central role. T cells specific for BP were cloned from the blood of multiple sclerosis patients and normal individuals, and expression of T-cell receptor variable region genes was analyzed. A remarkable bias for use of beta-chain variable region (V beta) 5.

Myelin basic protein specific T cell lines and clones derived from the CNS of rats with EAE only recognize encephalitogenic epitopes.

The epitope specificities of myelin basic protein (BP) specific T cell lines derived from the spinal cords (SC) and lymph nodes (LN) of rats with experimental autoimmune encephalomyelitis (EAE) were compared. To induce EAE, Lewis rats were immunized with guinea pig (GP)-BP and complete Freund's adjuvant. Mononuclear cells from the SC and LN of these animals proliferated in response to BP and the purified protein derivative (PPD) of mycobacterium.

Ganglioside (GM1)-treated T cells shed CD4.

In previous studies (Morrison et al., 1990), we showed that ganglioside (GM1) modulation of CD4 was associated with activation of phospholipase C and increased production of inositol triphosphate, but not with activation of protein kinase C. These results demonstrated a unique signal transduction pathway related to GM1 modulation of CD4 on T cells and raised the question as to whether intracellular Ca2+ levels and related protein kinases would be affected by GM1-induced signalling.

Clonal diversity of basic protein specific T cells in Lewis rats recovered from experimental autoimmune encephalomyelitis.

T cell lines selected from Lewis rats recovered from experimental autoimmune encephalomyelitis (EAE) respond not only to the immunodominant 72-89 epitope of basic protein (BP), but also to secondary epitopes including the I-A restricted 43-67 region of guinea pig (Gp) BP and the I-E restricted 87-99 sequence of rat (Rt) BP. The current study demonstrates at the clonal level the diversity of T cell responses to Gp- and Rt-BP in EAE-recovered rats. As predicted from the response pattern of BP-selected T cell lines, T cell clones from the lines responded to both the dominant and secondary epitopes of BP.

Protection against experimental encephalomyelitis. Idiotypic autoregulation induced by a nonencephalitogenic T cell clone expressing a cross-reactive T cell receptor V gene.

The recovery process in experimental autoimmune encephalomyelitis (EAE) in Lewis rats is characterized by an increasing diversity of T cell clones directed at secondary epitopes of myelin basic protein. Of particular interest, residues 55 to 69 of guinea pig basic protein could induce protection against EAE. A nonencephalitogenic T cell clone, C455-69, that was specific for this epitope transferred protection against both active and passive EAE.

Specificity of human T cell clones reactive to immunodominant epitopes of myelin basic protein.

Several recently discovered lines of evidence support the involvement of myelin basic protein (BP)-specific T cells in multiple sclerosis (MS). To identify potentially relevant immunodominant T cell epitopes, human BP (Hu-BP)-reactive T cell lines were selected from MS and normal donors and tested for reactivity to cleavage fragments and synthetic peptides of Hu-BP. The MS T cell lines responded to more Hu-BP epitopes than did normal lines, showing biased recognition of the N terminal half of the molecule, and one region in the C terminal half, suggesting increased sensitization to BP.

T cell receptor peptide therapy triggers autoregulation of experimental encephalomyelitis.

Encephalitogenic T cells specific for myelin basic protein share common V beta 8 peptide sequences in their T cell receptor (TCR) that can induce autoregulatory T cells and antibodies that prevent clinical signs of experimental autoimmune encephalomyelitis (EAE). It is not known, however, if TCR peptides can treat established disease. To test its therapeutic value, TCR-V beta 8-39-59 peptide was injected into rats with clinical signs of EAE.

T cell lines specific for an immunodominant epitope of human basic protein define an encephalitogenic determinant for experimental autoimmune encephalomyelitis-resistant LOU/M rats.

The LOU/M rat (RT-1w) haplotype, although resistant to an encephalitogenic challenge of guinea pig myelin basic protein (Gp-BP)/CFA and unresponsive to Gp-BP, responded strongly to human (Hu)-BP. Both T cell and antibody responses focused on the 110-129 determinant of Hu-BP, and T cells specific for this epitope transferred clinical and histologic experimental autoimmune encephalomyelitis (EAE) to naive LOU/M rats. Moreover, EAE could be induced actively with Hu-BP and a synthetic Hu-S110-129 peptide in CFA, but only with co-immunomodulation by pertussis toxin or cyclophosphamide.

Lymphocytes from SJL/J mice immunized with spinal cord respond selectively to a peptide of proteolipid protein and transfer relapsing demyelinating experimental autoimmune encephalomyelitis.

Relapsing experimental autoimmune encephalomyelitis (R-EAE) can be induced in SJL/J mice by immunization with spinal cord homogenate and adjuvant. The specific Ag(s) responsible for acute disease and subsequent relapses in this model is unknown. Myelin basic protein (BP), an encephalitogenic peptide of BP (BP 87-99), and proteolipid protein (PLP) can each induce R-EAE in SJL/J mice, and a peptide of PLP (PLP 139-151) has been reported to induce acute EAE.

Myelin basic protein-specific T cells induce demyelinating experimental autoimmune encephalomyelitis in Buffalo rats.

This is the first description of acute demyelinating experimental autoimmune encephalomyelitis (EAE) induced in rats by myelin basic protein (BP)-specific T lymphocytes without the administration of demyelinating antibodies. BP-specific T cell lines were selected from inbred Buffalo-strain rats (Rt-1b) following techniques used to develop similar lines from Lewis rats (Rt-1l). Unlike those of Lewis rats, the spinal cords of Buffalo rats with T cell line-mediated EAE had prominent perivascular demyelination associated with mononuclear inflammation.

Transmembrane signalling associated with ganglioside-induced CD4 modulation.

Ganglioside (GM1) treatment of CD4+ human CEM lymphoma cells stimulated transient phosphoinositide (PI) breakdown, production of inositol phosphates (IP), protein phosphorylation and rapid decrease of CD4 surface expression. A comparison between the actions of GM1 and other agents that affect these signal transduction pathways demonstrated a distinct mechanism for GM1-induced decrease of CD4. GM1 stimulated both phospholipase C activity and protein phosphorylation but had no effect on either cellular cAMP levels or tyrosine kinase activity.

Recombinant human beta-galactoside binding lectin suppresses clinical and histological signs of experimental autoimmune encephalomyelitis.

Human placental tissue contains regulatory molecules that may prevent allo-sensitization. Recently, a 14 kDa beta-galactoside binding protein with demonstrated immunoregulatory properties has been cloned using cDNA from human placenta and expressed in Escherichia coli. The present study assesses the ability of this recombinant immunomodulatory lectin (rIML-1), to prevent experimental autoimmune encephalomyelitis (EAE), a paralytic T cell-mediated disease directed against myelin basic protein (BP).

Antibodies specific for VB8 receptor peptide suppress experimental autoimmune encephalomyelitis.

Recent studies from our laboratory have shown, for the first time, that a synthetic peptide from that TCR VB chain used preferentially by encephalitogenic T cells induced the formation of protective, MHC class I-restricted T cells and prevented the development of EAE in Lewis rats. In this report we 1) demonstrate that immunization with the TCR-VB8-39-59 peptide generated peptide-specific antibodies that protect against experimental autoimmune encephalomyelitis induced by either of the two distinct encephalitogenic epitopes of basic protein, and 2) characterize the production and biologic functions of rat and rabbit antibody responses to the TCR peptide. The antibodies in both species increased in titer over time, were highly specific for the immunogen by direct reaction and inhibition assays, stained only VB8+ T cells, and suppressed clinical signs and to lesser extent the number of histologic lesions of experimental autoimmune encephalomyelitis mediated by VB8+ T cells.

Suppressor cell regulation of encephalitogenic T cell lines: generation of suppressor macrophages with cyclosporin A and myelin basic protein.

Chronic relapsing experimental allergic encephalomyelitis (CR-EAE) can be adoptively transferred using myelin basic protein (BP)-specific helper T cell lines, and suppressor cells may be important in recovery from EAE. In order to generate suppressor cells, spleen cells obtained from BP-complete Freund's adjuvant (CFA) inoculated SJL/J mice and from normal mice were cultured for 7 days with medium, with cyclosporin A (CsA), or with CsA and antigen (BP or purified protein derivative of mycobacterium (PPD)). Cultured spleen cells were assayed for suppressor activity in vitro by coculture with BP-specific and PPD-specific helper T cell lines derived from SJL/J mice.

Myelin basic protein, MHC restriction molecules and T cell repertoire.

Our laboratory has developed a broad base of information in rats and mice describing the properties of encephalitogenic T cells. Using the T cell line selection technique to identify dominant T cell specificities, we were the first to identify new encephalitogenic epitopes and MHC restriction molecules in the Lewis rat and the SJL mouse. Furthermore, using the soft agar technique, we have isolated encephalitogenic Lewis rat T cell clones specific for defined synthetic epitopes of BP.

Characterization of basic protein-specific T cell lines selected from Lewis rats with relapsing experimental autoimmune encephalomyelitis.

Relapsing experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats by intraperitoneal immunization with guinea pig whole central nervous system tissue. Basic protein (BP)-specific T cell lines selected from rats with relapsing EAE proliferated in response to BP, the 44-89 peptidase fragment of BP and the synthetic peptide, S72-89, as did lines selected from rats with non-relapsing EAE induced by immunization with guinea pig BP. BP-specific T cell lines selected from rats with relapsing EAE transferred acute but not relapsing EAE.

Determinants of human myelin basic protein that induce encephalitogenic T cells in Lewis rats.

Due to critical amino acid changes in the 72-89 sequence, the determinant of human (Hu) basic protein (BP) that induces experimental autoimmune encephalomyelitis (EAE) in Lewis rats most likely differs from rat and guinea pig BP. To discern encephalitogenic sequence(s), the immunodominant epitopes recognized by Hu-BP-specific T cell lines were identified using synthetic peptides that corresponded to the Hu-BP sequence. The Hu-BP-reactive T cell line contained two distinct specificities, one directed at the 87-99 (Hu) sequence restricted by I-E, and the second directed at the 55-74 (Hu) sequence restricted by I-A.