Biomedical subjects

R Whitham

Publications and source records attributed to R Whitham.

23 records · Page 2Linked to original sources

PubMed1991

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. The MS lines also differed from normal lines in their decreased percentage of CD8+ T cells. One hundred nine T cell clones isolated from these lines confirmed the reactivity pattern of the lines but did not reflect the mixed phenotype, since all but three clones tested were CD4+. T cell clones from HLA-DR2 homozygous donors responded to a variety of epitopes, indicating that this molecule was permissive in its ability to restrict T cell responses. Other epitopes, including the immunodominant 149-170 sequence, were restricted by several different major histocompatibility complex (MHC) molecules from both MS and normal donors. T cell receptor (TCR) V gene products could be identified on six of 38 clones tested using monoclonal antibodies. From one HLA-DR2 homozygous donor, four of eight clones utilized V beta 5.2 in response to different BP epitopes, providing initial support for the preferential use of a limited set of V region genes in the human response to BP. Preferential TCR V gene use in MS patients would provide the rationale to regulate selectively BP-reactive T cells through immunity directed at the TCR and thus test for the first time the hypothesis that BP-reactive T cells play a critical role in the pathogenesis of MS.

Adult↗

PubMed1989

Human T lymphocyte response to myelin basic protein: selection of T lymphocyte lines from MBP-responsive donors.

The goal of this study was to delineate the importance of blood T lymphocyte responses to several myelin basic protein (MBP) preparations in the ultimate selection of MBP-specific T lymphocyte lines. Proliferation responses to human myelin basic protein (MBP) were assessed in blood samples from 27 multiple sclerosis (MS) patients, 20 patients with other neurologic diseases (OND), and 26 normal subjects, using five MBP preparations with different histories and electrophoretic characteristics to enhance the spectrum of epitopes represented. Substantial variations were observed in the ability of different MBP preparations to induce blood T cell proliferation in a given donor. However, four out of five of the MBPs induced modest but significant proliferation in the MS study population relative to normal individuals, with intermediate responses occurring in OND patients. Positive responses occurred more frequently in MS patients (78%) than in normal donors (31%), and were an important prerequisite for the successful selection of MBP-specific T cell lines.

Adult↗

PubMed1989

Response of human T lymphocyte lines to myelin basic protein: association of dominant epitopes with HLA class II restriction molecules.

In animals, the selection in vitro of T cell lines to myelin basic protein (MBP) can define immunodominant and encephalitogenic epitopes which are preferentially associated with class II major histocompatibility (MHC) molecules. These principles were used to evaluate the specificity and MHC restriction of 14 human MBP-reactive T cell lines selected from normal individuals and patients with multiple sclerosis (MS) and other neurological diseases (OND). The four normal T cell lines recognized single, separate immunodominant MBP epitopes which were restricted by MHC molecules from the DR or in one case the DP class II locus. In contrast, the MS and OND T cell lines recognized multiple MBP epitopes, each in association with a discrete class II MHC molecule from the DR or DQ locus. Overall, HLA-DR molecules were used preferentially to associate with epitopes on human MBP, restricting 26/33 responses. As predicted from animal studies, T cells from genetically disparate individuals responded to different immunodominant epitopes on human MBP in association with distinct MHC class II molecules. HLA-DR2, which is overrepresented in MS patients, possessed an unusual capacity to restrict all eight epitopes identified on MBP in this study. These data provide the first evidence of genetically restricted human T cell recognition of potentially encephalitogenic epitopes of MBP.

Adult↗

PubMed1988

Basic protein-specific T-cell lines that induce experimental autoimmune encephalomyelitis in SJL/J mice: comparison with Lewis rat lines.

Myelin basic protein (BP)-specific T-cell lines were selected from SJL/J mice using techniques to select similar lines from Lewis rats. SJL/J BP-specific T-cell lines were composed of T cells with the helper/inducer phenotype (Lyt 1.2+, 2.2- and L3T4+) and proliferated in response to both the 1-37 and the 89-169 fragments of guinea pig BP. BP-specific T-cell lines transferred delayed-type hypersensitivity (DTH) responses to BP that persisted for over 60 days. Most recipient animals (32/41) developed acute experimental autoimmune encephalomyelitis (EAE), and most survivors (19/24) developed chronic relapsing EAE. Spinal cords of animals during both the acute and the chronic phases of illness contained plaques of demyelination and infiltrates of lymphocytes and macrophages. These findings differed from those of Lewis rat BP-specific lines which respond to a different region of BP, transfer DTH responses that last less than 12 days, and induce acute EAE in which demyelination does not occur.

Animals↗

PubMedDate not supplied

T-cell receptor peptide therapy in EAE and MS.

Synthetic peptides corresponding to germline TCR V beta 8.2 sequences overexpressed by Lewis rat encephalitogenic T cells are effective in the prevention and treatment of autoimmune encephalomyelitis (EAE). In evaluating optimal conditions for identifying disease-relevant target V beta genes, we found that the biased expression of V beta 8.2 was most pronounced in the CNS among activated, IL-2 responsive T cells, but was weakly reflected in the cerebrospinal fluid. Evaluation of basic protein reactive T cells from patients with multiple sclerosis revealed biased expression of V beta 5.2 and to a lesser degree, V beta 6.1. Treatment of 11 MS patients with synthetic TCR V beta 5.2 and V beta 6.1 CDR2 peptides boosted the frequency of anti-TCR reactive T cells in a majority of patients, without compromising recall immunity or causing side effects. TCR peptides may be useful in the treatment of human autoimmune diseases, providing that disease-relevant V genes can be identified.

Animals↗