Glutamine Uptake and Immunomodulation: An Overview

Frauwirth, Kenneth A.

doi:10.1007/978-1-4939-1932-1_4

Cited by 1 publication

(2 citation statements)

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“…All dosing groups significantly alleviated disease compared to the PBS control according to clinical disease score (Figure 8A) and clinical score AUC (Figure 8C). The cSAgA PLP:LABL dose of 50 nmol PLP 139-151 caused a significant reduction in clinical score on the greatest number of days (days [12][13][14][15][16][17][18] and exhibited the greatest reduction in clinical score AUC compared to PBS (p<0.001). Therefore, a cSAgA PLP:LABL dose of 50 nmol PLP 139-151 was selected for studies going forward.…”

Section: Preclinical Eae Studiesmentioning

confidence: 99%

“…[3][4][5][6] Activation of naïve T cells against autoantigen requires two signals from an antigen presenting cell (APC): (1) primary antigenic signal delivered through the major histocompatibility complex (MHC) on the APC to the T cell receptor (TCR) on the T cell, and (2) secondary costimulatory signal (i.e., CD80/CD86) delivered to the cognate receptor (i.e., CD28) on the T cell. [7][8][9][10][11][12][13][14][15] B cells, as professional APCs that possess antigen specificity and immunological memory, play a particularly pivotal role in immune regulation. [16][17][18] Indeed, loss of B cell tolerance has been implicated in numerous autoimmune diseases.…”

Section: Introductionmentioning

confidence: 99%

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Multivalent Soluble Antigen Arrays Exhibit High Avidity Binding and Modulation of B Cell Receptor-Mediated Signaling to Drive Efficacy against Experimental Autoimmune Encephalomyelitis

et al. 2017

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A pressing need exists for antigen-specific immunotherapies (ASIT) that induce selective tolerance in autoimmune disease while avoiding deleterious global immunosuppression. Multivalent soluble antigen arrays (SAgA), consisting of a hyaluronic acid (HA) linear polymer backbone cografted with multiple copies of autoantigen (PLP) and cell adhesion inhibitor (LABL) peptides, are designed to induce tolerance to a specific multiple sclerosis (MS) autoantigen. Previous studies established that hydrolyzable SAgA, employing a degradable linker to codeliver PLP and LABL, was therapeutic in experimental autoimmune encephalomyelitis (EAE) in vivo and exhibited antigen-specific binding with B cells, targeted the B cell receptor (BCR), and dampened BCR-mediated signaling in vitro. Our results pointed to sustained BCR engagement as the SAgA therapeutic mechanism, so we developed a new version of the SAgA molecule using nonhydrolyzable conjugation chemistry, hypothesizing it would enhance and maintain the molecule's action at the cell surface to improve efficacy. "Click SAgA" (cSAgA) uses hydrolytically stable covalent conjugation chemistry (Copper-catalyzed Azide-Alkyne Cycloaddition (CuAAC)) rather than a hydrolyzable oxime bond to attach PLP and LABL to HA. We explored cSAgA B cell engagement and modulation of BCR-mediated signaling in vitro through flow cytometry binding and calcium flux signaling assays. Indeed, cSAgA exhibited higher avidity B cell binding and greater dampening of BCR-mediated signaling than hydrolyzable SAgA. Furthermore, cSAgA exhibited significantly enhanced in vivo efficacy compared to hydrolyzable SAgA, achieving equivalent efficacy at one-quarter of the dose. These results indicate that nonhydrolyzable conjugation increased the avidity of cSAgA to drive in vivo efficacy through modulated BCR-mediated signaling.

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