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Roland Martin

Publications and source records attributed to Roland Martin.

At least 37 records · Page 2Linked to original sources
PubMed2005

Structure of a human autoimmune TCR bound to a myelin basic protein self-peptide and a multiple sclerosis-associated MHC class II molecule.

Multiple sclerosis is mediated by T-cell responses to central nervous system antigens such as myelin basic protein (MBP). To investigate self-peptide/major histocompatibility complex (MHC) recognition and T-cell receptor (TCR) degeneracy, we determined the crystal structure, at 2.8 A resolution, of an autoimmune TCR (3A6) bound to an MBP self-peptide and the multiple sclerosis-associated MHC class II molecule, human leukocyte antigen (HLA)-DR2a. The complex reveals that 3A6 primarily recognizes the N-terminal portion of MBP, in contrast with antimicrobial and alloreactive TCRs, which focus on the peptide center. Moreover, this binding mode, which may be frequent among autoimmune TCRs, is compatible with a wide range of orientation angles of TCR to peptide/MHC. The interface is characterized by a scarcity of hydrogen bonds between TCR and peptide, and TCR-induced conformational changes in MBP/HLA-DR2a, which likely explain the low observed affinity. Degeneracy of 3A6, manifested by recognition of superagonist peptides bearing substitutions at nearly all TCR-contacting positions, results from the few specific interactions between 3A6 and MBP, allowing optimization of interface complementarity through variations in the peptide.

Autoimmunity↗
PubMed2005

Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients.

Clinical trials have indicated that autologous hematopoietic stem cell transplantation (HSCT) can persistently suppress inflammatory disease activity in a subset of patients with severe multiple sclerosis (MS), but the mechanism has remained unclear. To understand whether the beneficial effects on the course of disease are mediated by lympho-depletive effects alone or are sustained by a regeneration of the immune repertoire, we examined the long-term immune reconstitution in patients with MS who received HSCT. After numeric recovery of leukocytes, at 2-yr follow-up there was on average a doubling of the frequency of naive CD4(+) T cells at the expense of memory T cells. Phenotypic and T cell receptor excision circle (TREC) analysis confirmed a recent thymic origin of the expanded naive T cell subset. Analysis of the T cell receptor repertoire showed the reconstitution of an overall broader clonal diversity and an extensive renewal of clonal specificities compared with pretherapy. These data are the first to demonstrate that long-term suppression of inflammatory activity in MS patients who received HSCT does not depend on persisting lymphopenia and is associated with profound qualitative immunological changes that demonstrate a de novo regeneration of the T cell compartment.

Adult↗
PubMed2005

HLA-DRB5*0101 and -DRB1*1501 expression in the multiple sclerosis-associated HLA-DR15 haplotype.

The HLA region, and particularly the DR15 haplotype (containing the two DRB* genes DRB1*1501 and DRB5*0101 and the tightly linked DQ alleles DQA*0102 and DQB1*0602, which together form the DQw6 molecule) in Caucasians, shows the strongest genetic association with multiple sclerosis (MS). In the DR15 haplotype, two beta-chains HLA-DRB1*1501 and -DRB5*0101 are co-expressed resulting in two different surface HLA-DR alphabeta heterodimers, DR2b and DR2a. Most previous studies focused on DRB1*1501, however, both DR2a and DR2b may contribute to MS pathogenesis via antigen presentation to myelin-specific T lymphocytes. We therefore analyzed the expression of the two DR15 genes in various antigen presenting cells (APCs), central nervous system and thymic tissues. Transcript levels were higher for DRB5*0101 in all cell types and tissues. Both HLA-DR heterodimers were expressed at significant levels on the cell surface, where they showed a differential expression pattern in different APCs. They were similarly regulated after stimulation with interferon-gamma and interleukin-4. Finally, immunohistochemistry experiments indicated that both molecules were expressed in thymic tissue. Our results encourage future research to investigate the potential functional relevance of both genes for the pathogenesis of MS.

Cells, Cultured↗
PubMed2005

Immunology of multiple sclerosis.

Multiple sclerosis (MS) develops in young adults with a complex predisposing genetic trait and probably requires an inciting environmental insult such as a viral infection to trigger the disease. The activation of CD4+ autoreactive T cells and their differentiation into a Th1 phenotype are a crucial events in the initial steps, and these cells are probably also important players in the long-term evolution of the disease. Damage of the target tissue, the central nervous system, is, however, most likely mediated by other components of the immune system, such as antibodies, complement, CD8+ T cells, and factors produced by innate immune cells. Perturbations in immunomodulatory networks that include Th2 cells, regulatory CD4+ T cells, NK cells, and others may in part be responsible for the relapsing-remitting or chronic progressive nature of the disease. However, an important paradigmatic shift in the study of MS has occurred in the past decade. It is now clear that MS is not just a disease of the immune system, but that factors contributed by the central nervous system are equally important and must be considered in the future.

Autoantibodies↗
PubMed2005

Autoantigens act as tissue-specific chemoattractants.

We have investigated the chemoattractant properties of self-antigens associated with autoimmune diseases and solid tumors. Many autoantigens induced leukocyte migration, especially by immature dendritic cells (iDC) by interacting with various chemoattractant Gi-protein-coupled receptors (GiPCR). Our initial observation that myositis-associated autoantigens, histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, were chemotactic for CC chemokine receptor 5 (CCR5)- and CCR3-expressing leukocytes, while other nonautoantigenic aminoacyl-tRNA synthesases were not, suggested that only self-antigens capable of interacting with receptors on antigen-presenting cells were immunogenic. We next determined that self-antigens associated with autoimmune diseases, e.g., multiple sclerosis or experimental autoimmune encephalomyelitis, type I diabetes, scleroderma, systemic lupus erythematosus, autoimmune uveitis, or experimental autoimmune uveitis (EAU), were chemotactic for GiPCR expressed by iDC. The majority of autoantigens were DC chemoattractants at 10-100 ng/ml, but did not induce DC maturation until they reached 1000-fold higher concentrations. Interphotoreceptor retinoid-binding protein and retinal arrestin (S-antigen) are targets of autoantibodies in human uveitis and are chemotactic for CXC chemokine receptor 5 (CXCR5)- and/or CXCR3-expressing iDC. However, although S-antigen does not induce EAU in wild-type mice, it is nevertheless a chemoattractant for murine iDC. These unexpected observations suggested that the chemotactic activity of these tissue-specific self-antigens could be involved in promotion of tissue repair and restoration. Thus, the primary role of autoantigens may be to alert the immune system to danger signals from invaded and damaged tissues to facilitate repair, and autoimmune responses subsequently develop only in subjects with impaired immunoregulatory function.

Animals↗
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

Unique clinical and pathological features in HLA-DRB1*0401-restricted MBP 111-129-specific humanized TCR transgenic mice.

Amino acid residues 111-129 represent an immunodominant epitope of myelin basic protein (MBP) in humans with human leukocyte antigen (HLA)-DRB1*0401 allele(s). The MBP 111-129-specific T cell clone MS2-3C8 was repeatedly isolated from a patient with multiple sclerosis (MS), suggesting an involvement of MS2-3C8 T cells in the pathogenesis. To address the pathogenic potential of the MS2-3C8 T cell clone, we generated transgenic (Tg) mice expressing its T cell receptor and restriction element, HLA-DRB1*0401, to examine the pathogenic characteristics of MS2-3C8 Tg T cells by adoptive transfer into HLA-DRB1*0401 Tg mice. In addition to the ascending paralysis typical of experimental autoimmune encephalomyelitis, mice displayed dysphagia due to restriction in jaw and tongue movements and abnormal gait. In accordance with the clinical phenotype, infiltrates of MS2-3C8 Tg T cells and inflammatory lesions were predominantly located in the brainstem and the cranial nerve roots in addition to the spinal cord and spinal nerve roots. Together, these data suggest a pathogenic role of MBP-specific T cells in inflammatory demyelination within the brainstem and cranial nerve roots during the progression of MS. This notion may help to explain the clinical and pathological heterogeneity of MS.

Amino Acid Sequence↗
PubMed2004

Development of biomarkers in multiple sclerosis.

Multiple sclerosis is a complex disease, as several pathophysiological processes (including inflammation, demyelination, axonal damage and repair mechanisms) participate in the disease process. Furthermore, as new pathological evidence reveals, these processes are not uniformly represented across patient populations but can selectively predominate in individual patients, thus contributing to the heterogeneity in phenotypic expression of the disease, its prognosis and response to therapies. While the armamentarium of available therapies for multiple sclerosis broadens, little is known about factors that predict treatment response in individual patients to a specific drug. More importantly, we are beginning to understand that, analogous to cancer therapy, the successful therapeutic strategy in multiple sclerosis might ultimately involve the combination of different therapeutics targeting several dominant pathophysiological processes. The development of these process-specific therapies will be impossible without the use of biomarkers that reflect the targeted process, can select patient population in which the targeted process is prevailing and can aid during the more rapid screening of therapeutic agents in the early phase of their development. This review summarizes the general concepts of biomarkers and their potential use as surrogate endpoints and tailors these concepts to specific applications in multiple sclerosis research.

Biomarkers↗
PubMed2004

Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta.

Identifying effective treatment combinations for MS patients failing standard therapy is an important goal. We report the results of a phase II open label baseline-to-treatment trial of a humanized monoclonal antibody against CD25 (daclizumab) in 10 multiple sclerosis patients with incomplete response to IFN-beta therapy and high brain inflammatory and clinical disease activity. Daclizumab was very well tolerated and led to a 78% reduction in new contrast-enhancing lesions and to a significant improvement in several clinical outcome measures.

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

The initiation of the autoimmune response in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Most evidence supports the autoimmune pathogenesis of the disease. According to this hypothesis, the activation of autoreactive T-cells is a central event in the development of autoimmune response in MS. We examined molecular events involved in the initiation of autoimmune response in MS. Recent studies in our laboratory have reported an unexpectedly high degree of T-cell receptor (TCR) degeneracy and molecular mimicry as a frequent phenomenon that might play a role in the initiation of autoimmune response in MS. This paper provides insights into the physiologic and pathologic role of autoreactive T-cells, and characterizes structurally and functionally the specific targets for new therapies of MS.

Antigens, CD↗
PubMed2004

Limited repertoire of HLA-DRB1*0401-restricted MBP111-129-specific T cells in HLA-DRB1*0401 Tg mice and their pathogenic potential.

Since myelin basic protein (MBP)111-129 is an immunodominant epitope in humans carrying HLA-DRB1*0401, we investigated the encephalitogenic potential of HLA-DRB1*0401-restricted MBP111-129-specific T cells using HLA-DRB1*0401/DRA*0101 transgenic (Tg) mice. Although we could not detect the primary recall response to MBP111-129 peptide after immunization of HLA-DRB1*0401/DRA*0101 Tg mice with human MBP, V beta 10(+) and V beta 2(+) HLA-DRB1*0401-restricted MBP111-129-specific T cells proliferated after restimulation of the lymph node cells with human MBP111-129 in vitro. The V beta 2(+) T cell line recognized only human MBP111-129 in the context of HLA-DRB1*0401, while the V beta 10(+) T cell line recognized both the human and murine MBP111-129 epitopes. Therefore, we examined the encephalitogenic potential of the V beta 10(+) T cell line in HLA-DRB1*0401/DRA*0101 Tg mice by adoptive transfer experiments. The V beta 10(+) T cell line induced mild EAE and inflammatory lesions were observed in the spinal cord and the brainstem. In the spinal cord, the inflammation was observed in the peripheral nerve roots as well as in the CNS. These data suggest the pathogenic potential of HLA-DRB1*0401-restricted MBP111-129-specific T cells in humans.

Adoptive Transfer↗
PubMed2004

A powerful combination: the use of positional scanning libraries and biometrical analysis to identify cross-reactive T cell epitopes.

Studies on the elucidation of the specificity of the T cell receptor (TCR) at the antigen and peptide level have contributed to the current understanding of T cell cross-reactivity. Historically, most studies of T cell specificity and degeneracy have relied on the determination of the effects on T cell recognition of amino acid changes at individual positions or MHC binding residues, and thus they have been limited to a small set of possible ligands. Synthetic combinatorial libraries (SCLs), and in particular positional scanning synthetic combinatorial libraries (PS-SCLs) represent collections of millions to trillions of peptides which allow the unbiased elucidation of T cell ligands that stimulate clones of both known and unknown specificity. PS-SCLs have been used successfully to study T cell recognition and to identify and optimize T cell clone (TCC) epitopes in infectious diseases, autoimmune disorders and tumor antigens. PS-SCL-based biometrical analysis represents a further refinement in the analysis of the data derived from the screening of a library with a TCC. It combines this data with information derived from protein sequence databases to identify natural peptide ligands. PS-SCL-based biometrical analysis provides a method for the determination of new microbial antigen and autoantigen sequences based solely on functional data rather than sequence homology or motifs, making the method ideally suited for the prediction and identification of both native and cross-reactive epitopes by virtue of its ability to integrate the examination of trillions of peptides in a systematic manner with all of the protein sequences in a given database. We review here the application of PS-SCLs and biometrical analysis to identify cross-reactive T cell epitopes, as well as the current efforts to refine this strategy.

Biometry↗
PubMed2004

Peptidic complex mixtures as therapeutic agents in CNS autoimmunity.

Limited success with antigen-specific immunotherapies has led to the identification of novel approaches which consider the degeneracy of the T cell response, i.e. their ability to respond to multiple antigenic peptides. Random complex mixtures of polypeptides such as glatiramer acetate (GA) were among the first to be applied as immunodulators that take into account T cell degeneracy. While the mechanisms of action are not completely understood, the immunogenicity of GA, its strong major histocompatability complex (MHC) binding, immune deviation and bystander suppression all appear to be important. In the present study we have designed peptidic complex mixtures (CM) of varied lengths and compositions to test their potential as immunomodulating agents. CM were synthesized that had defined lengths and contained aa corresponding to binding motifs of MHC class II molecules relevant in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), specifically HLA-DRB1*1501 and HLA-DRB5*0101, which are related to MS, and H2-IA(s) associated with EAE in SJL mice. Additional CM were designed based on specificity profiles derived from positional scanning synthetic combinatorial library (PS-SCL) testing of a GA-specific T cell clone (TCC). Several mixtures were strongly stimulatory for peripheral blood mononuclear cells (PBMC) from MS patients and healthy donors suggesting a high degree of cross-reactivity with other peptide antigens. A subset of these mixtures exhibited cross-reactivity to myelin antigens and prophylactic efficacy in reducing the severity of EAE. Based on these observations we envision mixture-based peptidic compounds can be developed not only for immunotherapeutic purposes in autoimmune diseases and cancer, but also in vaccine development.

Adjuvants, Immunologic↗