bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting glutamine metabolism mitigates Foxp3-deficiency mediated disease
Authors: Zhong Yuelin , Hill Charlotte Nicole , Charbonnier Louis-Marie 
Published: August 2023

Abstract
Regulatory T (Treg) cells play a key role in enforcing peripheral immunological tolerance to self-antigens. Foxp3 has been widely described as a master regulator for Treg differentiation and maintenance of their suppressive functions. Upon Foxp3 loss of function mutations, Foxp3-deficient Tregs (ΔTreg) develop in the thymus, however, these cells present impaired suppressive capacity and an effector T cell (Teff)-like phenotype. Among the Teff-like characteristics is the shift in their metabolism towards glycolysis and enhanced mitochondrial respiration. Metabolomic analysis revealed an increase in glutamine consumption. Here, we used 6-diazo-5-oxo-norleucine (DON), a broad inhibitor of glutamine-utilizing enzymes to treat Foxp3 deficient mice (Foxp3ΔeGFPiCre), and observed a significant decrease in Teff cell activation, and IFNγ production from both ΔTreg and Teff cells together with a significant increase in survival. This effect was enhanced when we combined DON treatment with a ΔTreg specific Rictor depletion (Foxp3ΔeGFPiCre RictorΔ/Δ). Given that glutamine is a key amino acid for T cell activation, we evaluated if this was a pan-T cell effect by inducing Treg depletion in Foxp3DTR mice with concomitant DON treatment. Surprisingly, in the absence of Tregs, DON was not able to prevent autoimmune disease. These results suggest that DON mitigates Foxp3-deficiency mediated disease in a ΔTreg dependent manner, by improving their suppressive capacities. We are currently performing metabolomic studies to better understand the role of glutamine usage in ΔTreg, more specifically if glutamine is directed to glutaminolysis, nucleotide or glutathione synthesis and how this contributes to Treg cell loss of function.
NIH grant 1R01AI153174
Nanotechnology-based drug delivery for targeted therapy of autoimmune arthritis improves the therapeutic profile of anti-arthritis drugs
Authors: Moudgil Kamal D , Nanjaiah Hemalatha , Venkatesha Shivaprasad H , Meka Rakeshchandra R 
Published: August 2023

Abstract
Rheumatoid arthritis (RA) is among the major human autoimmune diseases, and it affects over 1 percent of the population. Although many anti-arthritis drugs are available for RA therapy, their long-term use may lead to severe adverse effects. This, combined with high cost of many newer drugs, poses a hurdle for the effective control of RA as well as patient compliance with therapeutic regimens. Therefore, novel treatment modalities are required to overcome these limitations. In this context, we have developed a nanotechnology-based drug delivery system for targeted therapy of arthritic inflammation. Liposomal entrapment of drugs increases their shelf-life in vivo, whereas the display of a joint-homing peptide ligand on liposomal surface aids in guiding them to the site of inflammation. One such peptide (denoted as ART-1) was previously identified by us by phage peptide-display library screening of arthritic Lewis rats. When administered subcutaneously or intravenously, fluorescence-labeled ART-1 shows preferential homing to arthritic joints compared to normal (control) joints. We exploited this drug delivery system for the treatment of experimental arthritis with dexamethasone (Dex) using the rat adjuvant arthritis (AA) model. At the time of onset of AA, rats were treated with liposomal Dex, unpackaged (free) Dex, or the vehicle on alternate days. All rats were observed and graded regularly for arthritis severity. Sera obtained at the terminal step were tested for a panel of enzymes indicating tissue/organ toxicity. Liposomal Dex showed improved therapeutic profile (efficacy/toxicity ratio) over that of free Dex. We propose that this peptide ligand-targeted drug delivery approach can be adapted for effective control of human RA.
“Supported by grants from NIH (R01 AT004321), Veterans Affairs (5 I01 BX002424) and Silo Pharma”
Efficacy and safety of AK111, in patients with active ankylosing spondylitis: results from a randomized, double-blind, placebo-controlled, phase II clinical study
Authors: Li Zhanguo , Xia Yu , Wang Max , Li Baiyong , Ni Xiang , Wang Guoqin , Zhang Li 
Published: August 2023

Abstract

Background
As an inflammatory cytokine that can induce the repair of barrier tissue, IL-17 not only participates in the anti-infection immune response, but also plays a key role in some chronic inflammatory diseases, including Ankylosing spondylitis (AS). Inhibition of IL-17A can reduce the disease activity of AS and reduce joint damage. AK111 is a humanized IgG1 monoclonal antibody against IL-17A.

Methods
A total of 120 patients (male and female) with age ranging from 18 to 75 years were enrolled. There were 4 cohorts (AK111: 75mg, 150mg, 300mg and placebo) in this study. Subjects were randomized in a 1:1:1:1 ratio to receive one dose of AK111 or matching placebo.

Results
The Assessment Of SpondyloArthritis International Society Criteria For 20% Improvement (ASAS20) response rates of AK111 treatment groups at week 16 were 80.6% (25/31), 71.9% (23/32) and 66.7% (20/30) respectively, which were significantly higher than placebo group 37.5% (12/32) (as same as the ASAS 40 response rates of those groups). All dose groups of AK111 can improve ASAS20/ASAS40 response rate at week 16.
125 subjects enrolled in the study. 99(79.2%) subjects experienced at least one treatment-emergent adverse event (TEAE). 63(50.4%) subjects had TEAE related to study drug (TRAE), including 49(52.7%) subjects in AK111 groups and 14(43.8%) subjects in placebo group. The most of TEAE/TRAE were mild (80.6% and 52.7%) and recovered without any intervention. 2(1.6%) subjects with serious adverse event (SAE). Investigator assessed the SAEs were non-related and possible-related to study drug. No death was reported.

Conclusion
AK111 was generally safe and well tolerated, also able to improve ASAS20/ASAS40 response in Chinese subjects with active ankylosing spondylitis.
Impact of Lymphatic Pump Treatment and Methotrexate on Inflammation, Cytokine Production, and Leukocyte Infiltration in a Rat Model of Rheumatoid Arthritis
Authors: Volin Michael V , Suchy Stephen , Zanotti Brian , Emami Rachel , Incrocci Ryan , Del Toro Rosalinda Monroy , Swanson-Mungerson Michelle Anne 
Published: August 2023

Abstract
Rheumatoid Arthritis in autoimmune disease afflicting synovial joints leading to chronic joint damage. While the specific mechanisms have not been fully identified, the immune system and inflammatory factors are actively involved. T cells release cytokines and chemokines, such as TNF-alpha, IL-1 and IL-6, CINC-1 and CINC-2, and B cells produce self-reactive antibodies including rheumatoid factor and anti-citrullinated protein antibodies. All these factors result in a pronounced and aggressive inflammatory response within the joints. Lymphatic pump treatment (LPT) promotes lymphatic flow within the body, causing a flushing out of the immune-complexes and pro-inflammatory cells. Using a rat AIA model, the goal was to determine if LPT in conjunction with methotrexate had a greater impact on rheumatoid arthritis symptoms than methotrexate alone. A 21-day AIA rat study was performed using LPT and methotrexate treatments on days 14–21. Ankle circumference and articular index scores were recorded daily as a measurement of inflammation. ELISAs of arthritic ankles homogenates and serum were used to analyze cytokine, chemokine, and autoantibody concentrations. Immune cell infiltration into the ankles was determined using immunohistochemistry. We found that LPT with methotrexate treatment did not significantly alter ankle circumference, articular index scores, immune cell infiltration, cytokine, chemokine, or antibody concentrations compared to methotrexate alone. Overall, methotrexate combined with LPT treatments on days 14–21 did not significantly alter disease progression, however, it is possible that earlier LPT treatment may have a more significant impact on disease progression.
College of Graduate Studies Biomedical Sciences program at Midwestern University, Downers Grove, IL.
Discovery of a novel orally bioavailable NLRP3 inflammasome inhibitor, TTS-X, for potential treatment of inflammatory bowel disease
Authors: Gao Yingsheng , Li Lin , Pan Shan , Gao You , Zhao Zheng , Wu Di , Sheng Zejuan , Wu Yongqian 
Published: August 2023

Abstract
Inappropriate activation of the NLRP3 inflammasome has been implicated in multiple inflammatory diseases, including inflammatory bowel disease. Herein, we discovered a series of potent and selective NLRP3 inhibitors with non-sulfonylurea analogue. TTS-X, lead compound identified from this series, was found to bind directly to NLRP3 in cells by chemical proteomics study. It exhibited potent and specific inhibition against NLRP3 activation and IL-1β production in human macrophage and whole blood. In addition, in an acute peritonitis model, TTS-X inhibited NLRP3 dependent IL-1β production in a dose-dependent manner. In a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model, it demonstrated significant anti-inflammatory activity after oral administration. Collectively, these results suggest that TTS-X is a potent and oral bioavailable NLRP3 inhibitor with biological activity in vivo. Further characterization of this lead compound is under way for potential treatment of inflammatory bowel disease and other NLRP3-driven diseases
JAK1/2 Inhibitor Suppresses Neuroinflammation in the Thy1 α-Syn Mouse Model of Parkinson’s Disease
Authors: Hong Huixian , Wang Yong , Buckley Jessica A , Zhou Lianna , Trasher Drake , Menard Marissa , Volpicelli-Daley Laura , Standaert David G , Qin Hongwei , Benveniste Etty N 
Published: August 2023

Abstract
Parkinson’s Disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons and accumulation of α-synuclein (α-Syn). Targeting the JAK/STAT pathway to treat PD is under investigation due to its roles in inflammatory cytokine production and activation of immune cells. Striatal injection of sonicated human α-Syn pre-formed fibrils (PFF) enhances immune cell infiltration, phosphorylation of α-Syn and MHC Class II expression in the Thy1 α-Syn model (Thy1-PD). We investigated the effect of inhibiting the JAK/STAT pathway using the JAK1/2 inhibitor, AZD1480, on neuroinflammation. Immunofluorescence staining showed significantly decreased phosphorylation of α-Syn and MHC Class II expression in Thy1-PD mice after AZD1480 treatment. AZD1480 treatment reduced the infiltration of CD4+ T-cells, CD8+ T-cells, CD19+ B-cells and macrophages into the midbrain compared to vehicle-treated PFF mice, as assessed by flow cytometry. Furthermore, AZD1480 suppressed the infiltration of MHC class II+ macrophages and dendritic cells in PFF-injected mice. Importantly, single-cell RNAseq analysis of CD45+ cells identified 9 clusters of microglia, 5 clusters of macrophages and 5 clusters of T-cells, in which specific pathogenic clusters of microglia, macrophages and T-cells are critical for inflammatory responses in Thy1-PD mice. AZD1480 treatment reduced the numbers of the pathogenic clusters, comparable to cell clusters in control monomer/PBS mice. Together, these results suggest inhibiting the JAK/STAT pathway suppresses the infiltration and activation of innate and adaptive cells, thereby reducing the neuroinflammatory response in the Thy1-PD model.
This work was supported by grant P50NS108675.
Effect of delta-8-tetrahydrocannabinol (Δ8-THC) in modulating immune response and gut microbial dysbiosis in concanavalin-induced acute liver injury
Authors: Hamida F N U , Kakar Khadija , Nagarkatti Prakash , Nagarkatti Mitzi 
Published: August 2023

Abstract
Autoimmune hepatitis (AIH) is a serious health problem characterized by cellular infiltration and progressive destruction of the hepatic parenchyma resulting in cirrhosis, liver failure and death. In the current study, we assessed the ameliorative role of Δ8-THC in limiting the disease severity by its regulatory role on gut microbiota thereby altering the differentiation of T cell subsets in a murine model of Concanavalin A-induced hepatitis. AIH was induced in C57BL/6 mice by ConA (12.5mg/Kg i.v.) and treated i.p. with vehicle or 20mg/Kg Δ8-THC. Interestingly, Δ8-THC treatment after ConA challenge led to significantly decreased liver injury enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels than ConA exposed mice. Flow cytometry analysis of liver infiltrating cells revealed significantly reduced expression of pro-inflammatory cytokines IL-17A and IFNγ and elevated expression of immunosuppressive cytokines TGF-β1 and IL-10 in ConA-treated mice following Δ8-THC treatment. More importantly, Δ8-THC induced differentiation of CD4+ helper T cells from RORγt+ Th 17 cells and T-bet+ Th1 cells to Foxp3+ regulatory T cells in the liver of AIH mice. 16S rRNA sequencing of the gut microbiome revealed that ConA+Δ8-THC and naïve groups had lower abundance of bacteria belonging to families, Ruminococcaceae and Lachnospiraceae while higher abundance of Erysipelotrichaceae compared with ConA+Vehicle group. In addition, Δ8-THC treatment caused accumulation of Peptococcaceae family in AIH mice which may be responsible for a shift from pro-inflammatory to anti-inflammatory immune responses. Our data demonstrate that Δ8-THC may be used as a therapeutic drug against immune-mediated liver inflammation
Supported in part by NIH grants P01AT003961, P20GM103641, R01ES030144, R01AI129788, R01AI123947 and R01AI160896
Topical selective TYK2 inhibition attenuates inflammation and clinical symptoms in a mouse model of human psoriasis
Authors: Mallik Sanchari Basu , Tandon Amol , Kuriappan Jissy Akkarapattiakal , Kapure Jeevak Sopanrao , Halle Mahesh , Iyer Abishek 
Published: August 2023

Abstract
Psoriasis is a chronic skin condition, that affects ~8M patients in the United States. A majority (~7M) of patients suffer from mild to moderate form of disease that lacks safe & effective treatment options. Although antibodies targeting Th1/Th17 cytokines (eg IL12/IL23/IL17) are highly effective in moderate to severe psoriasis, they are not prescribed to mild to moderate patients due to high costs & safety concerns. There is a huge unmet need for developing safe and effective non-steroidal topical therapies. Small molecule inhibitors of Th1/Th17 pathways with optimal topical drug like properties can effectively address patient needs; making TYK2 inhibitors (TYK2i) attractive candidates for treating mild to moderate psoriasis. However, given the high degree of structural similarity among JAK family, designing topical selective TYK2i have remained a challenge. Using an innovative structure based approach, we have designed, synthesized and characterized TYK2i optimized for topical drug like properties and JAK family selectivity using free energy perturbation (FEP) methods and medchem SAR. We have identified TYK2i with pM to low nM potencies that are highly selective for TYK2 among 468 kinases. These analogs have enhanced topical bioavailability with suitable drug like properties. In a mouse model of psoriasis, these analogs dose-dependently suppressed PASI clinical scores, ear & back skin thickness and inflammation. Additionally, skin histology showed significant attenuation of epidermal thickening and pSTAT activation suggesting that topical TYK2 inhibition retains anti-inflammatory activity while eliminating potential for dose-limiting side effects observed with systemic non-selective TYK2 or other JAK inhibitors.
This research has been fully funded by Alembic Pharmaceuticals Ltd., including salary support to all authors.
Antigen-specific nanoparticle tolerance treatment actively induces regulatory mechanisms via the STING pathway
Authors: Podojil Joseph R , Cogswell Andrew C , Chiang Ming-Yi , Neef Tobias , Murthy Tushar , Boyne Michael T , Elhofy Adam , Miller Stephen D 
Published: August 2023

Abstract
Antigen (Ag)-specific T cells are the underlying cause of many autoimmune diseases. T cells found at the site of tissue destruction not only in the exacerbation of disease, but contribute to the release of additiotnal self-epitopes resulting in the activation of spread eptitope-specific T cell populations perpetuating disease. Treatment with Ag-containingbiodegradable poly(lactide-co-glycolide) (PLGA) nanoparticles, i.e. tolerogenic immune-modifying particles (TIMP), has been shown to be both safe and induces Ag-specific tolerance in mouse models of autoimmunity and allergy, as well as in a celiac disease Phase I/IIa clinical trial. We are in the process of assessing if the mechanism of action between Ag-specific TIMP treatment and Ag-coupled cell treatment, to thereby identify self-tolerance mechanisms in common between the two highly efficacious therapies. The PLP139–151 TCR transgenic model system was utilized to determine the cellular and molecular mechanisms driving Ag-specific tolerance mediated by tolerogenic nanoparticle treatment. These data show Ag-specific TIMP treatment induced both FoxP3+ iTregs and IL-10+ Tr1 regulatory in both naïve mice and mice pre-primed with Ag/CFA. Additionally, the expression of STING is required for the induction of tolerance. The involvement of the STING pathway for both TIMP and Ag-coupled cell treatment was confirmed in MOG35–55 EAE. The data also show that Ag-specific tolerance induction requires both Type I IFNs and PD-1/PD-L1 expression, which are downstream of STING activation and signaling. Treatment thus activates various Ag-specific Treg subsets capable of regulating responses to disease-relevant autoepitopes via a STING/IFNAR/PD-1/PD-L1 pathway.
Therapeutic recombinant immune complexes (rICs) inhibit T cell recruitment to the spinal cord during Experimental Autoimmune Encephalomyelitis (EAE)
Authors: Brown Kellie Nicole , Wang Jin , Danehy Margaret C , Thomas Fridtjof , Torgbe Kwame , Block David , Olsen Henrik , Strome Scott Eric , Fitzpatrick Elizabeth A 
Published: August 2023

Abstract
Multiple sclerosis (MS) is an autoimmune neurodegenerative disease mediated by autoreactive Th1 and Th17 cells that migrate into the central nervous system (CNS) and target myelin proteins ultimately leading to neuronal damage. Current immunomodulatory treatments reduce disease severity but do not cure the disease, and they do not work for all patients. Recombinant ICs recapitulate the anti-inflammatory properties of intravenous immunoglobulin and may be a viable therapy for MS. The objective of our study was to determine if a rIC, M019, could inhibit autoreactive T cell recruitment into the CNS using the EAE model. To demonstrate that M019 could inhibit disease severity when given therapeutically, C57BL/6 mice were immunized with a CFA-MOG35–55 emulsion followed by pertussis toxin to induce EAE. Upon symptom development, mice were randomly assigned to either the vehicle or M019 treatment groups and treated with M019 or vehicle daily. Mice treated with M019 exhibited reduced clinical scores and lethality compared to vehicle treated mice. Flow cytometric analysis of T cell infiltration into the CNS revealed that M019 inhibited CD4+ and CD8+ T cell infiltration compared to vehicle treated mice with EAE. However, spleen cells from M019 treated mice had similar levels of Th17 cells and increased Th1 cells compared to the vehicle treated group. These results suggest that M019 is not inhibiting Th17 responses in the periphery but is inhibiting their recruitment into the CNS. The effect of M019 is likely indirect, as in vivo drug binding studies show that M019 binds strongly to monocytes with low level binding to T cells. Our studies suggest that M019 may be an effective therapeutic for MS patients.
PAD4 controls the anti-tumor response by fine-tuning IFNγ signaling in macrophages
Authors: Pitter Michael Reginald , Zhang Hongjuan , Nagarsheth Nisha , Xia Houjun , Kryczek Ilona , Zou Weiping 
Published: August 2023

Abstract
MHC-II–mediated antigen presentation is essential for the function of the immune system. Recent evidence indicates that MHC-II expression shapes tumor immunity and response to immunotherapy. MHC-II expressing antigen presenting cells (APCs) mediate CD4+ T-cell priming and activation and license them to support the CD8+ T-cell response. Citrullination – catalyzed by peptidyl arginine deiminases (PADs) – is a post-translational modification at arginine residues. Here, we show that PAD4 negatively regulates anti-tumor immunity by tuning IFNγ-signaling gene expression, including that of MHC-II, in tumor associated macrophages (TAMs) in tumor bearing mouse models. Mechanistically, PAD4 citrullinates STAT1, thereby promoting the interaction between STAT1 and PIAS1 (protein inhibitor of activated STAT1) and resulting in reduced MHC-II expression in TAMs. Moreover, low levels of MHC-II expression in TAMs correlate with a reduced response to immunotherapy and are associated with poor cancer patient survival. These data suggest that targeting PAD4-mediated citrullination in macrophages may serve as a potential anti-cancer therapeutic approach.
Supported by grants from the NCI (R01CA217510, PA-21-071)
Immune checkpoint VISTA regulates DNA sensing and repair pathways that contribute to type I interferon (IFN-I) production in the skin
Authors: Peters Zachary T , Mendyka Lindsay , Shan Sicong , Noelle Randolph J , Skopelja-Gardner Sladjana 
Published: August 2023

Abstract
Skin sterile injury by ultraviolet (UV) light stimulates production of type I interferons. While in healthy skin IFN-I response to UV returns to baseline over time, the IFN-I signature persists in photosensitive diseases like lupus. The pathways that downregulate IFN-I production in healthy skin, and fail to do so in lupus skin, are unknown. Previous studies showing that activating VISTA suppresses the IFN-I signature in monocytes suggest a role for this immune checkpoint in the regulation of the IFN-I response. Indeed, we showed that the skin IFN-I signature is elevated in mice globally deficient in VISTA (Vsir−/−), as well as in mice with a conditional deletion of VISTA in keratinocytes. Having confirmed its expression in keratinocytes, we tested if VISTA regulates UV-triggered IFN-I production in the skin. Expression analysis of IFN-I stimulated genes in skin biopsies collected prior to and 3h after a single dose of UVB, revealed ~10-fold higher IFN-I score in Vsir−/− vs. B6 skin after UV. RNAseq studies showed DNA sensors, ZBP1, cGAS, and IFI204 were upregulated, while nucleotide excision repair genes, Polɛ and DNA Ligase1, were suppressed in Vsir−/− skin, both at baseline and 3h after UV. Moreover, Polɛ protein levels were lower in Vsir−/− skin by immunoblot. Relevant to its role in keratinocytes, IFN-k protein levels were higher in VISTA-deficient epidermal keratinocytes ex vivo, accompanied by elevated mRNA levels of ZBP1 and IFI204 before and after UV. Together, this study identifies VISTA as a novel regulator of IFN-I production, by modulating DNA damage repair and sensing. The keratinocyte-intrinsic role of VISTA is therapeutically relevant as lupus keratinocytes express high IFN-k and are direct targets of UV-induced DNA damage.
1R21AR079661 – 01, Hitchcock Foundation, DOD lupus award