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1.
J Immunol Methods ; 534: 113764, 2024 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-39406335

RESUMEN

Experimental autoimmune encephalomyelitis (EAE) is a model for central nervous system (CNS) autoimmune demyelinating diseases such as multiple sclerosis (MS) and MOG antibody-associated disease (MOGAD). Immunization with the extracellular domain of recombinant human MOG (rhMOG), which contains pathogenic antibody and T cell epitopes, induces B cell-dependent EAE for studies in mice. However, these studies have been hampered by rhMOG availability due to its insolubility when overexpressed in bacterial cells, and the requirement for inefficient denaturation and refolding. Here, we describe a new protocol for the high-yield production of soluble rhMOG in SHuffle cells, a commercially available E. coli strain engineered to facilitate disulfide bond formation in the cytoplasm. SHuffle cells can produce a soluble fraction of rhMOG yielding >100 mg/L. Analytical size exclusion chromatography multi-angle light scattering (SEC-MALS) and differential scanning fluorimetry of purified rhMOG reveals a homogeneous monomer with a high melting temperature, indicative of a well-folded protein. An in vitro proliferation assay establishes that purified rhMOG can be processed and recognized by T cells expressing a T cell receptor (TCR) specific for the immunodominant MOG35-55 peptide epitope. Lastly, immunization of wild-type, but not B cell deficient, mice with rhMOG resulted in robust induction of EAE, indicating a B cell-dependent induction. Our SHuffle cell method greatly simplifies rhMOG production by combining the high yield and speed of bacterial cell expression with enhanced disulfide bond formation and folding, which will enable further investigation of B cell-dependent EAE and expand human research of MOG in CNS demyelinating diseases.

2.
Proc Natl Acad Sci U S A ; 120(30): e2306572120, 2023 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-37463205

RESUMEN

Aquaporin-4 (AQP4)-specific Th17 cells are thought to have a central role in neuromyelitis optica (NMO) pathogenesis. When modeling NMO, only AQP4-reactive Th17 cells from AQP4-deficient (AQP4-/-), but not wild-type (WT) mice, caused CNS autoimmunity in recipient WT mice, indicating that a tightly regulated mechanism normally ensures tolerance to AQP4. Here, we found that pathogenic AQP4 T cell epitopes bind MHC II with exceptionally high affinity. Examination of T cell receptor (TCR) α/ß usage revealed that AQP4-specific T cells from AQP4-/- mice employed a distinct TCR repertoire and exhibited clonal expansion. Selective thymic AQP4 deficiency did not fully restore AQP4-reactive T cells, demonstrating that thymic negative selection alone did not account for AQP4-specific tolerance in WT mice. Indeed, AQP4-specific Th17 cells caused paralysis in recipient WT or B cell-deficient mice, which was followed by complete recovery that was associated with apoptosis of donor T cells. However, donor AQP4-reactive T cells survived and caused persistent paralysis in recipient mice deficient in both T and B cells or mice lacking T cells only. Thus, AQP4 CNS autoimmunity was limited by T cell-dependent deletion of AQP4-reactive T cells. In contrast, myelin oligodendrocyte glycoprotein (MOG)-specific T cells survived and caused sustained disease in WT mice. These findings underscore the importance of peripheral T cell deletional tolerance to AQP4, which may be relevant to understanding the balance of AQP4-reactive T cells in health and in NMO. T cell tolerance to AQP4, expressed in multiple tissues, is distinct from tolerance to MOG, an autoantigen restricted in its expression.


Asunto(s)
Autoinmunidad , Neuromielitis Óptica , Animales , Ratones , Acuaporina 4/metabolismo , Autoanticuerpos , Glicoproteína Mielina-Oligodendrócito , Parálisis , Receptores de Antígenos de Linfocitos T/metabolismo
3.
Artículo en Inglés | MEDLINE | ID: mdl-36657993

RESUMEN

BACKGROUND AND OBJECTIVES: Anti-CD20 monoclonal antibody (mAb) B-cell depletion is a remarkably successful multiple sclerosis (MS) treatment. Chimeric antigen receptor (CAR)-T cells, which target antigens in a non-major histocompatibility complex (MHC)-restricted manner, can penetrate tissues more thoroughly than mAbs. However, a previous study indicated that anti-CD19 CAR-T cells can paradoxically exacerbate experimental autoimmune encephalomyelitis (EAE) disease. We tested anti-CD19 CAR-T cells in a B-cell-dependent EAE model that is responsive to anti-CD20 B-cell depletion similar to the clinical benefit of anti-CD20 mAb treatment in MS. METHODS: Anti-CD19 CAR-T cells or control cells that overexpressed green fluorescent protein were transferred into C57BL/6 mice pretreated with cyclophosphamide (Cy). Mice were immunized with recombinant human (rh) myelin oligodendrocyte protein (MOG), which causes EAE in a B-cell-dependent manner. Mice were evaluated for B-cell depletion, clinical and histologic signs of EAE, and immune modulation. RESULTS: Clinical scores and lymphocyte infiltration were reduced in mice treated with either anti-CD19 CAR-T cells with Cy or control cells with Cy, but not with Cy alone. B-cell depletion was observed in peripheral lymphoid tissue and in the CNS of mice treated with anti-CD19 CAR-T cells with Cy pretreatment. Th1 or Th17 populations did not differ in anti-CD19 CAR-T cell, control cell-treated animals, or Cy alone. DISCUSSION: In contrast to previous data showing that anti-CD19 CAR-T cell treatment exacerbated EAE, we observed that anti-CD19 CAR-T cells ameliorated EAE. In addition, anti-CD19 CAR-T cells thoroughly depleted B cells in peripheral tissues and in the CNS. However, the clinical benefit occurred independently of antigen specificity or B-cell depletion.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Inmunoterapia Adoptiva , Animales , Humanos , Ratones , Anticuerpos Monoclonales , Antígenos CD19 , Autoinmunidad , Sistema Nervioso Central , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Ratones Endogámicos C57BL , Esclerosis Múltiple/tratamiento farmacológico , Glicoproteína Mielina-Oligodendrócito , Linfocitos T , Linfocitos B
4.
Mult Scler Relat Disord ; 70: 104484, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36608538

RESUMEN

BACKGROUND: Adequate response to the SARS-CoV-2 vaccine represents an important treatment goal in caring for patients with multiple sclerosis (MS) during the ongoing COVID-19 pandemic. Previous data so far have demonstrated lower spike-specific IgG responses following two SARS-CoV-2 vaccinations in MS patients treated with sphingosine-1-phosphate (S1P) receptor modulators and anti-CD20 monoclonal antibodies (mAb) compared to other disease modifying therapies (DMTs). It is unknown whether subsequent vaccinations can augment antibody responses in these patients. OBJECTIVES: The goal of this observational study was to determine the effects of a third SARS-CoV-2 vaccination on antibody and T cell responses in MS patients treated with anti-CD20 mAb or S1P receptor modulators. METHODS: Vaccine responses in patients treated with anti-CD20 antibodies (ocrelizumab and ofatumumab) or S1P receptor modulators (fingolimod and siponimod) were evaluated before and after third SARS-CoV-2 vaccination as part of an ongoing longitudinal study. Total spike protein and spike receptor binding domain (RBD)-specific IgG responses were measured by Luminex bead-based assay. Spike-specific CD4+ and CD8+ T cell responses were measured by activation-induced marker expression. RESULTS: MS patients and healthy controls were enrolled before and following SARS-CoV-2 vaccination. A total of 31 MS patients (n = 10 ofatumumab, n = 13 ocrelizumab, n = 8 S1P) and 10 healthy controls were evaluated through three SARS-CoV-2 vaccinations. Compared to healthy controls, total spike IgG was significantly lower in anti-CD20 mAb-treated patients and spike RBD IgG was significantly lower in anti-CD20 mAb and S1P-treated patients following a third vaccination. While seropositivity was 100% in healthy controls after a third vaccination, total spike IgG and spike RBD IgG seropositivity were lower in ofatumumab (60% and 60%, respectively), ocrelizumab (85% and 46%, respectively), and S1P-treated patients (100% and 75%, respectively). Longer treatment duration, including prior treatment history, appeared to negatively impact antibody responses. Spike-specific CD4+ and CD8+ T cell responses were well maintained across all groups following a third vaccination. Finally, immune responses were also compared in patients who were vaccinated prior to or following ofatumumab treatment. Antibody responses were significantly higher in those patients who received their primary SARS-CoV-2 vaccination prior to initiating ofatumumab treatment. CONCLUSIONS: This study adds to the evolving understanding of SARS-CoV-2 vaccine responses in people with MS treated with disease-modifying therapies (DMTs) known to suppress humoral immunity. Our findings provide important information for optimizing vaccine immunity in at-risk MS patient populations.


Asunto(s)
COVID-19 , Esclerosis Múltiple , Moduladores de los Receptores de fosfatos y esfingosina 1 , Humanos , Inmunidad Humoral , Vacunas contra la COVID-19 , Receptores de Esfingosina-1-Fosfato , SARS-CoV-2 , Estudios Longitudinales , Pandemias , Vacunación , Anticuerpos Monoclonales , Inmunoglobulina G , Anticuerpos Antivirales
5.
JCI Insight ; 7(4)2022 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-35030101

RESUMEN

BACKGROUNDVaccine-elicited adaptive immunity is a prerequisite for control of SARS-CoV-2 infection. Multiple sclerosis (MS) disease-modifying therapies (DMTs) differentially target humoral and cellular immunity. A comprehensive comparison of the effects of MS DMTs on SARS-CoV-2 vaccine-specific immunity is needed, including quantitative and functional B and T cell responses.METHODSSpike-specific Ab and T cell responses were measured before and following SARS-CoV-2 vaccination in a cohort of 80 study participants, including healthy controls and patients with MS in 6 DMT groups: untreated and treated with glatiramer acetate (GA), dimethyl fumarate (DMF), natalizumab (NTZ), sphingosine-1-phosphate (S1P) receptor modulators, and anti-CD20 mAbs. Anti-spike-Ab responses were assessed by Luminex assay, VirScan, and pseudovirus neutralization. Spike-specific CD4+ and CD8+ T cell responses were characterized by activation-induced marker and cytokine expression and tetramer.RESULTSAnti-spike IgG levels were similar between healthy control participants and patients with untreated MS and those receiving GA, DMF, or NTZ but were reduced in anti-CD20 mAb- and S1P-treated patients. Anti-spike seropositivity in anti-CD20 mAb-treated patients was correlated with CD19+ B cell levels and inversely correlated with cumulative treatment duration. Spike epitope reactivity and pseudovirus neutralization were reduced in anti-CD20 mAb- and S1P-treated patients. Spike-specific CD4+ and CD8+ T cell reactivity remained robust across all groups, except in S1P-treated patients, in whom postvaccine CD4+ T cell responses were attenuated.CONCLUSIONThese findings from a large cohort of patients with MS exposed to a wide spectrum of MS immunotherapies have important implications for treatment-specific COVID-19 clinical guidelines.FUNDINGNIH grants 1K08NS107619, K08NS096117, R01AI159260, R01NS092835, R01AI131624, and R21NS108159; NMSS grants TA-1903-33713 and RG1701-26628; Westridge Foundation; Chan Zuckerberg Biohub; Maisin Foundation.


Asunto(s)
Anticuerpos Antivirales/biosíntesis , Vacunas contra la COVID-19/inmunología , Esclerosis Múltiple/terapia , SARS-CoV-2/inmunología , Linfocitos T/inmunología , Anticuerpos Antivirales/inmunología , Humanos , Esclerosis Múltiple/inmunología
6.
medRxiv ; 2021 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-34580672

RESUMEN

Vaccine-elicited adaptive immunity is an essential prerequisite for effective prevention and control of coronavirus 19 (COVID-19). Treatment of multiple sclerosis (MS) involves a diverse array of disease-modifying therapies (DMTs) that target antibody and cell-mediated immunity, yet a comprehensive understanding of how MS DMTs impact SARS-CoV-2 vaccine responses is lacking. We completed a detailed analysis of SARS-CoV-2 vaccine-elicited spike antigen-specific IgG and T cell responses in a cohort of healthy controls and MS participants in six different treatment categories. Two specific DMT types, sphingosine-1-phosphate (S1P) receptor modulators and anti-CD20 monoclonal antibodies (mAb), resulted in significantly reduced spike-specific IgG responses. Longer duration of anti-CD20 mAb treatment prior to SARS-CoV-2 vaccination were associated with absent antibody responses. Except for reduced CD4+ T cell responses in S1P-treated patients, spike-specific CD4+ and CD8+ T cell reactivity remained robust across all MS treatment types. These findings have important implications for clinical practice guidelines and vaccination recommendations in MS patients and other immunosuppressed populations.

7.
J Vis Exp ; (126)2017 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-28872108

RESUMEN

While it is recognized that aquaporin-4 (AQP4)-specific T cells and antibodies participate in the pathogenesis of neuromyelitis optica (NMO), a human central nervous system (CNS) autoimmune demyelinating disease, creation of an AQP4-targeted model with both clinical and histologic manifestations of CNS autoimmunity has proven challenging. Immunization of wild-type (WT) mice with AQP4 peptides elicited T cell proliferation, although those T cells could not transfer disease to naïve recipient mice. Recently, two novel AQP4 T cell epitopes, peptide (p) 135-153 and p201-220, were identified when studying immune responses to AQP4 in AQP4-deficient (AQP4-/-) mice, suggesting T cell reactivity to these epitopes is normally controlled by thymic negative selection. AQP4-/- Th17 polarized T cells primed to either p135-153 or p201-220 induced paralysis in recipient WT mice, that was associated with predominantly leptomeningeal inflammation of the spinal cord and optic nerves. Inflammation surrounding optic nerves and involvement of the inner retinal layers (IRL) were manifested by changes in serial optical coherence tomography (OCT). Here, we illustrate the approaches used to create this new in vivo model of AQP4-targeted CNS autoimmunity (ATCA), which can now be employed to study mechanisms that permit development of pathogenic AQP4-specific T cells and how they may cooperate with B cells in NMO pathogenesis.


Asunto(s)
Acuaporina 4/metabolismo , Autoantígenos/metabolismo , Neuromielitis Óptica/complicaciones , Nervio Óptico/patología , Linfocitos T/metabolismo , Animales , Humanos , Ratones , Parálisis
8.
J Nat Sci ; 3(5)2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28748216

RESUMEN

Aquaporin-4 (AQP4)-specific antibodies are instrumental in promoting central nervous system (CNS) tissue injury in neuromyelitis optica (NMO), yet evidence indicates that AQP4-specific T cells also have a pivotal role in NMO pathogenesis. Although considerable effort has been devoted to creation of animal models to study how AQP4-specific T cells and antibodies may cooperate in development of both clinical and histologic opticospinal inflammatory disease, the initial attempts were unsuccessful. Recently, it was discovered that T cells from AQP4-deficient (AQP4-/-) mice recognize distinct AQP4 epitopes that were not identified previously in wild-type (WT) mice, and that donor Th17 cells from AQP4-/- mice that target those novel epitopes could cause paralysis and visual system injury associated with opticospinal inflammation in WT recipient mice. These observations indicate that the pathogenic AQP4-specific T cell repertoire is normally controlled by negative selection. Here, we describe the advances leading to development of an animal model for aquaporin-targeted CNS autoimmunity (ATCA). This new model provides a foundation to investigate immune mechanisms that may participate in NMO pathogenesis. It should also permit preclinical testing of agents considered for treatment of NMO.

9.
Proc Natl Acad Sci U S A ; 113(51): 14781-14786, 2016 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-27940915

RESUMEN

Aquaporin-4 (AQP4)-specific T cells are expanded in neuromyelitis optica (NMO) patients and exhibit Th17 polarization. However, their pathogenic role in CNS autoimmune inflammatory disease is unclear. Although multiple AQP4 T-cell epitopes have been identified in WT C57BL/6 mice, we observed that neither immunization with those determinants nor transfer of donor T cells targeting them caused CNS autoimmune disease in recipient mice. In contrast, robust proliferation was observed following immunization of AQP4-deficient (AQP4-/-) mice with AQP4 peptide (p) 135-153 or p201-220, peptides predicted to contain I-Ab-restricted T-cell epitopes but not identified in WT mice. In comparison with WT mice, AQP4-/- mice used unique T-cell receptor repertoires for recognition of these two AQP4 epitopes. Donor T cells specific for either determinant from AQP4-/-, but not WT, mice induced paralysis in recipient WT and B-cell-deficient mice. AQP4-specific Th17-polarized cells induced more severe disease than Th1-polarized cells. Clinical signs were associated with opticospinal infiltrates of T cells and monocytes. Fluorescent-labeled donor T cells were detected in CNS lesions. Visual system involvement was evident by changes in optical coherence tomography. Fine mapping of AQP4 p201-220 and p135-153 epitopes identified peptides within p201-220 but not p135-153, which induced clinical disease in 40% of WT mice by direct immunization. Our results provide a foundation to evaluate how AQP4-specific T cells contribute to AQP4-targeted CNS autoimmunity (ATCA) and suggest that pathogenic AQP4-specific T-cell responses are normally restrained by central tolerance, which may be relevant to understanding development of AQP4-reactive T cells in NMO.


Asunto(s)
Acuaporina 4/genética , Acuaporina 4/metabolismo , Autoantígenos/química , Epítopos de Linfocito T/inmunología , Neuromielitis Óptica/metabolismo , Linfocitos T/citología , Animales , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/metabolismo , Proliferación Celular , Sistema Nervioso Central , Mapeo Epitopo , Femenino , Citometría de Flujo , Tolerancia Inmunológica , Inmunoglobulina G/inmunología , Inflamación , Leucocitos/citología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Bazo/citología , Células Th17/citología
10.
JCI Insight ; 1(20): e87234, 2016 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-27942581

RESUMEN

Ectopic lymphoid tissues (ELT) can be found in multiple sclerosis (MS) and other organ-specific inflammatory conditions. Whether ELT in the meninges of central nervous system (CNS) autoimmune disease exhibit local germinal center (GC) activity remains unknown. In an experimental autoimmune encephalomyelitis model of CNS autoimmunity, we found activation-induced cytidine deaminase, a GC-defining enzyme, in meningeal ELT (mELT) densely populated by B and T cells. To determine GC activity in mELT, we excised meningeal lymphoid aggregates using laser capture microscopy and evaluated B cell repertoires in mELT and secondary lymphoid organs by next-generation immune repertoire sequencing. We found immunoglobulin heavy chain variable region sequences that were unique to mELT and had accumulated functionally relevant somatic mutations, together indicating localized antigen-driven affinity maturation. Our results suggest that B cells in mELT actively participate in CNS autoimmunity, which may be relevant to mELT in MS and ELT in other chronic inflammatory conditions.


Asunto(s)
Linfocitos B/citología , Encefalomielitis Autoinmune Experimental/patología , Estructuras Linfoides Terciarias/patología , Animales , Linfocitos B/clasificación , Sistema Nervioso Central/citología , Femenino , Centro Germinal/citología , Meninges/citología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Esclerosis Múltiple
11.
Proc Natl Acad Sci U S A ; 113(17): 4777-82, 2016 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-27078105

RESUMEN

Dimethyl fumarate (DMF) (BG-12, Tecfidera) is a fumaric acid ester (FAE) that was advanced as a multiple sclerosis (MS) therapy largely for potential neuroprotection as it was recognized that FAEs are capable of activating the antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, DMF treatment in randomized controlled MS trials was associated with marked reductions in relapse rate and development of active brain MRI lesions, measures considered to reflect CNS inflammation. Here, we investigated the antiinflammatory contribution of Nrf2 in DMF treatment of the MS model, experimental autoimmune encephalomyelitis (EAE). C57BL/6 wild-type (WT) and Nrf2-deficient (Nrf2(-/-)) mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 (p35-55) for EAE induction and treated with oral DMF or vehicle daily. DMF protected WT and Nrf2(-/-) mice equally well from development of clinical and histologic EAE. The beneficial effect of DMF treatment in Nrf2(-/-) and WT mice was accompanied by reduced frequencies of IFN-γ and IL-17-producing CD4(+) cells and induction of antiinflammatory M2 (type II) monocytes. DMF also modulated B-cell MHC II expression and reduced the incidence of clinical disease in a B-cell-dependent model of spontaneous CNS autoimmunity. Our observations that oral DMF treatment promoted immune modulation and provided equal clinical benefit in acute EAE in Nrf2(-/-) and WT mice, suggest that the antiinflammatory activity of DMF in treatment of MS patients may occur through alternative pathways, independent of Nrf2.


Asunto(s)
Inmunidad Adaptativa/inmunología , Dimetilfumarato/administración & dosificación , Inmunidad Innata/inmunología , Inmunomodulación/inmunología , Factor 2 Relacionado con NF-E2/inmunología , Bazo/inmunología , Inmunidad Adaptativa/efectos de los fármacos , Administración Oral , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Inmunidad Innata/efectos de los fármacos , Factores Inmunológicos/administración & dosificación , Inmunomodulación/efectos de los fármacos , Inmunosupresores/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Bazo/citología , Bazo/efectos de los fármacos
12.
Neurol Neuroimmunol Neuroinflamm ; 3(2): e212, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27027096

RESUMEN

OBJECTIVE: To investigate the role of very late antigen-4 (VLA-4) on regulatory B cells (Breg) in CNS autoimmune disease. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in mice selectively deficient for VLA-4 on B cells (CD19cre/α4(f/f)) by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide (p)35-55 or recombinant human (rh) MOG protein. B-cell and T-cell populations were examined by flow cytometry and immunohistochemistry. Breg were evaluated by intracellular IL-10 staining of B cells and, secondly, by coexpression of CD1d and CD5. RESULTS: As previously reported, EAE was less severe in B-cell VLA-4-deficient vs control CD19cre mice when induced by rhMOG, a model that is B-cell-dependent and leads to efficient B-cell activation and antibody production. Paradoxically, B-cell VLA-4-deficient mice developed more severe clinical disease than control mice when EAE was induced with MOG p35-55, a B-cell-independent encephalitogen that does not efficiently activate B cells. Peripheral T-cell and humoral immune responses were not altered in B-cell VLA-4-deficient mice. In MOG p35-55-induced EAE, B-cell VLA-4 deficiency reduced CNS accumulation of B but not T cells. Breg were detected in the CNS of control mice with MOG p35-55-induced EAE. However, more severe EAE in B-cell VLA-4-deficient mice was associated with virtual absence of CNS Breg. CONCLUSIONS: Our results demonstrate that CNS accumulation of Breg is VLA-4-dependent and suggest that Breg may contribute to regulation of CNS autoimmunity in situ. These observations underscore the need to choose the appropriate encephalitogen when studying how B cells contribute to pathogenesis or regulation of CNS autoimmunity.

13.
Ann Neurol ; 77(5): 902-8, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25712734

RESUMEN

Natalizumab, which binds very late antigen-4 (VLA-4), is a potent therapy for multiple sclerosis (MS). Studies have focused primarily upon its capacity to interfere with T-cell migration into the central nervous system (CNS). B cells are important in MS pathogenesis and express high levels of VLA-4. Here, we report that the selective inhibition of VLA-4 expression on B cells impedes CNS accumulation of B cells, and recruitment of Th17 cells and macrophages, and reduces susceptibility to experimental autoimmune encephalomyelitis. These results underscore the importance of B-cell VLA-4 expression in the pathogenesis of CNS autoimmunity and provide insight regarding mechanisms that may contribute to the benefit of natalizumab in MS, as well as candidate therapeutics that selectively target B cells.


Asunto(s)
Autoinmunidad/inmunología , Linfocitos B/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Integrina alfa4beta1/deficiencia , Animales , Linfocitos B/metabolismo , Susceptibilidad a Enfermedades , Encefalomielitis Autoinmune Experimental/metabolismo , Humanos , Leucocitos/inmunología , Leucocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Th17/inmunología , Células Th17/metabolismo
14.
PLoS One ; 7(3): e33797, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22479444

RESUMEN

Laquinimod is a novel oral drug that is currently being evaluated for the treatment of relapsing-remitting (RR) multiple sclerosis (MS). Using the animal model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we examined how laquinimod promotes immune modulation. Oral laquinimod treatment reversed established RR-EAE and was associated with reduced central nervous system (CNS) inflammation, decreased Th1 and Th17 responses, and an increase in regulatory T cells (Treg). In vivo laquinimod treatment inhibited donor myelin-specific T cells from transferring EAE to naive recipient mice. In vivo laquinimod treatment altered subpopulations of myeloid antigen presenting cells (APC) that included a decrease in CD11c(+)CD11b(+)CD4(+) dendritic cells (DC) and an elevation of CD11b(hi)Gr1(hi) monocytes. CD11b(+) cells from these mice exhibited an anti-inflammatory type II phenotype characterized by reduced STAT1 phosphorylation, decreased production of IL-6, IL-12/23 and TNF, and increased IL-10. In adoptive transfer, donor type II monocytes from laquinimod-treated mice suppressed clinical and histologic disease in recipients with established EAE. As effects were observed in both APC and T cell compartments, we examined whether T cell immune modulation occurred as a direct effect of laquinimod on T cells, or as a consequence of altered APC function. Inhibition of Th1 and Th17 differentiation was observed only when type II monocytes or DC from laquinimod-treated mice were used as APC, regardless of whether myelin-specific T cells were obtained from laquinimod-treated or untreated mice. Thus, laquinimod modulates adaptive T cell immune responses via its effects on cells of the innate immune system, and may not influence T cells directly.


Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Factores Inmunológicos/farmacología , Células Mieloides/efectos de los fármacos , Células Mieloides/inmunología , Quinolonas/farmacología , Administración Oral , Traslado Adoptivo , Animales , Células Presentadoras de Antígenos/efectos de los fármacos , Células Presentadoras de Antígenos/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/terapia , Femenino , Factores Inmunológicos/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Monocitos/efectos de los fármacos , Monocitos/inmunología , Quinolonas/administración & dosificación , Linfocitos T/inmunología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología
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