Subclinical CNS Inflammation as Response to a Myelin Antigen in Humanized Mice

Zayoud, Morad; Malki, Khalifa El; Frauenknecht, Katrin; Trinschek, Bettina; Kloos, Luise; Karram, Khalad; Wanke, Florian; Georgescu, Julia; Hartwig, Udo F.; Sommer, Clemens; Jonuleit, Helmut; Waisman, Ari; Kurschus, Florian C.

doi:10.1007/s11481-013-9466-4

Cited by 22 publications

(36 citation statements)

References 47 publications

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“…1C). Using this stepwise approach, 3 HLA-A2 (MOG 181-189 , MOG 156-164 , and MAG 509-517 ) and 2 HLA-A3 (PLP [45][46][47][48][49][50][51][52][53] and CNP [54][55][56][57][58][59][60][61][62][63] ) CD8 + T cell epitopes were validated (Fig. 1C).…”

Section: Resultsmentioning

confidence: 99%

“…To our knowledge, MOG 181-189 :HLA-A2 and CNP [54][55][56][57][58][59][60][61][62][63] :HLA-A3 have not been described in humans. Of interest, MOG 181-189 was previously reported as a CD8 + T cell epitope in HLA-A2 transgenic mice (21), and both the MOG 181-189 and PLP [45][46][47][48][49][50][51][52][53] epitopes were pathogenic in humanized mouse models of EAE (21,22). A potential pathogenic role for these populations is supported by the finding that all of the isolated myelin-specific CD8 + T cell populations produced significant amounts of IFNγ, TNFα, IL-2, GM-CSF, and CD107a (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

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Anti-CD20 therapy depletes activated myelin-specific CD8⁺T cells in multiple sclerosis

Sabatino

Wilson

Calabresi³

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

103

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CD8 + T cells are believed to play an important role in multiple sclerosis (MS), yet their role in MS pathogenesis remains poorly defined. Although myelin proteins are considered potential autoantigenic targets, prior studies of myelin-reactive CD8 + T cells in MS have relied on in vitro stimulation, thereby limiting accurate measurement of their ex vivo precursor frequencies and phenotypes. Peptide:MHC I tetramers were used to identify and validate 5 myelin CD8 + T cell epitopes, including 2 newly described determinants in humans. The validated tetramers were used to measure the ex vivo precursor frequencies and phenotypes of myelin-specific CD8 + T cells in the peripheral blood of untreated MS patients and HLA allele-matched healthy controls. In parallel, CD8 + T cell responses against immunodominant influenza epitopes were also measured. There were no differences in ex vivo frequencies of tetramerpositive myelin-specific CD8 + T cells between MS patients and control subjects. An increased proportion of myelin-specific CD8 + T cells in MS patients exhibited a memory phenotype and expressed CD20 compared to control subjects, while there were no phenotypic differences observed among influenza-specific CD8 + T cells. Longitudinal assessments were also measured in a subset of MS patients subsequently treated with anti-CD20 monoclonal antibody therapy. The proportion of memory and CD20 + CD8 + T cells specific for certain myelin but not influenza epitopes was significantly reduced following anti-CD20 treatment. This study, representing a characterization of unmanipulated myelin-reactive CD8 + T cells in MS, indicates these cells may be attractive targets in MS therapy. multiple sclerosis | CD8 + T cells | myelin antigen | anti-CD20 therapy

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Anti-CD20 therapy depletes activated myelin-specific CD8⁺T cells in multiple sclerosis

Sabatino

Wilson

Calabresi³

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

103

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“…Human T cells (CD4 + and CD8 + ) were specific to the soluble domain of myelin oligodendrocyte glycoprotein and produced proinflammatory cytokinesZayoud et al (2013)SLENSG mice engrafted with FL HSCs and injected with pristaneHumanized mice recapitulated key clinical and immunological features of SLE including production of human anti-nuclear autoantibodies, lupus nephritis, pulmonary serositis, decreased human lymphocytes in peripheral blood, hyperactivated B and T cells and increased proinflammatory cytokinesGunawan et al (2017)SjSNSG mice engrafted with PBMCs from patients with SjSMice engrafted with PBMCs from SjS patients had elevated levels of cytokines, particularly IFN-γ and IL-10. Histological analysis showed signs of inflammation within the lacrimal and salivary glands of mice engrafted with SjS.…”

Section: Models Of Human Diseases Established On Humanized Micementioning

confidence: 99%

Humanized Mice as Unique Tools for Human-Specific Studies

Yong

Her

Chen

2018

Arch. Immunol. Ther. Exp.

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With an increasing human population, medical research is pushed to progress into an era of precision therapy. Humanized mice are at the very heart of this new forefront where it is acutely required to decipher human-specific disease pathogenesis and test an array of novel therapeutics. In this review, “humanized” mice are defined as immunodeficient mouse engrafted with functional human biological systems. Over the past decade, researchers have been conscientiously making improvements on the development of humanized mice as a model to closely recapitulate disease pathogenesis and drug mechanisms in humans. Currently, literature is rife with descriptions of novel and innovative humanized mouse models that hold a significant promise to become a panacea for drug innovations to treat and control conditions such as infectious disease and cancer. This review will focus on the background of humanized mice, diseases, and human-specific therapeutics tested on this platform as well as solutions to improve humanized mice for future clinical use.

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“…Although human T cells obtained from spleens of humanized NSG mice were shown to mount robust MOG-specific immune responses, the classic signs of EAE (e.g. paralysis and paresis) were not observed in this novel model (187). Nevertheless, this new model of myelin-induced CNS inflammation will be a valuable tool to assess new drug therapies targeted at T cell trafficking and inflammatory cytokine production in a humanized system in vivo.…”

Section: Use Of Humanized Mice To Study Autoimmune and Inflammatory Dmentioning

confidence: 87%

“…Although these models have been instrumental in revealing important cellular and molecular pathways responsible for induction of CNS inflammation, they did not recapitulate human MS. An obvious reason for the differences is that CNS inflammation in mice is mediated by “mouse-specific” effector cell mechanisms. More recently, investigators have utilized the Hu-PBL-NSG model to produce a subclinical autoimmune model of encephalomyelitis (187). For this model, investigators co-transferred myelin oligodendrocyte glycoprotein (MOG)-pulsed, human DCs together with healthy human PBMCs obtained from the same donor as DCs into NSG mice.…”

Section: Use Of Humanized Mice To Study Autoimmune and Inflammatory Dmentioning

confidence: 99%

Use of Humanized Mice to Study the Pathogenesis of Autoimmune and Inflammatory Diseases

Koboziev

Jones-Hall

Valentine

et al. 2015

Inflammatory Bowel Diseases

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Animal models of disease have been used extensively by the research community for the past several decades to better understand the pathogenesis of different diseases as well as assess the efficacy and toxicity of different therapeutic agents. Retrospective analyses of numerous preclinical intervention studies using mouse models of acute and chronic inflammatory diseases reveal a generalized failure to translate promising interventions or therapeutics into clinically-effective treatments in patients. Although several possible reasons have been suggested to account for this generalized failure to translate therapeutic efficacy from the laboratory bench to the patient’s bedside, it is becoming increasingly apparent that the mouse immune system may not adequately recapitulate the immuno-pathological mechanisms observed in human diseases. Indeed, it is well-known that >80 major differences exist between mouse and human immunology; all of which contribute to significant differences in immune system development, activation and responses to challenges in innate and adaptive immunity. This inconvenient reality has prompted investigators to attempt to humanize the mouse immune system in order to address important, human-specific questions that are impossible to study in patients. The successful long-term engraftment of human hemato-lymphoid cells in mice would provide investigators with a relatively inexpensive, small animal model to study clinically-relevant mechanisms as well as facilitate the evaluation of human-specific therapies in vivo. The discovery that targeted mutation of the IL-2 receptor common gamma chain in lymphopenic mice allows for the long-term engraftment of functional human immune cells has advanced greatly our ability to humanize the mouse immune system. The objective of this review is to present a brief overview of the recent advances that have been made in the development and use of humanized mice with special emphasis on autoimmune and chronic inflammatory diseases. In addition, we discuss current challenges and possible solutions for utilizing these unique mouse models to define the human-specific immuno-pathological mechanisms responsible for the induction and perpetuation of chronic gut inflammation.

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Subclinical CNS Inflammation as Response to a Myelin Antigen in Humanized Mice

Cited by 22 publications

References 47 publications

Anti-CD20 therapy depletes activated myelin-specific CD8⁺T cells in multiple sclerosis

Anti-CD20 therapy depletes activated myelin-specific CD8⁺T cells in multiple sclerosis

Humanized Mice as Unique Tools for Human-Specific Studies

Use of Humanized Mice to Study the Pathogenesis of Autoimmune and Inflammatory Diseases

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Subclinical CNS Inflammation as Response to a Myelin Antigen in Humanized Mice

Cited by 22 publications

References 47 publications

Anti-CD20 therapy depletes activated myelin-specific CD8+T cells in multiple sclerosis

Anti-CD20 therapy depletes activated myelin-specific CD8+T cells in multiple sclerosis

Humanized Mice as Unique Tools for Human-Specific Studies

Use of Humanized Mice to Study the Pathogenesis of Autoimmune and Inflammatory Diseases

Contact Info

Product

Resources

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Anti-CD20 therapy depletes activated myelin-specific CD8⁺T cells in multiple sclerosis

Anti-CD20 therapy depletes activated myelin-specific CD8⁺T cells in multiple sclerosis