Biomedical subjects

Henry McFarland

Publications and source records attributed to Henry McFarland.

7 recordsLinked to original sources

PubMed2006

Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis.

Administration of daclizumab, a humanized mAb directed against the IL-2Ralpha chain, strongly reduces brain inflammation in multiple sclerosis patients. Here we show that daclizumab treatment leads to only a mild functional blockade of CD4(+) T cells, the major candidate in multiple sclerosis pathogenesis. Instead, daclizumab therapy was associated with a gradual decline in circulating CD4(+) and CD8(+) T cells and significant expansion of CD56(bright) natural killer (NK) cells in vivo, and this effect correlated highly with the treatment response. In vitro studies showed that NK cells inhibited T cell survival in activated peripheral blood mononuclear cell cultures by a contact-dependent mechanism. Positive correlations between expansion of CD56(bright) NK cells and contraction of CD4(+) and CD8(+) T cell numbers in individual patients in vivo provides supporting evidence for NK cell-mediated negative immunoregulation of activated T cells during daclizumab therapy. Our data support the existence of an immunoregulatory pathway wherein activated CD56(bright) NK cells inhibit T cell survival. This immunoregulation has potential importance for the treatment of autoimmune diseases and transplant rejection and toward modification of tumor immunity.

Animals↗

PubMed2005

Interferon-beta1a therapy in human T-lymphotropic virus type I-associated neurologic disease.

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an immune-mediated inflammatory disorder of the central nervous system. Immune activation in the host, which results from high levels of persistent antigenic stimulation and from transactivation of host immunoregulatory genes by HTLV-I, appears important in the pathogenesis of HAM/TSP. In a single-center, open-label trial, 12 patients with HAM/TSP were treated with doses of interferon-beta1a of up to 60mug twice weekly, based on its antiviral and immunomodulatory effects. Primary end points were immunological and virological measures that are potential biomarkers for HAM/TSP. Interferon-beta1a therapy reduced the HTLV-I tax messenger RNA load and the frequency of potentially pathogenic HTLV-I-specific CD8(+) cells. The HTLV-I proviral DNA load remained unchanged. Spontaneous lymphoproliferation, a marker of T-cell activation in HAM/TSP, also was reduced. Some measures of motor function were improved, and no significant clinical progression occurred during therapy. These results indicate that interferon-beta1a may beneficially affect the immune mechanisms central to the pathogenesis of HAM/TSP.

Adult↗

PubMed2004

Training-dependent plasticity in patients with multiple sclerosis.

Cortical reorganization has been demonstrated in the motor network that mediates performance of a motor task in patients with multiple sclerosis. How this network responds to motor training is not known. This study examined functional MRI (fMRI) activation patterns associated with performance of a motor task, consisting of repetition of directionally specific voluntary thumb movements, before and after motor training in a group of multiple sclerosis patients with mild motor impairment of the right upper extremity. Patients and healthy subjects were scanned in one session before, during and after a 30 min training period. fMRI data obtained during rest, thumb flexion (trained movement) and thumb extension (untrained movement) were analysed using random effects analysis (SPM99). Motor kinematics of training motions and EMG from the resting hand were monitored with an accelerometer and surface EMG electrodes. Kinematics of thumb movements before, during and after training were comparable in the absence of mirror EMG activity in the resting hand. Before training, thumb movements elicited more prominent activation of the contralateral dorsal premotor cortex [PMd, Brodmann area (BA) 6] in multiple sclerosis patients than in controls. After training, unlike the control group, multiple sclerosis patients did not exhibit task-specific reductions in activation in the contralateral primary somatosensory (S1), motor (M1) and adjacent parietal association (BA 40) cortices. These results indicate that patients engage the contralateral PMd more than controls in order to perform directionally specific movements before training. The absence of training-dependent reductions in activation in S1, M1 and BA 40 is consistent with a decreased capacity to optimize recruitment of the motor network with practice.

Adult↗

PubMed2004

Expansion and functional relevance of high-avidity myelin-specific CD4+ T cells in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease in which myelin-specific T cells are believed to play a crucial pathogenic role. Nevertheless, so far it has been extremely difficult to demonstrate differences in T cell reactivity to myelin Ag between MS patients and controls. We believe that by using unphysiologically high Ag concentrations previous studies have missed a highly relevant aspect of autoimmune responses, i.e., T cells recognizing Ag with high functional avidity. Therefore, we focused on the characterization of high-avidity myelin-specific CD4+ T cells in a large cohort of MS patients and controls that was matched demographically and with respect to expression of MHC class II alleles. We demonstrated that their frequency is significantly higher in MS patients while the numbers of control T cells specific for influenza hemagglutinin are virtually identical between the two cohorts; that high-avidity T cells are enriched for previously in vivo-activated cells and are significantly skewed toward a proinflammatory phenotype. Moreover, the immunodominant epitopes that were most discriminatory between MS patients and controls differed from those described previously and were clearly biased toward epitopes with lower predicted binding affinities to HLA-DR molecules, pointing at the importance of thymic selection for the generation of the autoimmune T cell repertoire. Correlations between selected immunological parameters and magnetic resonance imaging markers indicate that the specificity and function of these cells influences phenotypic disease expression. These data have important implications for autoimmunity research and should be considered in the development of Ag-specific therapies in MS.

Adult↗

PubMed2004

Magnetic resonance imaging of labeled T-cells in a mouse model of multiple sclerosis.

Multiple sclerosis (MS) is a T cell-mediated autoimmune disease with early lesions characterized by mononuclear cellular infiltrate, edema, demyelination, and axonal loss that contribute to the clinical course of the disease. Experimental autoimmune encephalomyelitis (EAE) in the mouse is a valuable model with a similar disease course to relapsing-remitting MS. The ability to detect the migration of encephalitogenic T cells into the central nervous system in EAE and MS would provide key information on these cells role in the development of lesions observed on magnetic resonance imaging (MRI). T cells were labeled for detection by magnetic resonance imaging using Food and Drug Administration-approved, superparamagnetic iron oxide nanoparticles (Ferumoxides) complexed to poly-L-Lysine (FE-PLL). EAE was induced by adoptive transfer of either labeled or unlabeled T cells. After disease onset, FE-PLL-labeled T cells were detected in the mouse spinal cord using in vivo and ex vivo cellular MRI. Excellent correlation was seen between MRI-visible lesions in the spinal cord and histopathology. The results demonstrate that T cells labeled with FE-PLL can induce EAE disease and can be detected in vivo in the mouse model. The magnetic labeling of cells opens the possibility of monitoring specific cellular phenotypes or pharmacologically or genetically engineered cells by MRI.

Adoptive Transfer↗

PubMed2004

Kinematic specificity of cortical reorganization associated with motor training.

Motor training consisting of repetition of directionally specific voluntary thumb movements elicits a short-term memory trace that encodes the kinematic details of the practiced motions in the primary motor cortex. Here, we studied activation patterns associated with this form of training using functional magnetic resonance imaging under careful monitoring of motor training kinematics and electromyography. We identified task-specific reductions in activation in contralateral motor cortex, a region that controls executive motor output, as well as somatosensory cortex and inferior parietal lobule, regions in charge of monitoring motor training kinematics. Our findings are consistent with the hypothesis that a short training period consisting of repetition of finger motions leads to cortical reorganization characterized by a smaller and more efficient network that is specific for the trained movement direction.

Adult↗

PubMed2003

Changes in cerebral perfusion precede plaque formation in multiple sclerosis: a longitudinal perfusion MRI study.

New MRI techniques such as the analysis of magnetization transfer or diffusion have provided evidence for subtle progressive alterations in tissue integrity prior to focal leakage of the blood-brain barrier (BBB) as part of plaque formation in multiple sclerosis. Since inflammation is capable of modulating the microcirculation, we investigated the hypothesis that changes in the local perfusion might be one of the earliest signs of lesion development. 20 patients with definite relapsing-remitting multiple sclerosis were analysed with regard to cerebral blood volume, cerebral blood flow, mean transit time and apparent diffusion coefficient (ADC), as well as conventional MRI parameters, on monthly follow-up scans. Among 89 gadolinium-enhancing lesions, we selected 18 that developed during the study and met strict inclusion criteria. In these, changes of perfusion parameters were detectable not only prior to the BBB breakdown, but also prior to increases in the ADC. Our data indicate that inflammation is accompanied by altered local perfusion, which can be detected prior to permeability of the BBB.

Adult↗