Interferons in relapsing remitting multiple sclerosis.
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Clinical Trials as Topic↗
Biomedical subjects
Richard A Rudick
Publications and source records attributed to Richard A Rudick.
Interferon gamma responses to myelin peptides in multiple sclerosis correlate with a new clinical measure of disease progression.
The relationship between autoreactivity to myelin antigens and disease progression in multiple sclerosis (MS) is not fully understood. We addressed this relationship by cross-sectionally comparing an objective measure of MS disability with immune cytokine responses to myelin proteins. The ELISPOT assay was used to determine the ex vivo interferon gamma (IFNgamma) and interleukin-10 (IL-10) production by peripheral blood mononuclear cells (PBMCs) in response to peptides spanning the entire proteolipid protein (PLP) and myelin basic protein (MBP) molecules in 20 patients with relapsing-remitting (RR) MS and 27 age- and sex-matched healthy controls. MS patients showed significantly higher MBP-induced IFNgamma responses and PLP-induced IL-10 responses compared with healthy controls. Using the Multiple Sclerosis Functional Composite (MSFC), a new multifactorial measure of disability, MS patients showed a significant correlation between the IFNgamma response to PLP peptides and MBP peptides, and disability. In contrast, in MS patients, there was no correlation between the MSFC and the response to unrelated control antigens or mitogens. These data show that myelin-specific T lymphocytes secreting the inflammatory cytokine IFNgamma correlate with functional impairment in MS, supporting an antigen-specific link between the immune response to myelin and disability in MS.
Adolescent↗
Interferon-beta 1a does not reduce expression of CCR5 and CXCR3 on circulating T cells.
The expression of CCR5 and CXCR3, two chemokine receptors involved with homing of T cells to inflamed tissue, was examined longitudinally on CD4+ and CD8+ T cells in patients with a first demyelinating event of the central nervous system (CNS) randomized to receive i.m. injections of interferon-beta1a (IFN-beta1a) or placebo. Blood for analysis was collected before and 48 h after injection at baseline and after 3 and 12 months of treatment. The results showed that treatment with IFN-beta1a did not affect numbers of T cells expressing CCR5 and CXCR3 during the first 12 months of treatment, either at the peak of biological response or at the trough of interferon effect, at steady-state.
CD4-CD8 Ratio↗
Flow cytometric analysis of chemokine receptor expression on cerebrospinal fluid leukocytes.
Collection of cerebrospinal fluid (CSF) from the lumbar subarachnoid space is a routine procedure in clinical neurology, providing an opportunity to obtain hematogenous cells from the central nervous system environment in vivo. The ability to study individual cells in samples with low cell numbers has made flow cytometry an attractive method for studies of chemokine receptor expression on such cells. Several methodological variables such as staining temperature and cell isolation techniques may, however, influence the final outcome of the staining. In addition, low numbers of cells in the normal lumbar CSF, together with a tendency of CSF cells to decay rapidly after sampling, require meticulous handling of the samples. Here, we describe the methodology used in our laboratory to study chemokine receptor expression on cells in paired samples from peripheral blood and CSF using flow cytometry.
Antibodies, Monoclonal↗
Expression of CCR2, CCR5, and CXCR3 by CD4+ T cells is stable during a 2-year longitudinal study but varies widely between individuals.
Blockade of chemokine receptors (CKRs) has recently emerged as a possible pathway for therapeutic intervention in disease. In the present report, the expression of CCR2, CCR5, and CXCR3, associated with migration of mononuclear cells to inflamed tissue, was determined on CD4+ T cells in a 2-year longitudinal study of healthy volunteers using flow cytometry. Large interindividual variations in the expression of these receptors on CD4+ T cells were observed, whereas levels remained remarkably stable over time within subjects. The expression of CCR2, CCR5, and CXCR3 on CD4+ T cells was directly proportional to percentages of CD45RO(hi)/CD4+ T cells. In addition, highly significant associations between levels of CCR2, CCR5, and CXCR3 on CD4+ T cells were demonstrated in individual subjects, implying a common mechanism for regulating the expression of these CKRs on circulating T cells. These associations were not due to coexpression of CKRs on individual CD45RA-/CD4+ T cells. The results provide insight into the regulation of CKR expression on CD4+ T cells in vivo, and suggest that major fluctuations of CKR expression in individuals are uncommon.
Adult↗
Factors that predict health-related quality of life in patients with relapsing-remitting multiple sclerosis.
Health-Related Quality of Life (HRQoL) research is gaining acceptance in the field of multiple sclerosis (MS). Little is known about what precipitates quality of life change. It was hypothesized that physical aspects of quality of life decline with worsening objective disease measures and psychosocial aspects remain relatively stable regardless of change in objective measures. These assumptions are tested using data from a Phase 3 study of relapsing-remitting MS patients treated with interferon beta-1a and reassessed approximately eight years after study initiation. The Sickness Impact Profile (SIP) questionnaire is the generic quality of life measure used in this study. Three summary scores of the SIP (Physical, Psychosocial, and Total scores), Expanded Disability Status Scores, Multiple Sclerosis Functional Composite, and Brain Parenchymal Fraction were determined at baseline, year 2, and after an average of 8.1 years from study entry. SIP data collected during a clinic visit were available from 137 of the original 172 participants. All objective indicators worsened by follow-up. SIP Physical and Total scores significantly worsened from baseline to follow-up. SIP Psychosocial showed nonsignificant worsening. Regression analysis indicated that final measures of SIP Physical and Total scores were most strongly associated with change in objective measures and follow-up SIP Psychosocial was most strongly related to earlier scores on the same measure.
Adjuvants, Immunologic↗
Sex differences in cytokine responses to myelin peptides in multiple sclerosis.
Many autoimmune diseases preferentially affect women; however, the underlying mechanisms for the sex differences are poorly understood. We examined sex-dependent differences in the immunologic response to myelin proteins in 22 multiple sclerosis (MS) patients and 22 healthy controls. Using ELISA spot assay (ELISPOT) methodology, interferon (IFN) gamma and IL-5 secretions were examined at the single cell level in response to overlapping proteolipid protein (PLP) peptides. As previously reported, we observed an overall disease effect in the IFNgamma response, such that MS patients were significantly higher than controls. With respect to PLP-induced IFNgamma secretion, both MS and control females responded higher than their corresponding males. Female MS patients demonstrated the highest responses compared to MS males or healthy controls of either sex. Although MS females had high IFNgamma responses to PLP, they had no IL-5 responses at all, suggesting strong Th1 skewing. In contrast, MS males had more IL-5 than control males, who lacked IL-5 responses. These IL-5 responses suggested that disease and gender are not independent, but rather interact to influence the cytokine response to myelin. The data suggest a gender bias towards Th1 responses in MS, which may contribute to the female predominance in this disease.
Adult↗