Blockade of CD127 Exerts a Dichotomous Clinical Effect in Marmoset Experimental Autoimmune Encephalomyelitis

Dunham, Jordon; Lee, Li-Fen; Driel, Nikki van; Laman, Jon D.; Ni, Irene; Zhai, Wenwu; Tu, Guanghuan; Lin, John; Bauer, Jan; Hart, Bert A. ’t; Kap, Yolanda S.

doi:10.1007/s11481-015-9629-6

Cited by 22 publications

(32 citation statements)

References 21 publications

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“…This formulation induces a progressive MS-like disease characterized by MS-like pathology in the white and cortical gray matter of brain and spinal cord. 11, 12 We first analyzed using RNAseq which B-cell genes relevant for T–B communication were expressed at higher level after LCV infection. For these experiments, we used EBV from the cell line B95-8.…”

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confidence: 99%

Analysis of the cross‐talk of Epstein–Barr virus‐infected B cells with T cells in the marmoset

et al. 2017

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Despite the well-known association of Epstein–Barr virus (EBV), a lymphocryptovirus (LCV), with multiple sclerosis, a clear pathogenic role for disease progression has not been established. The translationally relevant experimental autoimmune encephalomyelitis (EAE) model in marmoset monkeys revealed that LCV-infected B cells have a central pathogenic role in the activation of T cells that drive EAE progression. We hypothesized that LCV-infected B cells induce T-cell functions relevant for EAE progression. In the current study, we examined the ex vivo cross-talk between lymph node mononuclear cells (MNCs) from EAE marmosets and (semi-) autologous EBV-infected B-lymphoblastoid cell lines (B-LCLs). Results presented here demonstrate that infection with EBV B95-8 has a strong impact on gene expression profile of marmoset B cells, particularly those involved with antigen processing and presentation or co-stimulation to T cells. At the cellular level, we observed that MNC co-culture with B-LCLs induced decrease of CCR7 expression on T cells from EAE responder marmosets, but not in EAE monkeys without clinically evident disease. B-LCL interaction with T cells also resulted in significant loss of CD27 expression and reduced expression of IL-23R and CCR6, which coincided with enhanced IL-17A production. These results highlight the profound impact that EBV-infected B-LCL cells can have on second and third co-stimulatory signals involved in (autoreactive) T-cell activation.

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confidence: 99%

Analysis of the cross‐talk of Epstein–Barr virus‐infected B cells with T cells in the marmoset

et al. 2017

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“…Importantly, EBV-infected B cells, which are the requisite APCs for the late-acting autoaggressive CTLs in the rhMOG/CFA marmoset EAE model, produce high levels of IL-7. These findings prompted us to test a new chimeric IgG1κ mAb against human CD127 in marmosets immunized with MOG34-56/IFA (Dunham et al, 2016). Unexpectedly, we observed a dichotomous clinical effect of the treatment.…”

Section: Treatments Targeting T Cellsmentioning

confidence: 80%

“…Currently research is being undertaken for more in-depth pathological characterization of the marmoset EAE model. Preliminary results indicate that, in addition to grey-matter pathology, many of the desired pathological features of MS, not reflected in rodent EAE, are replicated in the marmoset EAE models (Dunham et al, 2016).…”

Section: Modeling Response To Myelin Injurymentioning

confidence: 91%

The common marmoset (<i>Callithrix jacchus</i>): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain

et al. 2016

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Abstract. The increasing prevalence of chronic autoimmune-mediated inflammatory disorders (AIMIDs) in aging human populations creates a high unmet need for safe and effective medications. However, thus far the translation of pathogenic concepts developed in animal models into effective treatments for the patient has been notoriously difficult. The main reason is that currently used mouse-based animal models for the pipeline selection of promising new treatments were insufficiently predictive for clinical success. Regarding the high immunological similarity between human and non-human primates (NHPs), AIMID models in NHPs can help to bridge the translational gap between rodent and man. Here we will review the preclinical relevance of the experimental autoimmune encephalomyelitis (EAE) model in common marmosets (Callithrix jacchus), a small-bodied neotropical primate. EAE is a generic AIMID model projected on the human autoimmune neuro-inflammatory disease multiple sclerosis (MS).

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“…A recent study shows that the immune response elicited by the immunization with MOG34–56/IFA is qualitatively heterogeneous, possibly reflecting genetic differences outside the MHC region between the monkeys (67). We observed only in high responder monkeys, which were characterized by a fast EAE progression rate, a clinical effect of IL-7 receptor blockade with an anti-human CD127 mAb.…”

Section: Unraveling the Atypical Marmoset Eae Model Induced With Mog3mentioning

confidence: 99%

“…Moreover, we observed reduced expression on T cells of CD127, the receptor of IL-7 on T cells, associated with increased expression of CD95 and PD1 (CD279). In this context, it is interesting to note that blocking of the IL-7R with an anti-human CD127 mAb abrogated fast EAE development in the MOG34–56/IFA model (67). The above-described cellular changes induced in LCV-infected B cells may need to be viewed as an immune escape strategy of the virus (71, 72).…”

Section: B-t Cross Talk In the Mog34–56/ifa Modelmentioning

confidence: 99%

A B Cell-Driven Autoimmune Pathway Leading to Pathological Hallmarks of Progressive Multiple Sclerosis in the Marmoset Experimental Autoimmune Encephalomyelitis Model

et al. 2017

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The absence of pathological hallmarks of progressive multiple sclerosis (MS) in commonly used rodent models of experimental autoimmune encephalomyelitis (EAE) hinders the development of adequate treatments for progressive disease. Work reviewed here shows that such hallmarks are present in the EAE model in marmoset monkeys (Callithrix jacchus). The minimal requirement for induction of progressive MS pathology is immunization with a synthetic peptide representing residues 34–56 from human myelin oligodendrocyte glycoprotein (MOG) formulated with a mineral oil [incomplete Freund’s adjuvant (IFA)]. Pathological aspects include demyelination of cortical gray matter with microglia activation, oxidative stress, and redistribution of iron. When the peptide is formulated in complete Freund’s adjuvant, which contains mycobacteria that relay strong activation signals to myeloid cells, oxidative damage pathways are strongly boosted leading to more intensive pathology. The proven absence of immune potentiating danger signals in the MOG34–56/IFA formulation implies that a narrow population of antigen-experienced T cells present in the monkey’s immune repertoire is activated. This novel pathway involves the interplay of lymphocryptovirus-infected B cells with MHC class Ib/Caja-E restricted CD8+ CD56+ cytotoxic T lymphocytes.

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Blockade of CD127 Exerts a Dichotomous Clinical Effect in Marmoset Experimental Autoimmune Encephalomyelitis

Cited by 22 publications

References 21 publications

Analysis of the cross‐talk of Epstein–Barr virus‐infected B cells with T cells in the marmoset

Analysis of the cross‐talk of Epstein–Barr virus‐infected B cells with T cells in the marmoset

The common marmoset (<i>Callithrix jacchus</i>): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain

A B Cell-Driven Autoimmune Pathway Leading to Pathological Hallmarks of Progressive Multiple Sclerosis in the Marmoset Experimental Autoimmune Encephalomyelitis Model

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Blockade of CD127 Exerts a Dichotomous Clinical Effect in Marmoset Experimental Autoimmune Encephalomyelitis

Cited by 22 publications

References 21 publications

Analysis of the cross‐talk of Epstein–Barr virus‐infected B cells with T cells in the marmoset

Analysis of the cross‐talk of Epstein–Barr virus‐infected B cells with T cells in the marmoset

The common marmoset (&lt;i&gt;Callithrix jacchus&lt;/i&gt;): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain

A B Cell-Driven Autoimmune Pathway Leading to Pathological Hallmarks of Progressive Multiple Sclerosis in the Marmoset Experimental Autoimmune Encephalomyelitis Model

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The common marmoset (<i>Callithrix jacchus</i>): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain