Biomedical subjects

Clara M Pelfrey

Publications and source records attributed to Clara M Pelfrey.

6 recordsLinked to original sources

PubMed2006

Immunological studies of mitoxantrone in primary progressive MS.

Mitoxantrone (MX) has demonstrated efficacy in multiple sclerosis (MS), but its immunologic mechanisms of action are poorly understood. Furthermore, no study has examined the immunological effects of MX in primary progressive MS (PPMS). This study investigated the immunological effects of MX therapy in PPMS patients. Lymphocyte phenotypes and chemokine receptor (CCR) expression were evaluated by flow cytometry on fresh PBMC from 20 PPMS patients enrolled in a placebo (PLC)-controlled trial of MX. Longitudinal data were collected at weeks 0, 12, 24, 36 and short-term data (pre-/post-infusion) were collected at weeks 0 and 36. CXCR3, CCR1, CCR2 and CCR5 on CD4 and CD8 T cells and CD14 monocytes were evaluated. MX therapy induced a significant increase in the proportion of CD8 T cells (CD45RO(-)) over 9 months. Expression of several CCR increased following MX treatment. Two of the eight MX-treated patients demonstrated dramatic upregulation (70-76%) of CCR2 on monocytes. These two patients were the only MX-treated patients to demonstrate active inflammation by magnetic resonance imaging (MRI). PLC patients did not show significant changes in CCR expression. MX therapy was not associated with selective loss of CD4, CD8 or CD14 cells 1 month after treatment or over 9 months. These results suggest that MX therapy leads to a longitudinal increase in CD8 T cells and may increase CCR in patients with inflammation on MRI. Overall, MX did not show extensive immune changes in PPMS, although patients with active disease (gadolinium enhancing lesions) may identify a subset of PPMS subjects who respond immunologically to MX therapy. An improved understanding of MX may help identify markers of disease activity and response to therapy.

Adult↗

PubMed2005

Effects of sex hormones on costimulatory molecule expression in multiple sclerosis.

Sex hormones play a central role as modulators of immune responses and autoimmune diseases. We hypothesized that suppression of MS disease during pregnancy may be mediated by sex steroid hormones via regulation of costimulatory molecules such as CD40L or CD80/CD86 (B7-1/B7-2). We tested two sex hormones that are implicated in immune suppression during pregnancy: estriol and progesterone. We also examined whether this regulation is gender-specific or disease-related. PBMC from untreated relapsing remitting multiple sclerosis (RR MS) patients and controls were examined for expression of T cell and monocyte costimulatory molecules following mitogen stimulation in the presence or absence of sex hormones. In the absence of hormones, we confirmed that mitogen stimulation induced significantly more CD40L on the surface of CD4(+)T cells in MS patients compared to controls, and we extend these findings by showing there were no gender differences in induction of CD40L. Although supra-physiologic doses of hormones mildly suppressed CD40L expression on activated T cells, in vitro exposure to typical pregnancy-related physiologic doses of estriol or progesterone showed very little or no suppression of CD40L. On monocytes, neither estriol nor progesterone significantly altered the expression of CD80/CD86. These results suggest that physiologic doses of estriol or progesterone cannot alter CD40L on T cells or CD80/CD86 on monocytes sufficiently to explain the improvement observed in MS during pregnancy. Thus, although amelioration of MS and other autoimmune diseases during pregnancy is thought to be due to increased sex hormones, the present results do not support a role for suppression of costimulation via estriol or progesterone.

Adult↗

PubMed2005

Epitope mapping in multiple sclerosis using the ELISPOT assay.

Multiple sclerosis (MS) is thought to be an autoimmune disease in which an unknown trigger initiates an immune response against brain proteins. This autoaggressive response causes the breakdown of the myelin sheaths that protect nerve axons, leading to impaired nerve conduction and subsequent neurodegeneration that are characteristic of MS. Many studies have attempted to determine the exact target within the brain. However, there appear to be multiple targets, which may change over time. No single study has examined all targets nor looked at how they can change over the course of the disease and whether these changes are related to the course of disease. We have approached this by using the single-cell resolution capability of the enzyme-linked immunospot assay to examine cytokine reactivity in MS patients in response to a very large set of overlapping peptides that span the two major proteins of myelin: myelin basic protein and proteolipid protein. Our goal was to use the enzyme-linked immunospot assay to perform comprehensive epitope mapping in relapsing-remitting MS patients in a longitudinal study to help define the role of myelin responses in disease progression.

Amino Acid Sequence↗

PubMed2003

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↗

PubMed2002

Interferon-gamma production to inner ear antigens by T cells from patients with autoimmune sensorineural hearing loss.

Autoimmune sensorineural hearing loss (ASNHL) typically produces bilateral rapidly progressive loss of hearing over a few days or weeks, but may also produce sudden loss over a few hours. The diagnosis is made by excluding ototoxicity, systemic disease, and other factors that mimic ASNHL and by showing a therapeutic response to corticosteroid treatment. Antibody production and T-cell proliferative responses to inner ear antigens have been implicated in the etiopathogenesis of ASNHL. In the current study, we have extended these autoimmune investigations by determining the frequencies of inner ear specific IFN-gamma producing T cells in peripheral blood mononuclear cells (PBMC) from ASNHL patients and from age- and sex-matched control subjects. ELISPOT analysis showed that 25% of ASNHL patients have significant increased frequencies of inner ear specific IFN-gamma producing T cells in their PBMC. All control subjects were relatively unresponsive. Our results implicate inner ear specific IFN-gamma producing proinflammatory T cells in the pathogenesis of ASNHL.

Adult↗

PubMed2002

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↗