Dataset Information

Systemic Administration of Acazicolcept, a Dual CD28 and Inducible T cell Costimulator Inhibitor, Ameliorates Experimental Autoimmune Uveitis.

ABSTRACT:

Purpose

Combined inhibition of CD28 and inducible T cell costimulator (ICOS) pathways with acazicolcept (ALPN-101) represents a potential new treatment for uveitis. Here, we evaluate preclinical efficacy using experimental autoimmune uveitis (EAU) in Lewis rats.

Methods

Efficacy was tested in 57 Lewis rats treated with either systemic (subcutaneous) or local (intravitreal) administration of acazicolcept and compared to treatment with a matched Fc-only control or corticosteroid. Impact of treatment on uveitis was assessed using clinical scoring, optical coherence tomography (OCT), and histology. Ocular effector T cell populations were determined using flow cytometry, and multiplex ELISA used to measure aqueous cytokine concentrations.

Results

When compared to Fc control treatment, systemic acazicolcept led to statistically significant decreases in clinical score (P < 0.01), histologic score (P < 0.05), and number of ocular CD45+ cells (P < 0.01). Number of ocular CD4+ and CD8+ T cells expressing IL-17A+ and IFNγ+ were also decreased with statistical significance (P < 0.01). Similar results were achieved with corticosteroids. Intravitreal acazicolcept decreased inflammation scores when compared to untreated fellow eyes and to Fc control treated eyes, although not statistically significant. Systemic toxicity, measured by weight loss, occurred in the corticosteroid-treated, but not in the acazicolcept-treated animals.

Conclusions

Systemic treatment with acazicolcept statistically significantly suppressed EAU. Acazicolcept was well-tolerated without the weight loss associated with corticosteroids. Acazicolcept may be an effective alternative to corticosteroids for use in treating autoimmune uveitis. Additional studies are needed to clarify the optimal dose and route for use in humans.

Translational relevance

We show that T cell costimulatory blockade could be an effective mechanism for treating uveitis.

SUBMITTER: Wilson L

PROVIDER: S-EPMC10064916 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

Systemic Administration of Acazicolcept, a Dual CD28 and Inducible T cell Costimulator Inhibitor, Ameliorates Experimental Autoimmune Uveitis.

Wilson Leslie L Lewis Katherine E KE Evans Lawrence S LS Dillon Stacey R SR Pepple Kathryn L KL

Translational vision science & technology 20230301 3

<h4>Purpose</h4>Combined inhibition of CD28 and inducible T cell costimulator (ICOS) pathways with acazicolcept (ALPN-101) represents a potential new treatment for uveitis. Here, we evaluate preclinical efficacy using experimental autoimmune uveitis (EAU) in Lewis rats.<h4>Methods</h4>Efficacy was tested in 57 Lewis rats treated with either systemic (subcutaneous) or local (intravitreal) administration of acazicolcept and compared to treatment with a matched Fc-only control or corticosteroid. Im ...[more]

PMID: 36976157

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Project description:BackgroundResolution of inflammation is an active and regulated process that leads to the clearance of cell debris and immune cells from the challenged tissue, facilitating the recovery of homeostasis. This physiological response is coordinated by endogenous bioactive lipids known as specialized pro-resolving mediators (SPMs). When resolution fails, inflammation becomes uncontrolled leading chronic inflammation and tissue damage, as occurs in multiple sclerosis (MS).MethodsSPMs and the key biosynthetic enzymes involved in SPM production were analysed by metabololipidomics and qPCR in active brain lesions, serum and peripheral blood mononuclear cells (PBMC) of MS patients as well as in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE). We also tested the therapeutic actions of the SPM coined Maresin-1 (MaR1) in EAE mice and studied its impact on inflammation by doing luminex and flow cytometry analysis.ResultsWe show that levels of MaR1 and other SPMs were below the limit of detection or not increased in the spinal cord of EAE mice, whereas the production of pro-inflammatory eicosanoids was induced during disease progression. Similarly, we reveal that SPMs were undetected in serum and active brain lesion samples of MS patients, which was linked to impaired expression of the enzymes involved in the biosynthetic pathways of SPMs. We demonstrate that exogenous administration of MaR1 in EAE mice suppressed the protein levels of various pro-inflammatory cytokines and reduced immune cells counts in the spinal cord and blood. MaR1 also decreased the numbers of Th1 cells but increased the accumulation of regulatory T cells and drove macrophage polarization towards an anti-inflammatory phenotype. Importantly, we provide clear evidence that administration of MaR1 in mice with clinical signs of EAE enhanced neurological outcomes and protected from demyelination.ConclusionsThis study reveals that there is an imbalance in the production of SPMs in MS patients and in EAE mice, and that increasing the bioavailability of SPMs, such as MaR1, minimizes inflammation and mediates therapeutic actions. Thus, these data suggest that immunoresolvent therapies, such as MaR1, could be a novel avenue for the treatment of MS.

Dataset Information

Systemic Administration of Acazicolcept, a Dual CD28 and Inducible T cell Costimulator Inhibitor, Ameliorates Experimental Autoimmune Uveitis.

Purpose

Methods

Results

Conclusions

Translational relevance

Publications

Systemic Administration of Acazicolcept, a Dual CD28 and Inducible T cell Costimulator Inhibitor, Ameliorates Experimental Autoimmune Uveitis.

Similar Datasets

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