bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gender difference in PPARα regulation of inflammation and demyelination in EAE model of multiple sclerosis (50.1)
Authors: Kanakasabai Saravanan , Walline Crystal C , Bright John J 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a neurological disorder that affects more than a million people worldwide. The disease usually begins in young adults and affects women more than men. About 30% of MS patients develop clinical paralysis and become wheel chair-bound for the rest of their lives. The etiology of MS is not known and there is no medical treatment that can cure MS. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor transcription factors that have anti-inflammatory properties. We and others have shown earlier that PPARγ, α and δ agonists ameliorate MS-like disease in experimental allergic encephalomyelitis (EAE) model. In this study we demonstrate that the PPARδ deficient male mice develop an exacerbated EAE, while the PPARδ deficient female mice developed comparable disease to wild type C57BL/6 mice, following immunization with MOGp35-55 antigen. The PPARδ deficient male mice showed an augmented Th17 response, without affecting neural antigen-specific T cell proliferation, Th1 differentiation and CD25+Foxp3+ regulatory T cells. Our findings highlight that PPARδ is a physiological regulator of EAE and confirm the use of PPARδ agonists for the treatment of MS patients.
Macrophages are required for anti-CD19 mAb mediated B cell depletion in mice (50.16)
Authors: Gallagher Sandra , Wang Yue , Groves Chris , Tedder Thomas , Coyle Anthony J , Herbst Ronald 
Published: January 2023

Abstract
Anti-CD20 mediated B cell depletion is an effective treatment for rheumatoid arthritis. An anti-CD19 mAb is under investigation as a new B cell depleting reagent. Studies have demonstrated that the interaction between the mAb Fc and Fc? receptors on effector cells is important for efficient target cell depletion. To enhance effector function, the anti-CD19 mAb was engineered with BioWa's Potelligent® technology to remove fucose from the Fc portion. The fucose-free mAb has increased affinity to human FCγRIIIa and mouse FCγRIV as well as improved cytotoxicity. The fucose-free anti-CD19 antibody (anti-CD19-aFuc) depleted &gt;90% of murine B cells in human CD19 Transgenic mice. Further studies were carried out to investigate the mechanisms of action of anti-CD19-aFuc. B cell depletion was not affected in mice which were treated with to deplete NK cells or neutrophils. Similarly, depletion of B cells was not impaired in mice in which complement activation was blocked. In contrast, B cell depletion by anti-CD19-aFuc was significantly inhibited in mice in which macrophages were eliminated. Furthermore, anti-CD19-aFuc showed robust activity in an antibody dependent cellular phagocytosis assay with freshly isolate mouse macrophages as effector cells. These results suggest that anti-CD19-aFuc depletes B cells in mice through a macrophage dependent mechanism. This study is funded by MedImmune, LLC.
Lipid rafts represent a novel therapeutic target in SLE (50.25)
Authors: Deng Guo-Min , Liu Lena , Tsokos George C 
Published: January 2023

Abstract
Lipid rafts play a crucial role in T cell receptor (TCR) signaling. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by abnormal TCR signaling. We found that lipid rafts are aggregated on the surface membrane of T cells from lupus-prone MRL/lpr mice. High levels of aggregated lipid rafts could also be reproduced on T cells of normal C57BL/6 mice treated with anti-CD3 plus CD28 antibodies. The aggregated lipid rafts peaked at the age of 6-7 weeks prior to the appearance of disease pathology in MRL/lpr mice. Depletion of lipid rafts with methyl-B-cyclodextrin (MBCD), which is known to disrupt lipid rafts, or atorvastatin, which is known to inhibit cholesterol biosynthesis delayed disease progression, whereas acceleration of their formation with cholera toxin B, which is known to induce lipid raft clustering, promoted disease progression in MRL/lpr mice. The aggregated lipid rafts harbor diverse molecules including TCR signaling, inflammatory, costimulatory, adhesion and Toll-like receptor molecules. Recruited diverse molecules have costimulation to enhance TCR-mediated response and production of IFN-gamma through intact lipid rafts. Further, crosslinking of lipid rafts promoted IFN-gamma production in vitro, a cytokine known to contribute to the expression of SLE pathology in mice. We propose that lipid rafts represent a novel therapeutic target in SLE.
A novel inhibitor of Smad-dependent transcriptional activation suppresses tissue fibrosis in model mice of systemic sclerosis (50.31)
Authors: Hasegawa Minoru , Matsushita Yukiyo , Horikawa Mayuka , Higashi Kiyoshi , Tomigahara Yoshitaka , Kaneko Hideo , Takehara Kazuhiko , Sato Shinichi 
Published: January 2023

Abstract
Tissue fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc). TGF-β is well known to be the principal factor that leads to tissue fibrosis. We tested a novel small compound HSc025, which is an antagonist of TGF-β/Smads signaling, would prevent tissue fibrosis in vitro or in mouse models of SSc. Human dermal fibroblasts were exposed at various doses of HSc025 in the presence of TGF-β, and the expression levels of collagen or fibronectin were determined. Administration of HSc025 (15 mg/kg/day, p.o.), halofuginone (1μg/mouse/day, i.p.) or placebo to tight skin mouse or to bleomycin-induced pulmonary fibrosis mice was performed for 14 days. Pretreatment with HSc025 prevented Smad-dependent promoter activation in a dose-dependent manner, however, HSc025 had no effect on TGF-β-induced phosphorylation of Smad3. The inhibitory effects of HSc025 on TGF-β-induced collagen or fibronectin expression were also confirmed in vitro. The oral administration of HSc025 dramatically reduced hypodermal thickness in tight skin mice, and markedly decreased hydroxyproline contents and histological score in the lungs of bleomycine-treated mice.
These results demonstrate that HSc025 is a novel inhibitor against TGF-β/Smads signaling, resulting in the improvement of skin and pulmonary fibrosis. Therefore, orally available HSc025 might be useful for the therapy of SSc.
Immunomodulatory effects of piperine on dendritic cell function (50.36)
Authors: Rodgers Gemma , Doucette Carolyn D , Spurrell David R , Hoskin David W , West Kenneth A , Liwski Robert S 
Published: January 2023

Abstract
Piperine is a major alkaloid in black and long pepper and has been shown to have potent anti-inflammatory properties. In this study we investigated the immunomodulatory effects of piperine on dendritic cells (DC), key initiators and modulators of T cell mediated immune responses.
C57BL/6 bone marrow derived DC were matured in the presence of 100 µM of piperine or vehicle control. DC maturation marker and chemokine receptor expression was assessed by flow cytometry. T cell proliferation was measured by CFSE dilution. Cytokine secretion was assessed by cytometric bead array assay. In vitro DC migration was assessed using CCL21 as the chemotactic stimulus.
Piperine treated DC showed decreased expression of CD40, CD86, class II MHC and CCR7 and increased expression of CCR5, consistent with an immature phenotype. DC production of IL-6, TNF and MCP-1 was significantly reduced following piperine treatment. Treatment with piperine also reduced DC migration and DC induced T cell proliferation. In addition, naïve T cells activated with piperine-treated DC secreted lower levels IFN-γ, IL-4, IL-17, and IL-2.
This study demonstrates that piperine inhibits DC maturation, migration and T cell stimulatory capacity. Further investigation of piperine mediated DC immunomodulation could lead to the development of novel therapies for the treatment of autoimmune disorders or allograft rejection.
This research is supported by CIHR.
Long term elimination of epitope-specific diabetogenic CD8+ T cells using toxin coupled tetramers in NOD mice (50.37)
Authors: Young Ellen F. , Vincent Ben , Buntzman Adam , Tisch Roland , Frelinger Jeffrey A. , Hess Paul 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which CD8+ T cells with help from CD4+ T cells and B cells kill the insulin-producing islet cells in the pancreas. Although islet transplants have been successful in treating T1D, the transplants may not persist because of the ongoing autoimmunity. Patients can be treated with immunosuppressants, however these drugs have serious side effects. Selective elimination of diabetogenic T cells should specifically eliminate islet autoimmunity. We previously showed MHC class I tetramers coupled to the toxin saporin could selectively kill transgenic virus specific T cells. We have now used saporin coupled NRP-V7 tetramers to target diabetogenic T cells in vitro and in vivo in non-obese diabetes-prone (NOD) mice. NRP-V7 is a high affinity mimotope that is recognized by the 8.3 T cell clone, a known diabetogenic T cell. Treatment with saporin coupled NRP-V7 tetramers acutely depleted NRP-V7+ CD8+ T cells expressing Vβ 13-3 and elimination appeared to be long term since very few NRP-V7+ T cells were detectable in the islets of toxic-NRP-V7 tetramer treated NOD mice up to 45 weeks later. Treatment with toxic NRP-V7 tetramers resulted in a delay of T1D with a mean onset of 24 weeks compared to 16 weeks for treatment with PBS. Toxic tetramers could potentially be used to treat T1D as well as other T cell mediated autoimmune disease. Supported by JDRF 5-2006-13 and 1-2008-24.
Nociceptin/Orphanin FQ antagonists ameliorate inflammatory bowel disease (50.45)
Authors: Alt Carsten , Shew Ken , Fujita Nahoko , Tran Thanh-Thuy , Zukic Maja , Polgar Willma , Toll Lawrence , D'Andrea Annalisa 
Published: January 2023

Abstract
Human inflammatory bowel disease (IBD), primarily Crohn's disease and ulcerative colitis, affect 1-1.5 million people in the United States, with estimated annual medical costs of about $18,500 per patient. Although the etiology of IBD is unclear, the disease is commonly thought to be mediated by an uncontrolled autoimmune response against the bowel. No cure is available for IBD. Nociceptin/Orphanin FQ (N/OFQ) is a neuropeptide that has been hypothesized to be a stimulator of inflammation, and the N/OFQ receptor is expressed at high levels in the gut. We evaluated the therapeutic potential of N/OFQ antagonists in C57Bl/6 mice in an IBD model induced by treatment for 5 days with DSS. N/OFQ antagonists were administered prophylactically. Our results indicate that treatment with N/OFQ antagonists dramatically ameliorated the development of colitis as observed by changes in body weight, disease activity index, fecal consistency, bleeding, and cytokine levels in the colon. Furthermore, our data suggest that N/OFQ affects the recruitment of leukocytes to the inflamed bowel. Additional studies are in progress to elucidate this complex mechanism of action of N/OFQ and N/OFQ antagonists in the context of IBD. Our results indicate that treatment of the animals with N/OFQ antagonists significantly ameliorates the DSS-induced colitis, suggesting that inhibition of N/OFQ may be an effective therapy for IBD.
Modulation of migration of immune cells and molecules into the central nervous system by adenosine receptor signaling (50.5)
Authors: Bynoe Margaret S , Mills Jeffrey H , Thompson Linda F 
Published: January 2023

Abstract
We have shown that mice lacking CD73, an extracellular enzyme of the purine catabolic pathway that catalyzes the breakdown of adenosine monophosphate (AMP) to adenosine, were resistant to EAE, the animal model of the central nervous system (CNS) inflammatory disease multiple sclerosis (MS). Furthermore, blockade of adenosine receptor signaling with an antagonist specific for the A2a adenosine receptor, which is expressed in the CNS, inhibited lymphocyte migration into the CNS and protected wild type mice from EAE. We now show that blockade of adenosine receptors with broad spectrum or a specific A2a receptor antagonist prohibits the entry of immune cells into the CNS of (SJL/J x PL/J)F1 mice (that develop a relapsing-remitting form of EAE), inhibits the development of EAE, and halts EAE relapse. Importantly, we have strong data showing that adenosine receptor blockade can inhibit the entry of molecules such as FITC-Dextran and Evans blue dye across CNS barriers. These data provide convincing evidence that modulation of adenosine receptors can have a profound effect on CNS mediated diseases such as MS and drug delivery across CNS barriers. This work was supported by NIH grants AI 57854 and NS 063011 (to MSB) and AI 18220 (to LFT).
Generation of SIINFEKL from ovalbumin is only partially inhibited by proteasome inhibitors (78.10)
Authors: Garg Manish , Srivastava Pramod K. 
Published: January 2023

Abstract
We have treated PIK23 cells ( P815 cells genetically modified to express ovalbumin in an inducible manner) with irreversible proteasome inhibitors AdaAhx3L3VS and lactacystin and analyzed (a) the ability of inhibitors to block proteasome activity by in-gel peptidase assay, and (b) the generation of new cell surface Kb-SIINFEKL complexes as measured by B3Z activation. Our results show that complete inhibition of proteasome activity results in only a modest inhibition in generation of new Kb-SIINFEKL complexes. Only a combined inhibition of proteasomes and other cytosolic proteases leads to a complete inhibition of generation of such complexes. These results point to existence of redundant pathways for generation of SIINFEKL.
Carbohydrate antigen processing is self-regulated and promotes conventional antigen processing (78.20)
Authors: Cobb Brian A. , Lewis Colleen J. 
Published: January 2023

Abstract
Processing of T cell-dependent carbohydrate antigens in professional antigen presenting cells (APCs) is driven by the production of nitric oxide (NO) via TLR2 stimulation. Published reports have shown that preservation of carbohydrate fragments containing at least 4 repeating units are required for class II MHC presentation and T cell stimulation, yet each repeating unit is equally susceptible to oxidative cleavage. These observations suggest that a mechanism exists to prevent complete degradation of key carbohydrate epitopes during the oxidative burst. Our results have revealed that oxidative breakdown of carbohydrates following endocytosis generates an acidic environment in a proton pump-independent fashion. This acid environment is the direct result of proton release from the oxidation reaction and serves to inhibit further carbohydrate degradation via a pH-driven feedback loop while promoting the activation of proteases within the conventional processing pathway. These findings suggest a novel mechanism within APCs in which endocytosis and oxidation of carbohydrate-encapsulated microbes generates a low pH environment that negatively self-regulates carbohydrate breakdown while facilitating protein antigen processing.
Modulating MHC Class II Antigen Processing in Dendritic Cells Prevents Diabetes in NOD mice (78.25)
Authors: Denzin Lisa K. , Yi Woelsung , Wucherpfennig Kai W. , Sant'Angelo Derek B. 
Published: January 2023

Abstract
The presentation of disease relevant self-peptides is clearly essential for type 1 diabetes (T1D). General inhibition of antigen presentation, however, would severely compromise a patient's immune system. The over-expression or complete loss of the MHC-like HLA-DO (DO) protein, which binds to and modulates the peptide loading ability of HLA-DM (DM; H2-M in mice), has not been shown to cause any significant deviation in immune function. Variations in the presentation of both antigenic and self-peptides have, however, been documented. Therefore, we sought to subtly alter MHC class II (MHCII) Ag processing and presentation in non-obese diabetic (NOD) mice by over-expressing the DM-modulator, DO specifically in dendritic cells (DCs).
Our studies show, that NOD mice over-expressing DO (NOD.DO) in DCs never develop T1D. DO expression in DCs, prevented the infiltration of lymphocytes into pancreatic islets (insulitis), however, NOD and NOD.DO mice had similar levels of peri-islet lymphocytic infiltration. Remarkably, DO-over expression was required in only half of NOD DCs to mediate protection. NOD.DO mice were also partially protected from T1D after challenge with diabetogenic T cells from newly diabetic NOD mice. In stark contrast to T cells from NOD mice, NOD.DO T cells did not promote the rapid development of T1D when transferred into immunocompromised NOD.scid recipients supporting that NOD.DO T cells have not been primed, most likely due to limited antigen availability. Studies are underway to determine the mechanism by which DO over-expression in NOD DCs mediates protection from T1D.
Molecular modeling and simulation studies of CD1 binding proteins (78.3)
Authors: Faraldo-Gómez José D , Garzón Diana 
Published: January 2023

Abstract
The presentation of small protein fragments, both foreign and native, on the surface of specialized cells is one of the cornerstones of our immune system. In complex with MHC binding proteins, these protein antigens will be recognized by T-cell membrane receptors either as self or non-self, and an appropriate response will be initiated. In recent years it has become apparent that immune responses may also be induced by a diverse array of lipid antigens. The presentation of these antigens involves a class of binding proteins referred to as CD1, analogous to MHC proteins. The CD1 family includes 5 isoforms of distinct specificity, of which CD1a, CD1b and CD1d have been characterized structurally in complex with diverse lipid antigens. Here we report the results of extensive computer simulation studies of this family, from which we gain insights into the mechanism of lipid binding. We also present a molecular model of CD1c, and based on this, rationalize its specificity for branched mycobacterial lipids.
IVIg decrease antigen-dependent T cell activation by reducing the FcγR-dependent antigen presentation ability of APC (78.36)
Authors: Aubin Eric , Paquin Proulx Dominic , Lemieux Real , Bazin Renee 
Published: January 2023

Abstract
Intravenous immunoglobulins (IVIg) have been shown to have anti-inflammatory effects in a variety of autoimmune diseases, but their mechanisms of action remain unclear. In autoimmune diseases, activated self-reactive T cells invade specific tissues and activate local APC which in turn present autoantigens on their surface, leading to T cell restimulation in a positive feedback loop. Although it was shown that IVIg could reduce T cell activation and modify their cytokine secretion pattern, it is still not clear whether this effect occurs following a direct interaction of IVIg with T cells or through an interference of IVIg with the ability of APC to present autoantigens. To address this question, we used an in vitro antigen presentation system using ovalbumin as model antigen, to study the effects of IVIg on antigen-mediated T cell activation. The results obtained showed that IVIg inhibited T cell activation but that this effect was the indirect consequence of a reduction in the antigen presentation ability of APC. We further showed that this inhibitory effect was not due to modulation of expression of MHC II or CD80/86 costimulatory molecules on the surface of APC and was independent of inhibitory FcγRIIb. Finally, we showed that F(ab')2 fragments of IVIg had no effect on antigen-mediated T cell activation, suggesting that IVIg must interact with activating FcγRs to mediate their inhibitory effect.
Listeriolysin O is strongly immunogenic on multiple MHC backgrounds (78.42)
Authors: Carrero Javier A , Vivanco-Cid Hector , Unanue Emil R 
Published: January 2023

Abstract
Listeriolysin O (LLO) is a key virulence determinant of the intracellular microbial pathogen Listeria monocytogenes. Previous work has shown the ability of LLO to induce a wide range of biological effects, including cytokine secretion, MAP kinase signaling, cellular lysis and apoptosis. LLO is also the source of immunodominant antigenic determinants for both CD4 and CD8 T cell responses against L. monocytogenes on multiple MHC backgrounds. We have examined the presentation of LLO protein delivered as a soluble antigen and after bacterial infection. LLO is a powerful immunogen, eliciting T cell responses at femtomolar levels of presentation in vitro. In vivo immunization with LLO in incomplete Freund's adjuvant led to the induction of a robust CD4 and CD8 T cell response as detected by ELIspot. This effect can be shown with APC and T cells derived from C57/BL6 (H-2b), C.B-17/Balb/c (H-2d) and B6.g7/NOD (H-2g7) haplotypes. Interestingly, there is an immunogenicity cluster located in domains 2 and 3 of LLO which donates most of the MHC-II epitopes for presentation. We have engineered non-hemolytic mutants of LLO and can show that they are also presented with great efficiency to CD4 T cells. Addition of ectopic antigens derived from ovalbumin and hen-egg lysozyme to the amino-terminus of LLO allowed for robust presentation to CD4 T cells directed to these antigens. Our initial data suggests that LLOs ability to be a potent antigen is based on a very fast and efficient uptake and catabolism by APC. We detected maximal presentation to T cells within 30 minutes of giving LLO to APC. APC also internalized LLO and catabolized it completely to TCA precipitable peptides within 6 hours of treatment. We conclude that LLO is a good candidate for delivering antigenic peptides in vivo and in vitro.
Transforming Growth Factor β-Dependent Inhibition of CD1d1-Mediated Antigen Presentation (78.6)
Authors: Bailey Jennifer C. , Renukaradhya G. J. , Brutkiewicz Randy R. 
Published: January 2023

Abstract
CD1d is an antigen presenting molecule structurally similar to MHC class I and presents lipid antigens to natural killer T (NKT) cells. We have previously shown that the mitogen-activated protein kinases (MAPK), p38 and ERK1/2, reciprocally regulate CD1d-mediated antigen presentation--p38 activation leads to its inhibition, whereas ERK1/2 activation leads to its promotion. Transforming growth factor β (TGFβ) is a strong regulator of immune responses as well as cell proliferation, apoptosis and differentiation, and can induce the activation of p38. Our studies have shown that CD1d-mediated antigen presentation is inhibited by TGF β in murine LMTK fibroblasts expressing CD1d. Similar inhibition occurs after TGF β treatment of bone marrow-derived dendritic cells (BMDC). Our studies are aimed at dissecting the mechanisms by which TGF β influences CD1d-mediated antigen presentation. This work is supported by NIH grant PO1 AI056097 to RRB.