Multiple sclerosis (MS) is a chronic demyelinating disease with prominent axon dysfunction. Our previous studies in an MS mouse model, experimental autoimmune encephalomyelitis (EAE), demonstrated that major histocompatibility complex Class II constructs can reverse clinical signs of EAE. These constructs block binding and downstream signaling of macrophage migration inhibitory factors (MIF-1/2) through CD74, thereby inhibiting phosphorylation of extracellular signal-regulated kinase (ERK) activation and tissue inflammation and promoting remyelination. To directly assess the effects of a novel third generation construct, DRhQ, on axon integrity in EAE, we compared axon conduction properties using electrophysiology on corpus callosum slices and optic nerves. By using two distinct white matter (WM) tracts, we aimed to assess the impact of the EAE and the benefit of DRhQ on myelinated and unmyelinated axons as well as to test the clinical value of DRhQ on demyelinating lesions in CC and optic myelitis. Our study found that EAE altered axon excitability, delayed axon conduction and slowed spatiotemporal summation correlated with diffuse astrocyte and microglia activation. Because MS predisposes patients to stroke, we also investigated and showed that vulnerability to WM ischemia is increased in the EAE MS mouse model. Treatment with DRhQ after the onset of EAE drastically inhibited microglial and astrocyte activation, improved functional integrity of the myelinated axons and enhanced recovery after ischemia. These results demonstrate that DRhQ administered after the onset of EAE promotes WM integrity and function, and reduces subsequent vulnerability to ischemic injury, suggesting important therapeutic potential for treatment of progressive MS.

2020-08-01·Cellular Immunology

Surviving the storm: Dealing with COVID-19

Letter

作者: Offner, Halina ; Meza-Romero, Roberto ; Vandenbark, Arthur A

A correspondence that discusses the development of a second generation bifunctional drug called DRhQ that can simultaneously bind to and inhibit both the TCR and CD74 through distinct regions of the construct.DRhQ is comprised of the HLA-DRa1 domain with an L50Q amino acid substitution (to enhance binding afinity for CD74) linked to an autoantigen peptide (myelin oligodendroglial cell glycoprotein, i.e. MOG-35-55 peptide)(Fig. 1)As partial TCR agonists these constructs, containing various disease-associated MHC and antigenic peptide components, could indeed inhibit MHC-restricted antigen specific T cells, but translation of RTL1000 for human use in a Phase 1 clin. trial(showing safety and tolerability) required MHC-matched recipients.Thus, the simpler DRhQ construct was designed, retaining just the conserved-in-human DRa1 domain (without the polymorphic HLA-DRβ1 domain) linked to the MOG-35-55 peptide extension, with the added benefit that it can be administered to all recipients without need for tissue type matching.This has enabled use of the DRα1-MOG-35-55 construct to reverse ongoing neuroinflammation and disease signs in animal models of multiple sclerosis, stroke, methamphetamine disorders and traumatic brain injury.These and other studies ([9-11]& unpublished data) revealed down-regulation of multiple proinflammatory components driven by both innate and adaptive immune responses that also contribute to the SARS-CoV-2 cytokine storm, including complement receptor C5aR1, platelet activation, IL-1β, IL-2, IL-6,TNF-αa, CCR2(receptor for CCL2) and CXCR2.Of further importance, a partial HLA-DP RTL construct could inhibit activated pleural T cell infiltrates from patients with beryllium-induced lung fibroma [12], suggesting more-directly-relevant activity that could be potentially beneficial as a treatment of COVID-19 patients with ARDS.Development of new generation immunol. based cytokinestorm inhibitors remains an important endeavor.Even if a successful vaccine is developed for COVID-19 patients, there will be ongoing mortality in vulnerable populations after vaccination as has been observed in flu virus and other current or future coronavirus infections as well as those with sepsis.In these conditions, resolution or chronicity of disease depends upon the strength of regulatory immune processes which appear to be compromised in COVID-19 patients that develop ARDS.To this end, the DRhQ construct could lend a helping hand.

2020-07-01·CNS Neuroscience & Therapeutics2区 · 医学

Spleen participation in partial MHC class II construct neuroprotection in stroke

2区 · 医学

ReviewOA

作者: Brown, John ; Borlongan, Cesar V. ; Lee, Jea‐Young ; Kingsbury, Chase ; Vandenbark, Arthur A. ; Offner, Halina ; Meza‐Romero, Roberto

AbstractPathological progression of stroke in the peripheral and central nervous systems (PNS and CNS) is characterized by multiple converging signalling pathways that exacerbate neuroinflammation‐mediated secondary cell death. This creates a need for a novel type of immunotherapy capable of simultaneously lowering the synergistic inflammatory responses in the PNS and CNS, specifically the spleen and brain. Previously, we demonstrated that partial major histocompatibility complex (MHC) class II constructs can be administered subcutaneously to promote histological and behavioural effects that alleviate common symptoms found in a murine model of transient stroke. This MHC class II manipulates T cell cytokine expression in both PNS and CNS, resulting in dampened inflammation. In our long‐standing efforts towards translational research, we recently demonstrated that a potent next generation mouse‐based partial MHC class II construct named DRmQ (DRa1L50Q‐mMOG‐35‐55) similarly induces neuroprotection in stroke rats, replicating the therapeutic effects of the human homolog as DRhQ (DRa1L50Q‐human (h)MOG‐35‐55) in stroke mice. Our preclinical studies showed that DRmQ reduces motor deficits, infarct volume and peri‐infarct cell loss by targeting inflammation in this second species. Moreover, we provided mechanistic support in both animal studies that partial MHC class II constructs effectively modulate the spleen, an organ which plays a critical role in modulating secondary cell death. Together, these preclinical studies satisfy testing the constructs in two stroke models, which is a major criterion of the Stroke Therapy Academic Industry Roundtable (STAIR) criteria and a key step in effectively translating this drug to the clinic. Additional translational studies, including dose‐response and larger animal models may be warranted to bring MHC class II constructs closer to the clinic.

100 项与 DRalpha1-hMOG-35-55 (Virogenomics Biodevelopment) 相关的药物交易

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