Tocopherol Emulsions as Functional Autoantigen Delivery Vehicles Evoke Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis

Griffin, J. Daniel; Christopher, Matthew A.; Thati, Sharadvi; Salash, Jean Remy; Pressnall, Melissa M.; Weerasekara, Dhanushka; Lunte, Susan M.; Berkland, Cory

doi:10.1021/acs.molpharmaceut.8b00887

“…Detection of Anti-PLP IgG. PLP-specific IgG titers were assessed in an ELISA format as previously described [47,48]. Briefly, 1µg/mL PLP was dissolved in a pH 9.5 solution of 50 mM NaHCO3.…”

Section: Methodsmentioning

confidence: 99%

“…At the conclusion of the study, serum and whole brain homogenates were collected. Anti-PLP139-151 IgG ELISA was used as previously described [47][48][49] to detect relative autoantibody titers between the periphery (serum) and CNS (homogenized whole brain, Fig. 3f, Supp.…”

Section: Subcutaneous Implantation Of Asids Prevents Eae In Vivomentioning

confidence: 99%

“…Sponges were washed, and bound anti-PLP139-151 IgG was detected with HRP-conjugated anti-mouse IgG.Induction of EAE and TherapeuticStudy. EAE was induced as previously described[47,59] in 4-6 week-old, female SJL/J mice from Envigo Laboratories. Mice were housed under specified, pathogen-free conditions at the University of Kansas with authorization approved under a protocol passed by the University's Institutional Animal Care and Use Committee.…”

mentioning

confidence: 99%

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Antigen-specific immune decoys intercept and exhaust autoimmunity to prevent disease

Griffin

¹

,

Song

²

,

Huang

³

et al. 2019

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Relapsing-remitting patterns of many autoimmune diseases such as multiple sclerosis (MS) are perpetuated by a recurring circuit of adaptive immune cells that amplify in secondary lympho id organs (SLOs) and traffic to compartments where antigen is abundant to elicit damage. Some of the most effective immunotherapies impede the migration of immune cells through this circuit, however, broadly suppressing immune cell migration can introduce life-threatening risks for patients. We developed antigen-specific immune decoys (ASIDs) to mimic tissues targeted in autoimmunity and selectively intercept autoimmune cells to preserve host tissue. Using Experimental Autoimmune Encephalomyelitis (EAE) as a model, we conjugated autoantige n PLP139-151 to a microporous collagen scaffold. By subcutaneously implanting ASIDs after induction but prior to the onset of symptoms, mice were protected from paralysis. ASID impla nts were rich with autoimmune cells, however, reactivity to cognate antigen was substantia lly diminished and apoptosis was prevalent. ASID-implanted mice consistently exhibited engorged spleens when disease normally peaked. In addition, splenocyte antigen-presenting cells were highly activated in response to PLP rechallenge, but CD3+ and CD19+ effector subsets were significantly decreased, suggesting exhaustion. ASID-implanted mice never developed EAE relapse symptoms even though the ASID material had long since degraded, suggesting exhausted autoimmune cells did not recover functionality. Together, data suggested ASIDs were able to sequester and exhaust immune cells in an antigen-specific fashion, thus offering a compelling approach to inhibit the migration circuit underlying autoimmunity.

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“…EAE was induced as previously described [47,59] Detection of Anti-PLP IgG. PLP-specific IgG titers were assessed in an ELISA format as previously described [47,48]. Briefly, 1µg/mL PLP was dissolved in a pH 9.…”

Section: Discussionmentioning

confidence: 99%

Antigen-Specific Immune Decoys Intercept and Exhaust Autoimmunity to Prevent Disease

Griffin

¹

,

Song

²

,

Huang

³

et al. 2019

Preprint

Self Cite

1

0

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Relapsing-remitting patterns of many autoimmune diseases such as multiple sclerosis (MS) are perpetuated by a recurring circuit of adaptive immune cells that amplify in secondary lympho id organs (SLOs) and traffic to compartments where antigen is abundant to elicit damage. Some of the most effective immunotherapies impede the migration of immune cells through this circuit, however, broadly suppressing immune cell migration can introduce life-threatening risks for patients. We developed antigen-specific immune decoys (ASIDs) to mimic tissues targeted in autoimmunity and selectively intercept autoimmune cells to preserve host tissue. Using Experimental Autoimmune Encephalomyelitis (EAE) as a model, we conjugated autoantige n PLP139-151 to a microporous collagen scaffold. By subcutaneously implanting ASIDs after induction but prior to the onset of symptoms, mice were protected from paralysis. ASID impla nts were rich with autoimmune cells, however, reactivity to cognate antigen was substantia lly diminished and apoptosis was prevalent. ASID-implanted mice consistently exhibited engorged spleens when disease normally peaked. In addition, splenocyte antigen-presenting cells were highly activated in response to PLP rechallenge, but CD3+ and CD19+ effector subsets were significantly decreased, suggesting exhaustion. ASID-implanted mice never developed EAE relapse symptoms even though the ASID material had long since degraded, suggesting exhausted autoimmune cells did not recover functionality. Together, data suggested ASIDs were able to sequester and exhaust immune cells in an antigen-specific fashion, thus offering a compelling approach to inhibit the migration circuit underlying autoimmunity.

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“…All protocols were approved through the University’s Institutional Animal Care and Use Committee, and all animals were housed in pathogen-free conditions. EAE induction and treatment schedule were based on methods previously described ( 18 – 20 ). An emulsion was prepared containing 200 μg free PLP in PBS emulsified with Complete Freund’s Adjuvant (CFA) containing 4 mg/ml heat killed M. Tuberculosis strain H37RA.…”

Section: Methodsmentioning

confidence: 99%

Synthetic Cationic Autoantigen Mimics Glatiramer Acetate Persistence at the Site of Injection and Is Efficacious Against Experimental Autoimmune Encephalomyelitis

Song

¹

,

Griffin

²

,

Larson

³

et al. 2021

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A synthetic peptide, K-PLP, consisting of 11-unit poly-lysine (K11) linked via polyethylene glycol (PEG) to proteolipid protein epitope (PLP) was synthesized, characterized, and evaluated for efficacy in ameliorating experimental autoimmune encephalomyelitis (EAE) induced by PLP. K-PLP was designed to mimic the cationic nature of the relapsing-remitting multiple sclerosis treatment, glatiramer acetate (GA). With a pI of ~10, GA is able to form visible aggregates at the site of injection via electrostatic interactions with the anionic extracellular matrix. Aggregation further facilitates the retention of GA at the site of injection and draining lymph nodes, which may contribute to its mechanism of action. K-PLP with a pI of ~11, was found to form visible aggregates in the presence of glycosaminoglycans and persist at the injection site and draining lymph nodes in vivo, similar to GA. Additionally, EAE mice treated with K-PLP showed significant inhibition of clinical symptoms compared to free poly-lysine and to PLP, which are the components of K-PLP. The ability of the poly-lysine motif to retain PLP at the injection site, which increased the local exposure of PLP to immune cells may be an important factor affecting drug efficacy.

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Tocopherol Emulsions as Functional Autoantigen Delivery Vehicles Evoke Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis

Cited by 8 publications

References 60 publications

Antigen-specific immune decoys intercept and exhaust autoimmunity to prevent disease

Antigen-specific immune decoys intercept and exhaust autoimmunity to prevent disease

Antigen-Specific Immune Decoys Intercept and Exhaust Autoimmunity to Prevent Disease

Synthetic Cationic Autoantigen Mimics Glatiramer Acetate Persistence at the Site of Injection and Is Efficacious Against Experimental Autoimmune Encephalomyelitis

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