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Moses Rodriguez

Publications and source records attributed to Moses Rodriguez.

At least 19 recordsLinked to original sources
PubMed2023

Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis.

BACKGROUND: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown. OBJECTIVE: To test whether genes harboring rare variants associated with adult-onset MS risk (PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS. METHODS: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method "SKAT-O," we tested the association between candidate genes and POMS risk. RESULTS: After correction for multiple comparisons, one adult-onset MS gene (PRF1, p = 2.70 × 10-3) and two MHC genes (BRD2, p = 5.89 × 10-5 and AGER, p = 7.96 × 10-5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501. CONCLUSION: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.

Child↗
PubMed2003

Naturally occurring human IgM antibody that binds B7-DC and potentiates T cell stimulation by dendritic cells.

A human IgM Ab, serum-derived human IgM 12 (sHIgM12), is identified that binds mouse and human dendritic cells (DC), inducing dramatic immunopotentiation following treatment of the mouse DC in vitro. Competition, transfection, and knockout studies identified the ligand on mouse DC as the costimulatory molecule family member B7-DC. Potent T cell responses are stimulated by Ag-pulsed DC treated with the sHIgM12 Ab in vitro and upon adoptive transfer of Ab-treated Ag-pulsed DC into animals. The multivalent structure of pentameric IgM provides the potential for cross-linking cell surface targets, endowing the soluble Abs with biological potential not normally associated with immune function. The ability of the sHIgM12 Ab to potentiate the immune response is dependent on the multimeric structure of IgM, as bivalent monomers do not retain this property. Furthermore, pretreatment of DC with IgM monomers blocks subsequent potentiation by intact IgM pentamers, an indication that cross-linking of B7-DC on the cell surface is critical for potentiation of Ag presentation. These findings imply that, in addition to known costimulatory roles, B7-DC can function as a receptor for signals delivered by cells expressing B7-DC ligands.

Adjuvants, Immunologic↗
PubMed2003

Interleukin-6 protects anterior horn neurons from lethal virus-induced injury.

We evaluated the role of interleukin-6 (IL-6) in neuronal injury after CNS infection. IL-6-/- and IL-6+/+ mice of resistant major histocompatibility complex (MHC) H-2b haplotype intracerebrally infected with Theiler's virus cleared the infection normally without development of viral persistence, lethal neuronal infection, or late phase demyelination. In contrast, infection of IL-6-/- mice on a susceptible H-2q haplotype resulted in frequent deaths and severe neurologic deficits within 2 weeks of infection as compared with infected IL-6+/+ H-2q littermate controls. Morphologic analysis demonstrated dramatic injury to anterior horn neurons of IL-6-/- H-2q mice at 12 d after infection. Infectious viral titers in the CNS (brain and spinal cord combined) were equivalent between IL-6-/- H-2q and IL-6+/+ H-2q mice. In contrast, more viral RNA was detected in the spinal cord of IL-6-/- mice compared with IL-6+/+ H-2q mice. Virus antigen was localized predominantly to anterior horn cells in infected IL-6-/- H-2q mice. IL-6 deletion did not affect the humoral response directed against virus, nor did it affect the expression of CD4, CD8, MHC class I, or MHC class II in the CNS. Importantly, IL-6 was expressed by astrocytes of infected IL-6+/+ mice but not in astrocytes of IL-6-/- mice or uninfected IL-6+/+ mice. Furthermore, expression of various chemokines was robust at 12 d after infection in both H-2b and H-2q IL-6-/- mice, indicating that intrinsic CNS inflammatory responses did not depend on the presence of IL-6. Finally, in vitro analysis of virus-induced death in neuroblastoma-spinal cord-34 motor neurons and primary anterior horn cell neurons showed that IL-6 exerted a neuroprotective effect. These data support the hypothesis that IL-6 plays a critical role in protecting specific populations of neurons from irreversible injury.

Animals↗
PubMed2003

Efficient central nervous system remyelination requires T cells.

We demonstrate a role for immune functions in the spontaneous remyelination of central nervous system (CNS) axons after lysolecithin-induced demyelination in the spinal cord. Rag-1-deficient mice lack both B cells and T cells and show significantly reduced spontaneous remyelination compared with control mice of matching genetic background. Mice lacking or depleted of either CD4(+) T cells or CD8(+) T cells also exhibit reduced remyelination. These data indicate that T cells are necessary for efficient CNS remyelination. Thus, general nonspecific immunosuppression as a therapeutic approach for the treatment of CNS injury and demyelinating disease may have undesirable effects on subsequent tissue repair.

Animals↗
PubMed2003

Clearance of Theiler's virus infection depends on the ability to generate a CD8+ T cell response against a single immunodominant viral peptide.

Theiler's murine encephalomyelitis virus (TMEV) induces a chronic demyelinating disease in the central nervous system of susceptible mice. Resistance to persistent TMEV infection maps to he D locus of the major histocompatibility complex suggesting a prominent role of antiviral CTL in the protective immune response. Introduction of the D(b) gene into the FVB strain confers resistance to this otherwise susceptible mouse line. Infection of the FVB/D(b) mouse with TMEV provides a model where antiviral resistance is determined by a response elicited by a single class I molecule. Resistant mice of the H-2(b) haplotype mount a vigorous H-2D(b)-restricted immunodominant response to the VP2 capsid protein. To investigate the extent of the contribution of the immunodominant T cell population in resistance to TMEV, FVB/D(b) mice were depleted of VP2-specific CD8(+) T cells by peptide treatment prior to virus infection. Peptide-treated mice were not able to clear the virus and developed extensive demyelination. These findings demonstrate that the D(b)-restricted CD8(+) T cells specific for a single viral peptide can confer resistance to TMEV infection. Our ability to manipulate this cellular response provides a model for investigating the mechanisms mediating protection against virus infection by CD8(+) T cells.

Animals↗
PubMed2003

More severe neurologic deficits in SJL/J male than female mice following Theiler's virus-induced CNS demyelination.

Although multiple sclerosis (MS) is more prevalent in women than men, male MS patients develop more severe clinical symptoms and deteriorate faster than female patients. We investigated the differences in CNS demyelinating disease between SJL/J male and female mice following Theiler's murine encephalomyelitis virus (TMEV) infection. Infected female mice had consistently higher serum levels of virus-specific IgG at 14 and 21 days and and 7 months postinfection, which resulted in less infectious virus in CNS. All male mice infected for 6 to 7 months developed paralysis, with 50% displaying bilateral posterior limb paralysis, whereas 77% of age-matched female mice were paralyzed, all displaying unilateral posterior limb paralysis. Male mice infected for 6 to 7 months performed up to threefold fewer spontaneous horizontal and vertical movements (activity box test) compared to infected age-matched females. In addition, infected male mice performed the coordination and balance (Rotarod) test at 27 +/- 4% of the expected level (expressed as a percentage of that of uninfected age-matched mice), whereas infected female mice performed at 41 +/- 5% of the expected level. Male mice had a small increase in the extent of spinal cord white matter demyelination analyzed at both 45 days and between 6 and 7 months postinfection. For individual male and female mice, the extent of demyelination had a negative linear relationship with the neurologic performances. The emergence of a disease paradigm similar to MS supports using the TMEV model to investigate molecular and genetic factors responsible for the gender dimorphism in MS and other autoimmune diseases.

Acute Disease↗
PubMed2003

Remyelination-promoting antibodies activate distinct Ca2+ influx pathways in astrocytes and oligodendrocytes: relationship to the mechanism of myelin repair.

Our laboratory has identified mouse and human monoclonal antibodies that promote myelin repair in multiple models of demyelinating disease. We have proposed that these antibodies promote remyelination by directly activating central nervous system glia. Intracellular calcium concentration was monitored using a Fura2 ratiometric assay. Repair-promoting antibodies induced distinct Ca2+ signals in both astrocytes and oligodendrocytes. Astrocyte Ca2+ signaling is mediated by a phospholipase C-dependent pathway while oligodendrocyte Ca2+ signaling is mediated via AMPA-sensitive glutamate receptors. An antibody's ability to induce Ca2+ signals is statistically correlated with promotion of myelin repair. These findings support the hypothesis that remyelination-promoting antibodies are acting directly at the surface of glial cells to induce calcium-dependent physiologic reparative function.

Animals↗
PubMed2003

HLA class II transgenic mice authenticate restriction of myelin oligodendrocyte glycoprotein-specific immune response implicated in multiple sclerosis pathogenesis.

Myelin oligodendrocyte glycoprotein (MOG) is a potential target antigen of the central nervous system (CNS), known to induce autoreactive T cell response and demyelinating anti-MOG antibodies in multiple sclerosis (MS) patients. Association of HLA class II genes with MS is well established. To better understand the role of HLA class II molecules in disease pathogenesis, we generated transgenic mice that express HLA-DR2, -DR3, -DR4, -DQB1*0601, -DQB1*0604 and -DQ8 without mouse class II (Abeta(0)). We have for the first time characterized the T and B cell epitopes of human MOG restricted by different HLA class II molecules. Immunization with recombinant MOG (rMOG) generated a strong CD4(+) T cell-mediated response in an HLA class II-restricted manner. Cytokine analysis revealed an increase in pro-inflammatory (IFN-gamma, IL-12 and IL-6) and anti-inflammatory (IL-10) cytokines. T cell autoreactivity to MOG was directed against peptides 1-20, 31-50, 61-80 and 91-110, of which three are also immunodominant epitopes for MOG in MS. A strong B cell response to MOG was observed in all transgenic mice, and major B cell epitopes recognized were located within amino acids 1-30, 51-80 and 101-120 of human MOG, which consists of two epitopes reported in MS. Transgenic mice used in this study recognized the immunodominant MOG epitopes similar to HLA class II-restricted human T cells, and would therefore be valuable in elucidating the roles of HLA class II genes and autoantigens in MS.

Animals↗
PubMed2003

Membrane lymphotoxin is required for resistance to Theiler's virus infection.

Lymphotoxin (LT) and tumor necrosis factor (TNF) are important in immune system development and function. LT consists of soluble LT-alpha(3), which binds to TNF-R1 and TNF-R2, and membrane LT-alpha(1)beta(2), which binds to LT-beta-R. We investigated the role of LT and TNF in disease induced by Daniel's (DA) strain of Theiler's murine encephalomyelitis virus (TMEV) since the immune response is believed to be important in both resistance to DA infection as well as mediation of virus-induced demyelination. DA persisted and induced inflammatory demyelination in LT-alpha(-/-) (but not TNF(-/-)) weanling mice of a normally resistant haplotype (C57BL/6), suggesting that LT, but not TNF, is critical for resistance to DA infection. This activity of LT depends on membrane LT-alpha(1)beta(2) and not soluble LT-alpha(3), since DA virus persisted and induced inflammatory demyelination in LT-beta-R(-/-), but not TNF-R1(-/-) or TNF-R2(-/-), mice. The LT-alpha(-/-) and LT-beta-R(-/-) mice failed to mount a virus-specific cytotoxic T cell response. Treatment of weanling C57BL/6 mice with LT-beta-R-Ig, which blocks membrane LT activity, failed to increase susceptibility, suggesting that the LT effect is related to its action on immune system development which is fixed by 3 weeks of age. Our data suggest that membrane LT is important in resistance to DA infection (possibly through interference with CD8+ T cell development and function). There was relatively little demyelination associated with inflammation in LT-alpha(-/-) and LT-beta-R(-/-) mice compared to susceptible SJL mice, suggesting the possibility that LT plays a role in mediating demyelination.

Animals↗
PubMed2003

Direct comparison of demyelinating disease induced by the Daniel's strain and BeAn strain of Theiler's murine encephalomyelitis virus.

We compared CNS disease following intracerebral injection of SJL mice with Daniel's (DA) and BeAn 8386 (BeAn) strains of Theiler's murine encephalomyelitis virus (TMEV). In tissue culture, DA was more virulent then BeAn. There was a higher incidence of demyelination in the spinal cords of SJL/J mice infected with DA as compared to BeAn. However, the extent of demyelination was similar between virus strains when comparing those mice that developed demyelination. Even though BeAn infection resulted in lower incidence of demyelination in the spinal cord, these mice showed significant brain disease similar to that observed with DA. There was approximately 100 times more virus specific RNA in the CNS of DA infected mice as compared to BeAn infected mice. This was reflected by more virus antigen positive cells (macrophages/microglia and oligodendrocytes) in the spinal cord white matter of DA infected mice as compared to BeAn. There was no difference in the brain infiltrating immune cells of DA or BeAn infected mice. However, BeAn infected mice showed higher titers of TMEV specific antibody. Functional deficits as measured by Rotarod were more severe in DA infected versus BeAn infected mice. These findings indicate that the diseases induced by DA or BeAn are distinct.

Analysis of Variance↗
PubMed2003

Magnetic resonance imaging of immune cells in inflammation of central nervous system.

AIM: To develop a novel, magnetic resonance-based method for in vivo cell localization in the central nervous system (CNS) of the animals without sacrificing them. METHODS: Cells were labeled in vivo by intravenous injection of cell marker-specific antibodies covalently bound to ultrasmall superparamagnetic iron oxide particles (USPIO). This enabled the visualization of specific cell types by magnetic resonance microscopy (MRM). RESULTS: USPIOs covalently attached to antibodies affected the contrast in MRM scan, and their accumulation on cells manifested as signal weakening in T2*-weighted images or signal enhancement in T1-weighted images. With this method applied in the experimental autoimmune encephalomyelitis (EAE) murine multiple sclerosis (MS) model, CNS-infiltrating CD4+ T cells were easily visualized with cell-specific MRM. CONCLUSION: MRM with targeted contrast materials can be used to localize CNS-infiltrating lymphocytes of interest. Due to its noninvasive character, this method could potentially be used in human MR imaging as well.

Animals↗
PubMed2002

Heterogeneity of pathogenesis in multiple sclerosis: implications for promotion of remyelination.

Enhancing myelin repair remains an important therapeutic goal in primary demyelinating diseases of the central nervous system (CNS) such as multiple sclerosis (MS). The emerging heterogeneity of pathology within MS lesions, and differential oligodendrocyte survival in particular, suggests that therapeutic strategies may need to be tailored to an individual patient's requirements. A number of therapeutic strategies have been proposed to enhance myelin repair in the CNS: cell transplantation, growth factor therapy, and antibody therapy, but each proposed therapy has different implications with respect to pathogenetic mechanisms of demyelination. Of these, antibody therapy is the most amenable to immediate application in patients-but a combination of therapeutic approaches may be required in practice.

Animals↗
PubMed2002

Cross-linking the B7 family molecule B7-DC directly activates immune functions of dendritic cells.

B7-DC molecules are known to function as ligands on antigen-presenting cells (APCs), enhancing T cell activation. In this study, cross-linking B7-DC with the monoclonal antibody sHIgM12 directly potentiates dendritic cell (DC) function by enhancing DC presentation of major histocompatibility complex-peptide complexes, promoting DC survival; and increasing secretion of interleukin (IL)-12p70, a key T helper cell type 1 promoting cytokine. Furthermore, ex vivo treatment of DCs or systemic treatment of mice with sHIgM12 increases the number of transplanted DCs that reach draining lymph nodes and increases the ability of lymph node APCs to activate naive T cells. Systemic administration of the antibody has an equivalent effect on DCs transferred at a distant site. These findings implicate B7-DC expressed on DCs in bidirectional communication. In addition to the established costimulatory and inhibitory functions associated with B7-DC, this molecule can also function as a conduit for extracellular signals to DCs modifying DC functions.

Adoptive Transfer↗
PubMed2002

Impaired infiltration of tumor-specific cytolytic T cells in the absence of interferon-gamma despite their normal maturation in lymphoid organs during CD137 monoclonal antibody therapy.

Engagement of CD137 receptor by agonistic monoclonal antibodies (mAb) stimulates IFN-gamma production and eradicates established tumors in syngeneic mouse models. Using IFN-gamma-deficient mice or neutralizing mAb, we demonstrate that IFN-gamma is an absolute requirement for the antitumor effect of CD137 mAb. Despite progressive tumor growth in IFN-gamma-depleted mice, a fully competent CD8(+) cytolytic T cell (CTL) response developed in the lymph nodes. In addition, tumor cell sensitivity to IFN-gamma was not required because expression of a dominant-negative IFN-gamma receptor on the tumor did not affect the therapeutic effect of CD137 mAb. However, in the absence of IFN-gamma, the number of tumor-infiltrating CD8(+) CTLs was drastically decreased. Our results demonstrate that IFN-gamma is a critical factor regulating the infiltration of antigen-specific CTL into the tumor.

Animals↗
PubMed2002

Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic-progressive demyelinating disease.

Certain human sera from patients with monoclonal gammopathies contain factors that induce myelin repair in animals with demyelinating disease. We hypothesize that antibodies functionally distinguish the serum of one patient from another. However, pooled normal polyclonal human IgM antibodies also induce remyelination. Definitive proof that specific antibodies are the biologically active components of serum is missing because unquestionably pure preparations of antibody molecules cannot be generated by fractionation. To demonstrate definitively that antibody is the biologically active component of patient serum, recombinant antibody was generated for evaluation in bioassays. The induction of remyelination in vivo requires milligram quantities of antibody. Consequently, an expression system was engineered to express high-titer, recombinant human IgM antibodies in vitro. A resulting recombinant antibody (rHIgM22) was evaluated for its ability to induce remyelination in the Theiler's virus mouse model of chronic-progressive demyelinating disease. We demonstrate that a single recombinant monoclonal antibody recapitulates the key characteristics of patient serum, including binding specificity, the induction of calcium signals in oligodendrocytes in vitro, and the induction of myelin repair within demyelinated plaques in vivo. The rHIgM22 antibody provides a new venue for the analysis of mechanisms governing remyelination and may prove useful in the treatment of demyelinating diseases.

Animals↗
PubMed2002

Polyreactive antibodies to glatiramer acetate promote myelin repair in murine model of demyelinating disease.

Using a murine model of demyelinating disease, we demonstrate that remyelination of spinal cord axons is promoted by antibodies to glatiramer acetate (GA, Copolymer-1, Copaxone), a therapeutic agent for multiple sclerosis (MS). Glatiramer acetate is a mixture of randomly synthesized peptides that induces both T cell activation and antibody production in all treated individuals. These observations prompted us to compare the independent effects of adoptively transferred GA-reactive T cells and antibodies in mice with chronic inflammatory demyelination induced by Theiler's virus. Transferred T cells had no effect on lesion load or the extent of remyelination. Purified polyclonal GA antibodies also did not alter lesion load, which suggests that neither GA T cells or antibodies were pathogenic. On the contrary, GA antibodies enhanced the normally low level of remyelination in chronic lesions. The antibodies, which were primarily immunoglobulin (Ig) G1 and IgG2, cross-reacted with oligodendrocytes, perivascular infiltrating cells, astrocytes, and neurons in spinal cord sections. In glial cultures they bound subsets of early lineage oligodendrocytes and microglia. Thus, several mechanisms may have contributed to the promotion of remyelination. These results support the hypothesis that the antibody response in GA-treated patients is beneficial by facilitating repair of demyelinated lesions.

Adjuvants, Immunologic↗
PubMed2002

Human antibodies accelerate the rate of remyelination following lysolecithin-induced demyelination in mice.

Immunoglobulin-based therapies are becoming increasingly common for the treatment of neurologic and autoimmune diseases in humans. In this study, we demonstrate that systemic administration of either polyclonal human immunoglobulins or specific human monoclonal antibodies can accelerate the rate of CNS remyelination following toxin-induced demyelination. Injection of lysolecithin directly into the spinal cord results in focal demyelinated lesions. In contrast to other murine models of demyelinating disease, the mechanism of demyelination following lysolecithin injection is independent of immune system activation, and chronic inflammation at the site of the lesion is minimal. Administration of polyclonal human IgM (pHIgM) or a serum-derived human monoclonal antibody (sHIgM22) resulted in approximately a twofold increase in remyelinating axons when compared to animals treated with saline or with antibodies that do not promote repair. Both pHIgM and sHIgM22 show strong binding to CNS white matter and oligodendrocytes, while antibodies that did not accelerate remyelination do not. This differential staining pattern suggests that enhanced remyelination may result from direct stimulation of oligodendrocyte remyelination by binding to surface receptors on oligodendrocytes or glial progenitor cells. We propose the use of human polyclonal IgM or specific human monoclonal IgM antibodies as potential therapies to enhance myelin repair following CNS injury and disease.

Animals↗