Rituximab Therapy Reduces Organ-Specific T Cell Responses and Ameliorates Experimental Autoimmune Encephalomyelitis

Monson, Nancy; Cravens, Petra D.; Hussain, Rehana Z.; Harp, Christopher; Cummings, Matthew; Martin, Maria de Pilar; Ben, Li Hong; Do, Julie; Lyons, Jeri A.; Lovette-Racke, Amy; Cross, Anne H.; Racke, Michael K.; Stüve, Olaf; Shlomchik, Mark J.; Eagar, Todd N.

doi:10.1371/journal.pone.0017103

Cited by 73 publications

(68 citation statements)

References 22 publications

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“…This indicates that B cell depletion affected the efficacy of local disease control, at least in some granulomas and some animals. B cells are known to interact with macrophages and T cells (14,21,32,39,40) and can affect differential macrophage activation states and T helper cell polarization depending on antigen presentation or cytokine secretion. B cell and macrophage interaction is further complicated by Fc receptor engagement, which can further modulate pro-or anti-inflammatory reactions (38,41).…”

Section: Discussionmentioning

confidence: 99%

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Effects of B Cell Depletion on Early Mycobacterium tuberculosis Infection in Cynomolgus Macaques

et al. 2016

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(2,4,7,9,10). B cell-deficient mice display enhanced susceptibility to M. tuberculosis, as assessed by tissue bacterial burden (4, 11), which is associated with aberrant lung cytokine (4) and granulomatous inflammatory response (4, 12, 13), as well as tissue neutrophilia (4, 13). Of note, there is evidence suggesting that the inflammation regulatory role of B cells during M. tuberculosis infection can be strain and infection phase specific (4, 12, 13). Studies using specific Fc␥ receptor knockout mouse strains have shown that signaling through distinct receptors can differentially regulate susceptibility to M. tuberculosis, as measured by tissue bacterial load, and lung cytokine production, suggesting a role for immunoglobulins in regulating the immune response to the pathogen (14). Indeed, enhanced susceptibility to M. tuberculosis that is associated with aberrant lung cytokine production has been observed in agammaglobulinemic AID Ϫ/Ϫ S Ϫ/Ϫ mice (15). Treatment with a number of monoclonal antibodies against specific mycobacterial components has been shown to be protective against challenge with M. tuberculosis (16), and coating M. tuberculosis bacilli with a monoclonal antibody of the IgG3 isotype against arabinomannan attenuated virulence relative to uncoated bacilli (17).The present study explored the effects of B cell depletion in the cynomolgus macaque model of tuberculosis (TB) (18,19). Cynomolgus macaques recapitulate the full infection outcome and pathological spectrum of M. tuberculosis infection seen in humans. Like humans, macaques are extremely variable in their response to M. tuberculosis infection, with substantial animal-toanimal and within-animal variability in terms of immune responses and bacterial numbers. We published previously that CFU per granuloma varied from 0 to 10 5 within individual animals, and T cell responses were equally variable in granulomas from an individual animal. This variability suggests that local mechanisms of control of infection, and the immune responses necessary for control of M. tuberculosis differ from granuloma to

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Section: Discussionmentioning

confidence: 99%

“…Rituximab is in clinical use for the treatment of certain B cell lymphomas and autoimmune conditions such as systemic lupus erythematosis, rheumatoid arthritis, and multiple sclerosis (21). B cells are thought to be depleted via antibody-dependent cell-mediated cytotoxicity mode of clearance by natural killer cells (22).…”

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confidence: 99%

Effects of B Cell Depletion on Early Mycobacterium tuberculosis Infection in Cynomolgus Macaques

et al. 2016

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“…Both CD19 and CD20 mAbs significantly suppressed disease severity in a myelin-induced, B cell-dependent EAE model (29). Intriguingly, CD19 mAb surpassed CD20 mAb in disease alleviation, suggesting that autoreactive ASCs targeted by CD19 mAb (but not CD20 mAb) likely impact disease severity.…”

Section: G Rowing Evidence Suggests That B Cells and Abs Play An Impomentioning

confidence: 93%

“…A B cell-dependent EAE model was used to study the impact of CD19 and CD20 mAb treatment on disease progression (29). hCD19Tg mice were treated with a single 250-mg dose of either an anti-human CD19 (MEDI551) or an anti-mouse CD20 mAb (MB20-11) at day 7 after rhMOG immunization (Fig.…”

Section: Cd19 Mab Is More Effective Than Cd20 Mab In Suppressing Eaementioning

confidence: 99%

Autoreactive CD19+CD20− Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis

Chen

Ireland

Davis

et al. 2016

The Journal of Immunology

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The contribution of autoantibody-producing plasma cells in multiple sclerosis (MS) remains unclear. Anti-CD20 B cell depletion effectively reduces disease activity in MS patients, but it has a minimal effect on circulating autoantibodies and oligoclonal bands in the cerebrospinal fluid. Recently we reported that MEDI551, an anti-CD19 mAb, therapeutically ameliorates experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. MEDI551 potently inhibits pathogenic adaptive immune responses, including depleting autoantibody-producing plasma cells. In the present study, we demonstrated that CD19 mAb treatment ameliorates EAE more effectively than does CD20 mAb. Myelin oligodendrocyte glycoprotein–specific Abs and short-lived and long-lived autoantibody-secreting cells were nearly undetectable in the CD19 mAb–treated mice, but they remained detectable in the CD20 mAb–treated mice. Interestingly, residual disease severity in the CD20 mAb–treated animals positively correlated with the frequency of treatment-resistant plasma cells in the bone marrow. Of note, treatment-resistant plasma cells contained a substantial proportion of CD19+CD20− plasma cells, which would have otherwise been targeted by CD19 mAb. These data suggested that CD19+CD20− plasma cells spared by anti-CD20 therapy likely contribute to residual EAE severity by producing autoreactive Abs. In patients with MS, we also identified a population of CD19+CD20− B cells in the cerebrospinal fluid that would be resistant to CD20 mAb treatment.

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“…B cells are critical for the presentation of self-antigens and production of autoantibodies, and depleting B cells reduced disease in preclinical models of T1D and MS (Hu et al 2007;Monson et al 2011). …”

Section: Immune Tolerance and Autoimmunitymentioning

confidence: 99%

Current and Future Immunomodulation Strategies to Restore Tolerance in Autoimmune Diseases

Bluestone

Bour-Jordan

2012

Cold Spring Harbor Perspectives in Biology

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Autoimmune diseases reflect a breakdown in self-tolerance that results from defects in thymic deletion of potentially autoreactive T cells (central tolerance) and in T-cell intrinsic and extrinsic mechanisms that normally control potentially autoreactive T cells in the periphery ( peripheral tolerance). The mechanisms leading to autoimmune diseases are multifactorial and depend on a complex combination of genetic, epigenetic, molecular, and cellular elements that result in pathogenic inflammatory responses in peripheral tissues driven by self-antigen-specific T cells. In this article, we describe the different checkpoints of tolerance that are defective in autoimmune diseases as well as specific events in the autoimmune response which represent therapeutic opportunities to restore long-term tolerance in autoimmune diseases. We present evidence for the role of different pathways in animal models and the therapeutic strategies targeting these pathways in clinical trials in autoimmune diseases.

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Rituximab Therapy Reduces Organ-Specific T Cell Responses and Ameliorates Experimental Autoimmune Encephalomyelitis

Cited by 73 publications

References 22 publications

Effects of B Cell Depletion on Early Mycobacterium tuberculosis Infection in Cynomolgus Macaques

Effects of B Cell Depletion on Early Mycobacterium tuberculosis Infection in Cynomolgus Macaques

Autoreactive CD19+CD20− Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis

Current and Future Immunomodulation Strategies to Restore Tolerance in Autoimmune Diseases

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