bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of VEGF-R2 reverses type 1 diabetes in NOD mice by abrogating insulitis and restoring islet function. (P5181)
Authors: Villalta S. , Lang Jiena , Kubeck Samantha , Kabre Beniwende , Szot Gregory , Calderon Boris , Brekken Rolf , Pullen Nick , Arch Robert , Bluestone Jeffery 
Published: January 2023

Abstract
The dysregulation of receptor tyrosine kinases (RTKs) in multiple cell types during chronic inflammation is indicative of their pathogenic role in autoimmune diseases. Among the many RTKs, vascular endothelial growth factor receptor (VEGFR) stands out for its multiple effects on immunity, vascularization and cell migration. Herein, we examined whether VEGFR participated in the pathogenesis of type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. We found that RTK inhibitors (RTKIs) and VEGF or VEGFR-2 antibodies reversed diabetes when administered at the onset of hyperglycemia. Increased VEGF expression promoted islet vascular remodeling in NOD mice, and inhibition of VEGFR activity with RTKIs abrogated the increase in islet vascularity, impairing T cell migration into the islet and improving glucose control. Metabolic studies confirmed that RTKIs worked by preserving islet function as treated mice had improved glucose tolerance without affecting insulin sensitivity. Finally, examination of human pancreata from patients with T1D revealed that VEGFR-2 was confined to the islet vascularity, which was increased in inflamed islets. Collectively, this work reveals an unappreciated role for VEGFR-2 signaling in the pathogenesis of T1D by controlling T cell accessibility to the pancreatic islets, and highlights a novel application of VEGFR-2 antagonists for the therapeutic treatment of T1D.
Dietary supplements of curcumin attenuate scurfy-induced immune disorder with interaction on CD4 T cells (P5183)
Authors: Lee Gihyun , Kim Hyunseong , Park Soojin , Joo Hwansoo , Song Joohyun , Shin Minkyu , Hong Moochang , Bae Hyunsu 
Published: January 2023

Abstract
Background/Aims: Curcumin has been used in Asian traditional medicine for its medicinal properties. Recent studies have demonstrated that curcumin has antioxidant, anti-tumor, and anti-inflammatory activities. The aim of this study is to investigate the effects of curcumin on the the scurfy-induced immune disorder, in particular its interaction on CD4+ T cells. Methods: Starting at 3 weeks of age, mice were fed a standard diet or a diet containing 1% curcumin for 7 days. The survival period of mice were measured. Additionally, the total CD4+ T cells population and th1, th2 and th17 population and absolute number were compared between curcumin treated mice and control mice. Results: A dietary curcumin delays lethality in scurfy mice. The population of CD4+ T cells in spleen was reduced in curcumin treated mice. Furthermore, Th1, Th2 and Th17 percentage and cell count were decreased after curucumin treatment. Conclusion: Curcumin exerted a protective effect in scurfy mice. We speculate that the protective effects of curcumin in scurfy may involve, at least in part, its interaction on CD4 T cells.
Pharmacological inhibition of PI3Kδ opposes the progression of autoimmune diabetes in non-obese diabetic mice. (P5149)
Authors: Puri Kamal , Durand Caylib , Richer Martin , Brenker Kathrin , Graves Marcia , Shanina Iryna , Choi Kate , Horwitz Marc , Gold Michael 
Published: January 2023

Abstract
B-lymphocytes have been implicated in many autoimmune diseases, and non-obese diabetic (NOD) mice that lack B cells do not develop spontaneous autoimmune diabetes. The catalytic activity of PI3Kδ is important for B cell migration, activation, proliferation, and antigen presentation. We tested whether a PI3Kδ inhibitor could delay the onset or reduce the incidence of autoimmune diabetes in NOD mice. We found that preventative treatment of pre-diabetic NOD mice with GS-548202 (IC87114), a highly selective small molecule inhibitor of PI3Kδ, reduced the infiltration of inflammatory cells into the pancreatic islets and, accordingly, delayed and reduced the loss of glucose homeostasis. Diabetes developed in about 75% of vehicle-treated NOD mice by 18 weeks of age but in only 33% of GS-548202-treated animals at this same time point. Moreover in a therapeutic treatment mode, GS-548202 treatment conferred prolonged protection from progression to overt diabetes in a number of animals. Within 28 days, all of the NOD mice that received only the vehicle developed overt diabetes, with blood glucose levels rising substantially above 300 mg/dl. In contrast, 4 of the 7 GS-548202-treated NOD mice maintained their blood glucose levels below 300 mg/dl for at least 60 days after initiating treatment when they first exhibited blood glucose levels of 200-300mg/dl. These findings suggest that PI3Kδ inhibitors could be useful for managing autoimmune diabetes.
Anti-inflammatory effects of WF10 in a mouse model of rheumatoid arthritis (P5185)
Authors: Leichsenring Anna , Lange Franziska , Isensee Thomas , Guntermann Henrich , Sack Ulrich 
Published: January 2023

Abstract
The purpose of our study was to investigate whether the immune modulator WF10 has an impact on clinical signs of experimentally induced rheumatoid arthritis in DBA/1 mice. Female DBA/1 mice were sensitized with a collagen II emulsion on day 0 and boosted on day 21. The animals were scored from day 17 for clinical signs of collagen induced arthritis (CIA). If the evaluated score exceeded a value of 5, CIA was considered to be established. From the day of CIA onset animals were treated with WF10 or saline in different doses and treatment regimens. Scoring was done for a total of 21 days after CIA onset. Animals which developed CIA within the first 35 days after the immunization were included into the study. Control animals as well as mice treated with WF10 exhibited CIA and showed an increasing score within the observation period, whereas animals treated with the compound showed a reduction of clinical symptoms. 21 days after CIA onset, animals were sacrificed and samples were preserved for further investigations like cytokine measurements, histology and mRNA expression analyses. In conclusion, WF10 had a reducing effect on the severity of CIA symptoms in mice and may therefore present a novel therapeutic approach for patients suffering from rheumatoid arthritis and other inflammatory autoimmune diseases.
Lovastatin in combination with metformin provides neuroprotection in experimental animal model of multiple sclerosis (P5195)
Authors: Singh Inderjit , Mohan Sarumathi , Paintlia Ajaib 
Published: January 2023

Abstract
Studies from our laboratory have previously reported that modulation of AMPK by metformin and isoprenylation of RhoA GTPase by statins attenuate inflammatory and autoimmune responses. Here, we evaluated the therapeutic efficacy of these drugs in combination to protect CNS in EAE, animal model of MS. Metformin and lovastatin are neuroprotective per se. Combination therapy using the suboptimal dose of the drugs following EAE induction provided synergistic effects in neuroprotection. Mechanistically, the neuroprotection offered was primarily through decreased infiltration of the immune cell (CD4, CD8 and CD68) and decreased axonal degeneration. Combination therapy also inhibited the EAE induced demyelination (LFB and MBP staining). The shattered homeostasis of phosphorylated form of neurofilament binding protein (SMI-31) during the EAE pathology was reverted back with the drug treatment. Further, CNPase, the marker of myelinating oligodendrotyes was increased by the metformin and lovastatin treatment. Combination treatment with lovastatin and metformin biased the class of elicited myelin basic protein antibody from IgG2a to IgG1 and IgG2b, suggesting a shift from Th1 to Th2 response. In summary, metformin and lovastatin treatment individually as well as in combination combats EAE disease. Since, metformin and lovastatin are FDA approved drugs; the present study suggests for a possible therapeutic application of their combination treatment for MS.
Removal of HMGB1 in inflammatory bowel disease using DNA-beads. (P5197)
Authors: Ju Zhongliang , Li Jianhua , Lu Ben , Dancho Meghan , Mahenda Ochani , Chavan Sangeeta , Tracey Kevin , Yang Huan 
Published: January 2023

Abstract
Inflammatory bowel disease (IBD) affects millions of Americans, and costs 1.7 billion annually. High mobility group box 1 (HMGB1) is a cytokine mediator of inflammation in the pathogenesis of IBD. Elevated levels of HMGB1 have been observed in human IBD and in mouse models of colitis (Vitali R, et al. Am J Gastroenterol. 2011. Yamasaki H, et al. Mol Med Report. 2009). Blocking HMGB1 induction by either anti-HMGB1 antibody or ethyl pyruvate (HMGB1 inhibitor) was able to ameliorate the inflammation in colitis mice. DNA with certain sequences or structures has been shown with high affinity binding to HMGB1, and has been reported to attenuate inflammatory responses by blocking HMGB1. In this study, we conjugated DNA sequences to sepharose beads and utilized them as novel reagents to remove HMGB1. We found that the DNA-beads were able to bind HMGB1 with a capacity of 7.6 μmol/L, and each immobilized DNA molecule was able to bind three HMGB1 molecules (DNA:HMGB1 ratio = 1:3). DNA-beads were able to capture HMGB1 from RAW 264.7 cell supernatant stimulated with LPS and from sera of septic mice induced by cecal ligation and puncture. When applied to stools of mice with dextran sulfate sodium (DSS) induced colitis, DNA-beads were able to capture HMGB1 from stools of these colitis mice. Hence, our data suggest a therapeutic potential for DNA-beads to remove HMGB1 in inflammatory diseases such as IBD.
An immuno-protective treatment strategy for autoimmune diseases (P5201)
Authors: McNally Jonathan , Elfers Eileen , Terrell Catherine , Grubblatt Eli , Jordan Michael , Hildeman David , Katz Jonathan 
Published: January 2023

Abstract
The current clinical approach for treating autoimmune diseases is to blunt all immune responses as a means of preventing autoimmune pathology. A major side effect of this strategy is depressed beneficial immunity, and increased rates of infections and tumors. Here we report the novel application of etoposide, a topoisomerase inhibitor, to treat experimental autoimmune encephalomyelitis (EAE), a model for human multiple sclerosis. The moderate and temporally-limited use of etoposide results in significant reduction and severity of EAE while sparing beneficial naïve and memory immunity. Our approach of eliminating activated encephalogenic effector T cells reduces clinical scores, pathogenic cytokine production, and overall pathology, while dramatically limiting the off-target effects on naïve and memory adaptive immunity. Etoposide-treated mice exhibited ameliorated or no EAE pathology and reduced antigenic spread, yet had normal T cell and T-dependent B cell responses to de novo antigenic challenges, as well as unimpaired memory T cells responses to viral rechallenge. Thus, dosage limiting etoposide therapy can selectively ablate effector T cells and limit pathology in an animal model of autoimmunity, while sparing protective immune responses. This strategy could lead to a broad new paradigm for the treatment of autoimmune diseases with both enhanced efficacy and decreased treatment-associated morbidities.
Inhibiting Th17 cells and reducing insulitis in diabetic NOD mice by GW9508, a GPR40 and GPR120 dual agonist (P5203)
Authors: Guo Zhiguang , Ansarullah A. , Lu Yan , Holstein Martha , Brittany Deruyter 
Published: January 2023

Abstract
G-protein coupled receptor 40 (GPR40) and G-protein coupled receptor (GPR120) are expressed on intestinal L cells, monocytes and/or macrophages. We investigated the effect of GW9508 (GW), a GPR40 and GPR120 dual agonist, on modulating autoimmunity in NOD mice. New-onset diabetic NOD mice were treated with GW for up to 8 weeks. Nonfasting blood glucose was monitored. After the treatment, CD4+CD25+FoxP3+ T (Treg) cells in thymus, spleen and pancreatic lymph nodes were measured. To detect IL-17+CD4+ T (Th17) cells, lymphocytes from these mice were cultured for 5 days. To determine in vitro effect of GW on Th17 cells, lymphocytes from NOD mice were cultured with or without GW. Cytokines and chemokines in supernatants were determined. Diabetes was reversed in 13% of vehicle (DMSO) treated mice, in 54% of mice treated with GW at 10mg/kg/day and in 69% of mice treated with GW at 20 mg/kg/day (P&lt;0.01). The insulitis score was significantly lower in GW-treated mice (P&lt;0.05). Although the percentage of Treg cells was not significant different, the percentage of Th17 cells and the ratio of Th17 cells to Treg cells in GW-treated mice were significantly lower (P&lt;0.01). Th17 cells in GW-treated lymphocytes in culture were significantly reduced (P&lt;0.05). IL-17, IFN-γ, IP-10, RANTES, and MIP-1α in supernatants of GW-treated lymphocytes were also significantly reduced (P&lt;0.05). Our data indicate that targeting GPR40 /GPR120 is a new therapeutic approach for treating type 1 diabetes.
Lipoxin A4 decreases human memory B cell antibody production via an ALX/FPR2-dependent mechanism: A link between resolution signals and adaptive immunity (P5151)
Authors: Ramon Sesquile , Bancos Simona , Serhan Charles , Phipps Richard 
Published: January 2023

Abstract
Specialized proresolving mediators (SPMs) are endogenous bioactive lipid molecules that play a fundamental role in the regulation of inflammation and its resolution. SPMs are classified into lipoxins, resolvins, protectins and maresins. Lipoxins and other SPM have been identified in immunological tissues including bone marrow, spleen and blood. Lipoxins regulate functions of the innate immune system such as monocyte recruitment and inhibition of neutrophil infiltration to the site of inflammation. A major knowledge gap is whether lipoxins influence adaptive immune cells. Here, we discovered that B cells express the lipoxin A4 (LXA4) receptor, ALX/FPR2, and upregulate its expression following mitogen activation. Furthermore, LXA4 decreased IgM and IgG production on activated B cells through an ALX/FPR2-dependent mechanism. This caused a reduction in NF-κB p65 nuclear translocation. We found that memory B cells express higher levels of ALX/FPR2 compared to naïve B cells. Interestingly, LXA4 inhibited human memory B cell antibody production and proliferation, but not naïve B cell function. LXA4 also decreased antigen-specific antibody production in vivo. To our knowledge, this is the first description of the effects of lipoxins on B cells, which provides a link between resolution signals and adaptive immunity. The ability of lipoxins to decrease memory B cell antibody production could be particularly beneficial to threat chronic inflammatory diseases and autoimmune disorders.
A novel aza-anthrapyrazole modulates the development of CD4+ effector T cells (P5207)
Authors: Clark Matthew , Hacker Miles , Quinn Anthony 
Published: January 2023

Abstract
BBR3378 is a novel aza-anthrapyrazole that antagonizes autoimmunity and the progression of MOG-induced EAE without the complications noted with anthracycline-based (mitoxantrone) therapy in EAE and human multiple sclerosis. Mitoxantrone induces cell death in rapidly proliferating cells and significant lymphopenia in vivo; however, while most splenic CD4+ cells take up BBR3378 in vivo, only a few are deleted. Moreover, increased dosages of BBR3378 were associated with improved therapeutic impact without concomitant increases in lymphopenia. To determine if BBR3378-mediates regulation of EAE via lymphocyte deletion, splenic T cells were stimulated with anti-CD3 in the presence of low-dose BBR3378 or mitoxantrone. The CD3 blasts showed increased expression of CD25 and CD69, but the enhanced CD4 expression (CD4hi) typically associated with Th progressison to “effector” status was blocked on BBR3378 and mitoxantrone-treated cells, leading to enrichment of slowly proliferating CD4lo-CD69hi T cells. Cytokine production was confined to CD4hi-CD69hi blasts; however, in contrast to mitoxantrone, IL-17 and IFN-gamma production were significantly reduced in the BBR3378-treated cells in the absence of Th cell death. These findings suggest that BBR3378 can regulate specific genes in viable Th cells while impeding the progression of naïve Th cells to full effector status. The Th subsets associated with the induction of EAE were particularly sensitive to BBR3378-mediated suppression.
Dissecting fingolimod’s action: a novel immunomodulatory effect of the unphosphorylated compound on cytotoxic T cell function (P5159)
Authors: Ntranos Achilles , Grishkan Inna , Robinson Dionne , Hall Olivia , Klein Sabra , Calabresi Peter , Gocke Anne 
Published: January 2023

Abstract
Fingolimod (FTY), a sphingosine-1-phosphate receptor modulator, is a multiple sclerosis (MS) therapeutic that upon phosphorylation traps CCR7+ T cells in lymph nodes (LN). CCR7- effector T cells are spared, thus allowing effective infection clearance. Nonetheless, FTY-treated patients are more susceptible to viral infections, indicating a cytotoxic T (Tc) cell defect. Yet, FTY’s effect on Tc cells remains unclear. To address this question, we utilized experimental autoimmune encephalomyelitis (EAE) and a murine influenza model. FTY ameliorated EAE by sequestering T cells, but also inhibited splenic Tc cell IFNγ and Granzyme B(GrB) expression. Influenza was exacerbated and mortality was increased, as FTY inhibited Tc cell activation and lung infiltration. To elucidate its mechanism of action, murine splenocyte cultures were treated with phosphorylated and unphosphorylated FTY, as both exist in vivo. Remarkably, only the latter reduced IFNγ and GrB levels in Tc cells and inhibited their function in an LDH cytotoxicity assay. The addition of arachidonic acid rescued Tc cell function, suggesting that FTY’s effect is due to inhibition of cytosolic phospholipase A2. Herein, we demonstrate that FTY suppresses Tc cell function independently of its cell trafficking effects. This provides a novel explanation not only for the increased rate of viral infections in FTY-treated patients, but also for its efficacy in MS, as Tc cells have emerged as crucial mediators of MS pathogenesis.
Histone deacetylase inhibition by ITF2357 reduces SLE pathogenesis in vivo (P5161)
Authors: Regna Nicole , Chafin Cristen , Hammond Sarah , Caudell David , Reilly Christopher 
Published: January 2023

Abstract
Histone deacetylase (HDAC) inhibitors are important modifiers of gene and protein expression. In our studies, we sought to determine if a specific HDAC I and II inhibitor (ITF2357) was able to decrease disease in lupus-prone New Zealand Black/White (NZB/W) F1 female mice through regulation of T cell profiles. From 22 - 38 weeks-of-age, NZB/W and non-lupus New Zealand White (NZW) mice were injected intraperitoneally with 10mg/kg of ITF2357 (high dose), 5mg/kg of ITF2357 (low-dose), or the vehicle control. Body weight and proteinuria were measured every 2 weeks, while sera anti-dsDNA and cytokine levels were measured every 4 weeks. Kidney disease was determined by sera BUN and creatinine, immune complex deposition, and renal pathology. T lymphocyte profiles were assessed using flow cytometric analyses and T regulatory cell function was determined by CFSE assay. Our results showed NZB/W mice treated with the high-dose of ITF2357 had increased histone acetylation resulting in a decrease in overall renal disease and inflammatory cytokines in the sera. Treatment with ITF2357 at 10 mg/kg decreased the Th17 phenotype while increasing the percentage and function of Treg cells as well as Foxp3 acetylation. These results suggest that specific HDAC inhibition may decrease disease by altering T cell differentiation and function.
CD19+CD24highCD38high B cells exhibit higher ability in TGF-β and IL-10 secretion and suppressing of CD4+ T cell proliferation but are quantitatively decreased in G-BM of healthy donors (P2146)
Authors: Chang Ying-Jun , Zhao Xiao-Su , Lv Meng , Zhao Xiang-Yu , Han Ting-Ting , Wang Hong-Tao , Huang Xiao-Jun 
Published: January 2023

Abstract
In this study, we investigated the alteration of B cell compartment before and after treating healthy donors with granulocyte colony-stimulating factor (G-CSF) and the principal role of CD19+CD24highCD38high B cells in suppressing T cell proliferation. Our studies revealed that G-CSF-primed bone marrow (G-BM) contains significantly lower numbers of CD19+CD24highCD38high B cells than that of steady-state bone marrow (SS-BM) (P=0.001). Compared to SS-BM, the expression of L-selectin, LFA-1, and ICAM-1 on CD19+CD24highCD38high B cells was significantly lower than that of SS-BM (P=0.019, 0.001, 0.015, respectively). The percentages of interleukin-10 (IL-10), and transform growth factor-β (TGF-β) producing CD19+CD24highCD38high B cells were significantly higher in G-BM than those in SS-BM (P=0.011, and 0.001, respectively). The concentration of IL-10 and TGF-β in cultural supernatant of purified bone marrow B cells in G-BM was also significantly higher than those of SS-BM (P&lt;0.05 for all). Ability in suppression of CD4+CD25- T cell proliferation by activated bone marrow B cells in G-BM was significantly higher than that of SS-BM (P=0.001). Our results suggest that CD19+CD24highCD38high B cells in G-BM of healthy donors exhibit higher ability in TGF-β and IL-10 secretion and suppressing of CD4+ T cell proliferation but are quantitatively decreased. ** Address for Correspondence: Xiao-Jun. Huang, MD E-mail: huangxiaojun@bjmu.edu.cn
Transplant tolerance depends on regulatory T cells induced by TGF-β-producing regulatory B cells (P2168)
Authors: Lee Kang Mi , Kim James , Yeh Heidi , Stott Ryan , Shi Shuai , Deng Shaoping , Markmann James 
Published: January 2023

Abstract
Regulatory B cells (Bregs) have been shown to play a critical role in immune homeostasis and in autoimmunity models. We have recently demonstrated that combined anti-TIM-1 and anti-CD45RB antibody treatment results in tolerance to full MHC mismatch islet allografts in mice, generating Bregs that are necessary for tolerance, and capable of transferring tolerance to untreated animals. Herein, we demonstrate that adoptively transferred Bregs require the presence of Tregs to establish tolerance, and that adoptive transfer of Bregs increases the number of Tregs. Bregs induce significantly more Foxp3 expression in CD4+CD25- T cells, in vivo, compared to naive B cells. We also show that Bregs express the TGF-β associated latency-associated peptide (LAP). Furthermore, Breg-mediated graft prolongation post-adoptive transfer is abrogated by neutralization of TGF-β activity. Collectively, these findings suggest that in this model of antibody-induced transplantation tolerance, Bregs promote graft survival by promoting Treg development, possibly via TGF-β production.