Biomedical subjects

L R Tranquill

Publications and source records attributed to L R Tranquill.

11 recordsLinked to original sources

PubMed1998

Cytokine gene expression in cells derived from CSF of multiple sclerosis patients.

Cytokines are produced by numerous cell types in the peripheral blood and central nervous system (CNS), and have been implicated in the immunopathogenesis of multiple sclerosis (MS). We examined the relationship between cytokine gene expression of cerebrospinal fluid (CSF) derived cells from MS patients and disease activity as measured by contrast enhanced MRI. There was a significant correlation between the number of CSF cells and the number of contrast enhancing MRI lesions. Cytokine gene expression of TNF-alpha, IFN-gamma, and IL-10 was routinely seen, but IL-4 expression was absent except in two clinically quiescent patients. Trends were observed toward decreased TNF-alpha expression, but increased IL-10 expression, after treatment with IFN-beta1b.

Antisense Elements (Genetics)↗

PubMed1998

Phase 1 trial of transforming growth factor beta 2 in chronic progressive MS.

Transforming growth factor (TGF)-beta2 is a pleiotropic cytokine associated with remissions in multiple sclerosis (MS) and amelioration of allergic encephalomyelitis. We assessed the safety of TGF-beta2 in an open-label trial of 11 patients with secondary progressive (SP) MS. Five patients had a reversible decline in the glomerular filtration rate. There was no change in expanded disability status scale or MRI lesions during treatment. Systemic TGF-beta2 may be associated with reversible nephrotoxicity, and further investigation of its therapeutic potential in MS should be performed with caution.

Adult↗

PubMed1997

Immunodominance of a low-affinity major histocompatibility complex-binding myelin basic protein epitope (residues 111-129) in HLA-DR4 (B1*0401) subjects is associated with a restricted T cell receptor repertoire.

The pathogenesis of multiple sclerosis (MS) is currently ascribed in part to a T cell-mediated process targeting myelin components. The T cell response to one candidate autoantigen, myelin basic protein (MBP), in the context of HLA-DR15Dw2, has been previously studied in detail. However, the characteristics of cellular immunity in the context of other MS-associated HLA-DR haplotypes are scarcely known. MBP-specific T cell lines (TCL) were generated from HLA-DR4 (B1*0401)-positive MS subjects. Out of 275 MBP-specific TCL, 178 (64. 7%) specifically recognized region MBP(111-129), predominantly in the context of DRB1*0401. The major T cell epitope for MBP recognition corresponded to residues MBP(116-123). These TCL expressed disparate profiles of cytokine secretion and cytotoxicity. T cell receptor analysis, on the other hand, revealed a strikingly limited heterogeneity of rearrangements. In contrast to MBP(81-99), which binds with high affinity to HLA-DR15 and is recognized by a diverse T cell repertoire, MBP(111-129) binds weakly to DRB1*0401, suggesting that only high affinity T cell receptors might be able to efficiently engage such unstable MHC/peptide complexes, thus accounting for the T cell receptor restriction we observed. This study provides new insight about MBP recognition and proposes an alternative mechanism for immunodominance of self-antigen T cell epitopes in humans.

Adult↗

PubMed1997

Increases in soluble VCAM-1 correlate with a decrease in MRI lesions in multiple sclerosis treated with interferon beta-1b.

Interferon beta-1b reduces clinical exacerbations and disease activity in multiple sclerosis as shown by magnetic resonance imaging, but the mechanism of action is unknown. We investigated the correlation between the levels of soluble adhesion molecules and a reduction in contrast-enhancing lesions on gadopentetate dimeglumine magnetic resonance images after treatment with interferon beta-1b. We determined levels of soluble vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, L-selectin, and tumor necrosis factor receptor (60 kd) in monthly serum samples from patients with definite multiple sclerosis before and during treatment with interferon beta-1b. The level of soluble adhesion molecules was correlated with the number of newly enhancing lesions on monthly contrast-enhanced images. Levels of soluble vascular cell adhesion molecule during treatment were significantly increased compared to control or pretreatment values. The median levels (ng/ml) of this adhesion molecule were 580.3 (range; 373.0-640.7) for the healthy subjects, and 551.4 (489.7-875.5) for patients prior to treatment and 847.9 (591.5-1,232.9) during treatment. Levels of the other soluble adhesion molecules and soluble tumor necrosis factor receptor were not significantly changed during treatment. The increase in soluble vascular cell adhesion molecule correlated with a decrease in the number of contrast-enhancing lesions on magnetic resonance images. These data suggest a novel mechanism of action for interferon beta-1b by direct interference with the adhesion cascade, which may prevent activated T cells from trafficking into the central nervous system.

Adult↗

PubMed1997

VLA-4 expression on peripheral blood lymphocytes is downregulated after treatment of multiple sclerosis with interferon beta.

Adhesion molecules are likely to play a critical role in the immunopathogenesis of multiple sclerosis (MS). The interaction of vascular cell adhesion molecule-1 (VCAM-1) with its lymphocyte ligand very late antigen-4 (VLA-4) may mediate migration of lymphocytes into the CNS. We have previously demonstrated that MS patients treated with interferon beta (IFN-beta) have a significant increase in soluble VCAM-1 (sVCAM-1) soon after the initiation of treatment, and this effect correlated with the resolution of contrast-enhancing MRI lesions. We studied the cell surface expression of VLA-4 by flow cytometry in 10 MS patients before and during IFN-beta treatment. We found a significant decrease in mean VLA-4 fluorescence of MS patients' lymphocytes on treatment and no change in untreated controls. In vitro treatment of lymphocytes with IFN-beta did not reproduce this effect, but the addition of sVCAM-1 did result in a decrease in VLA-4 expression. These data indicate that the previously identified increase in sVCAM-1 may lead to a decrease in VLA-4 expression and that this effect may partially explain the mechanism of action of IFN-beta.

Adjuvants, Immunologic↗

PubMed1996

Human T lymphocytes specific for the immunodominant 83-99 epitope of myelin basic protein: recognition of golli MBP HOG 7.

Myelin basic protein (MBP) is a candidate autoantigen in the disease multiple sclerosis. Although MBP was thought to be sequestered behind the blood-brain barrier, isoforms of MBPs have recently been demonstrated in lymphoid tissues. These isoforms, termed golli MBPs, contain sequences that are shared with "classic" MBP within the CNS. In the present study, we have determined that epitopes within golli MBP isoforms may be recognized by human T lymphocyte clones specific for classic MBP. Ten of 12 T-cell clones recognized golli MBP. Although 11 clones were specific for the immunodominant 83-99 sequence, the clones differed with respect to human leukocyte antigen (HLA) restriction, T-helper phenotype, cytolytic activity, and T-cell receptor usage. Greater responses to classic MBP than to golli MBP suggested a difference in the ability of the two proteins to be processed and to present epitopes therein. These data advance the hypothesis that golli MBP sequences expressed within lymphoid tissues may be recognized by classic MBP-specific T lymphocytes during central or peripheral tolerance.

Antibody Specificity↗

PubMed1996

T cell response to two immunodominant proteolipid protein (PLP) peptides in multiple sclerosis patients and healthy controls.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system in which autoimmune T lymphocytes reacting with myelin antigens are believed to play a pathogenic role. Since HLA binding is involved in the selection of T cell responses, we have examined PLP peptide binding to HLA DR2, an HLA allele frequently found in MS patients. Both PLP 40-60 and PLP 89-106 show significant, high affinity binding to HLA DR2. We then tested whether responses to PLP peptides 40-60 and 89-106 are elevated in multiple sclerosis patients compared to matched controls. We also analysed T cell responses to MBP 87-106, which is considered to be the immunodominant region of MBP in humans. Here we demonstrate heterogenous T cell responses to PLP 40-60, PLP 89-106 and MBP 87-106 in both MS patients and controls. The overall number of TCL and the HLA restriction of those TCL did not vary significantly in the two groups. PLP 40-60 specific cytolytic TCL were increased in MS patients, whereas healthy controls had increased percentages of cytolytic TCL responding to PLP 89-106 and MBP 87-106. Although the data presented here shows heterogenous responses in T cell numbers, differences in numbers and specificity of cytolytic cells could be involved in the pathogenesis of autoimmune demyelinating disease.

Amino Acid Sequence↗

PubMed1995

Two mechanisms of antigen-specific apoptosis of myelin basic protein (MBP)-specific T lymphocytes derived from multiple sclerosis patients and normal individuals.

Several stimuli induce mature T cells to undergo apoptosis or programmed cell death (PCD) including specific Ag. We have demonstrated previously that Ag induces the death of encephalitogenic T cells in vitro and deletion in vivo, leading to amelioration of autoimmune encephalomyelitis. We have now examined whether activated, myelin basic protein (MBP)-specific human T cells may be eliminated by Ag-induced PCD. We demonstrate that activated MBP-specific T cell lines (TCL) undergo the classic nuclear morphologic changes and DNA fragmentation characteristic of apoptosis when given a TCR challenge. We found evidence that two mechanisms led to apoptosis: a propriocidal mechanism that was highly Ag-specific and dependent on the dose of exogenously added rIL-2, and a cytolytic mechanism in which MBP-specific TCL lysed B cell targets and engaged in considerable "fratricidal" cytolysis of other MBP-specific T cells. These two pathways leading to MBP-specific apoptotic death could be distinguished by their glucocorticoid sensitivity. Glucocorticoid treatment significantly blocked MBP-induced propriocidal apoptosis but had no effect on T cell cytolysis of B cell targets. Although it has been proposed that autoimmune disease could result from the failure of normal deletional mechanisms, this preliminary survey of MBP-reactive mature TCL from multiple sclerosis patients revealed that such cells are highly susceptible to TCR-induced PCD and comparable with TCL from normal subjects. Thus, therapeutic strategies based on Ag-induced PCD of T lymphocytes may be feasible in man.

Apoptosis↗

PubMed1994

Identification of a second T cell epitope of human proteolipid protein (residues 89-106) recognized by proliferative and cytolytic CD4+ T cells from multiple sclerosis patients.

Research into the pathogenesis of multiple sclerosis (MS) has focused on myelin antigens as potential targets of autoimmune attack. Proteolipid protein (PLP) is the most abundant myelin protein comprising more than 50% of central nervous system myelin. Although PLP is a hydrophobic membrane protein which has made it difficult to study, the use of synthetic peptides based on the PLP sequence provides an alternative method for studying the immunological properties of PLP. Using peripheral blood lymphocytes from MS patients, long-term TCL established in the presence of PLP reacted weakly to PLP in proliferation assays; however, these same lines were much more reactive to synthetic peptides of PLP. Thus, we established short-term T cell lines (TCL) from the peripheral blood lymphocytes (PBL) of MS patients in the presence of five separate synthetic PLP peptides. In 6/7 MS patients, proliferative responses were elicited most often to PLP 40-60 compared to four other PLP peptides (PLP 89-106, 103-120, 125-143, and 139-154) (Pelfrey et al., 1993). Interestingly, however, the magnitude of the proliferative response was greatest in response to PLP 89-106. Characterization of PLP 89-106-responsive TCL from several MS patients, indicated that TCL proliferating to the peptide also lysed PLP 89-106 pulsed autologous targets. The majority of cytolytic PLP 89-106 TCL were CD4+ and MHC class II restricted and the predominant restriction elements were those most commonly found in MS patients. These findings suggest that the use of synthetic peptides represents a viable alternative approach to the study of PLP reactivity in humans. We report here that MS PBL recognize several PLP peptides, with the predominant responses to PLP 40-60 and PLP 89-106. Since these cells have both helper (CD4+) and cytolytic capabilities, it is possible that they may play a role in the pathogenesis or progression of MS.

Amino Acid Sequence↗

PubMed1993

Identification of a novel T cell epitope of human proteolipid protein (residues 40-60) recognized by proliferative and cytolytic CD4+ T cells from multiple sclerosis patients.

Research into the pathogenesis of multiple sclerosis (MS) has focused on myelin antigens as potential targets of autoimmune attack. Proteolipid protein (PLP), which makes up more than 50% of central nervous system myelin, is a hydrophobic membrane protein with many properties that historically have made it difficult to study. The use of synthetic peptides based on the PLP sequence provides an alternative method for studying the immunological properties of PLP. Using peripheral blood lymphocytes from MS patients, long-term TCL established in the presence of PLP reacted weakly to PLP in proliferation assays; however, these same lines were much more reactive to synthetic peptides of PLP. Thus, we established short-term T cell lines (TCL) from the peripheral blood lymphocytes (PBL) of MS patients in the presence of five separate synthetic PLP peptides. In six out of seven MS patients, proliferative responses were elicited most often to PLP 40-60 compared to four other PLP peptides (PLP 89-106, 103-120, 125-143, and 139-154). Characterization of PLP 40-60-responsive TCL from a single MS patient, MS1, indicated that six out of seven TCL proliferating to the peptide also lysed PLP 40-60 pulsed autologous targets. All cytolytic PLP 40-60 TCL were CD4+ and MHC class II restricted and further analysis of MS1 TCL showed that the PLP 40-60 TCL were restricted by DR4 whereas the MBP TCL from MS1 were restricted by DR6. These findings suggest that difficulties in examining the immune response to PLP have been due to the poor response generated in vitro using the whole molecule and that the use of synthetic peptides may represent an alternative approach to the study of PLP. These results also suggest that MS PBL recognize several PLP peptides, with the predominant response to PLP 40-60. Since these cells phenotypically resemble T cells known to mediate experimental autoimmune encephalomyelitis, it is possible that they may play a role in the pathogenesis of MS.

Amino Acid Sequence↗

PubMed1993

A novel candidate autoantigen in a multiplex family with multiple sclerosis: prevalence of T-lymphocytes specific for an MBP epitope unique to myelination.

Although the major isoform of myelin basic protein (MBP) in the healthy adult CNS is the 18.5-kDa protein, other isoforms containing exon 2 encoded protein (21.5 kDa and 20.2 kDa) exist and are expressed primarily during myelin formation. Since remyelination is a prominent feature in MS lesions, we examined the frequencies of T cell lines (TCLs) specific for epitopes within exon 2 encoded MBP (X2MBP), and also within 18.5-kDa MBP, in members of a multiplex family with MS. TCLs specific for X2MBP were as prevalent as TCLs specific for immunodominant epitopes within 18.5-kDa MBP. In addition, while frequencies of TCLs specific for 18.5-kDa MBP were no different between the affected and unaffected, the frequency of X2MBP-specific TCLs correlated with disease.

Aged↗