bluuebunny/crossref_metadata_2025_split huggingface dataset:
Suppression of Collagen-Induced Arthritis with Type-II collagen peptide linked Soluble MHC II (I-Aq) molecules (131.12)
Authors: Park Yoon-Kyung , Jung Sundo , Park Se-Ho 
Published: January 2023

Abstract
In collagen-induced arthritis (CIA) of mouse, self-reactive T cells recognize a peptide antigen from type II collagen (CII). CII is of particular interest, as an autoimmune response to this protein leads to CIA in mice, rats, and primates. Activation of T cells is believed to be an important pathogenic factor in autoimmune disease. So, T cells have become a focal point of study for the development of novel therapeutic approaches to the treatment of autoimmune disease. In this study, we evaluated the efficacy and mechanism of recombinant MHC II molecules in regulation of the antigen-specific T cell clones by using mouse I-Aq, combined with an auto-antigen peptide from type II collagen (CII260-274) in CIA model. It was found that recombinant I-Aq/CII260-274 molecules not only activate CII-specific T cell clone but also inhibit the same clone in vitro according to the condition of stimulation. Furthermore, development of CIA in mice was successfully prevented by the in vivo injection of a recombinant soluble I-Aq/CII260-274. Thus, recombinant soluble MHC II molecules, complex with the immuno-dominant self peptide, offer a new possibility for the treatment of chronically active autoimmune inflammation such as rheumatoid arthritis.
Determination of genetic factors influencing susceptibility to disease and response to interferon-B in multiple sclerosis (131.16)
Authors: O’Doherty Catherine , Hawkins Stanley , Hutchinson Michael , Vandenbroeck Koen 
Published: January 2023

Abstract
Treatment strategies of multiple sclerosis (MS) aim to slow progression of the disease and provide symptomatic relief. Interferon B (IFN B) is the most prominent disease modifying drug used in the treatment of MS. It has been shown to decrease relapse rates and delay progression of the disease. There are currently three proprietary IFN B products on the market; Avonex and Rebif (IFN B1a), and Betaferon (IFN B1b). Despite demonstrated efficacy, these products are not without their problems. There is considerable variation in response, with an estimated 30–50% of patients showing treatment failure, and high treatments costs. In essence, treatment is on a trial and error basis. To date there is no method of treatment outcome prediction at onset of treatment. In this study we have screened approximately 60 polymorphisms in over 30 candidate response genes, based on notions of their known function and the literature. We selected SNPs in the promoter region, hypothesising that polymorphisms may modify IFN inducibility. Additionally non-synonymous SNPs and those potentially affecting splicing, were also selected. Polymorphisms were typed in DNA samples from 260 Irish patients classified as responders or non-responders. A cohort of 120 healthy controls was also included in the study to determine whether these SNPs influenced susceptibility to MS.
In vivo therapeutic potential of classes B and R inhibitory oligonucleotides (INH-ODH) for animal lupus (131.18)
Authors: Lenert Petar , Pareigis Elizabeth R. , Seyfer Sarah , Lawry Molly , Ashman Robert F. 
Published: January 2023

Abstract
TLR receptors are implicated in the pathogenesis of systemic lupus erythematosus. Interestingly, MRL mice lacking TLR9 develop more aggressive kidney disease, while those lacking TLR7 show a milder disease. INH-ODNs (linear, Class B) have recently been developed that can block TLR9 activation at low nanomolar concentrations. This holds true particularly for INH-ODNs made with the nuclease-resistant phosphorothioate backbone (PS). Here we show that (PS)-INH-ODNs, in addition to blocking TLR9 stimulation, can also block TLR7 stimulation of mouse macrophages and B cells induced by several (but not all) TLR7 ligands like imiquimod, loxoribine, CL075, CL097 and CL087. Interestingly, certain TLR7/8 ligands escape inhibition by INH-ODNs and may actually enhance B cell G1-M entry, survival and polyclonal IgM secretion. Both inhibition and enhancement are independent of the TLR9 expression. We have recently refined these ODNs to produce INH-ODN sequences capable of forming stable secondary structures. These “innate” INH-ODNs (Class R) showed higher potency for macrophages, dendritic cells and marginal zone B cells over follicular B cells, in vitro. In vivo, both linear and Class R INH-ODNs provided better survival and ameliorated spontaneous lupus disease in MRL-lpr/lpr mice.
This work was supported by NIH grant 1 R56 AI064736-01A2 and by a grant from the Carver Trust fund.
Modulation of CD4+Foxp3− T-cells with a JAK-STAT5 kinase inhibitor (131.2)
Authors: Davoodi-Semiromi Abdoreza , Cheikhi Amin , Xia ChangQing , Litherland Sally , Clare-Salzler Michael 
Published: January 2023

Abstract
In this study we report AG490 treatment reprograms CD4+CD25− Fox3−T-cells into Foxp3 expressing T-cells which possess regulatory function both in-vitro and in-vivo. CD4+CD25− Fox3−T-cells from transgenic BALB/c DO11.10 mice became Foxp3+ when treated in-vitro with AG490. These T-cells possessed regulatory function as they suppressed proliferation of syngenic responding population (CD4+CD25− T-cells) in response to OVA323–329 peptide in-vitro. Purified CD4 T-cells from BALB/c mice treated with AG490 failed to suppress proliferation of transgenic CD4+CD25− T-cells of BALB/c DO11.10 suggesting antigen-specific function of converted population. Our in-vivo preliminary data regarding adoptive co-transfer of bulk CD4+CD25− Foxp3−T-cells treated with AG490 and diabetogenic splenocytes delayed onset of diabetes in 20% of treated mice for 9-weeks. Furthermore we show treatment of diabetic NOD.scid mice (recipient of diabetic splenocytes and CD4+CD25− T-cells) with AG490 increased numbers of CD4+CD25+Foxp3+ T-cells when compared with the same population in B6 and NOD mice and posses regulatory function. Splenocytes of treated mice were anergic to anti-CD3 and CD28 stimulation and purified CD4+CD25+ T-cells suppressed proliferation of responding population in-vitro. In this report, we for the first time uncovered new properties of AG490 in the immune system by demonstrating upregulation of Foxp3 in CD4+CD25− T-cells and propose that NOD islet antigen-specific CD4+Foxp3− T-cells reprograms by AG490 may significantly delay/prevent onset of diabetes in NOD mice.
This study is supported by a JDRF innovative grant awarded to ADS (5-2006-937) and in part by a grant awarded to MCS (JDRF # 1-2004-690).
Fc dependent mechanisms are necessary for ADCC and effective depletion of murine B cells by humanized anti-CD19 mAb. (131.27)
Authors: Groves Christopher J , Wang Y , Sims G P , Kuta E , Rowe D , Ward E , Mittereder N , Carlesso G , Cheng L , Cook K , Tedder T , Damschroeder M , DallAcqua W , Kiener P , Herbst R , Coyle A J 
Published: January 2023

Abstract
B cell depletion is an effective treatment for autoimmune diseases and B cell malignancies. Successful B cell depletion may be limited by the surface expression of the target antigen. CD19 represents an attractive molecular target that is expressed on the surface of early B cell progenitors through the latter stages of B cell differentiation. In this study we developed a fully humanized CD19 monoclonal antibody mAb 19-1 and two variants with either reduced (19-2) or enhanced (19-3) Fc-FcR binding and evaluated their potential to deplete B cells. In vitro antibody-dependent cellular-mediated cytotoxicity (ADCC) activity of 19-3&gt;19-1&gt;19-2 on human peripheral blood B cells as well as B cell lines (Raji, Daudi, and Ramos) by LDH release or Granzyme B assays. We evaluated in vivo depletion in human CD19 transgenic mice using 19-1, 19-2, and 19-3. 19-1 at 50 ug/mouse i.v. depleted most B cells in blood, spleen, and bone marrow after 7 days following treatment. 19-2 showed little depletion of B cells at a high dose, whereas 19-3 efficiently eliminated B cells in the spleen and blood at low dose. These data demonstrate that transgenic mice expressing human antigens provide an excellent model for testing humanized antibodies in depletion studies, and that Fc-FcR interactions represent the most important mechanism. Targeting B cells with anti-CD19 mAb may be a more effective strategy than existing B cell depletion protocols.
The Impact of B Lymphocyte Depletion on the Pathogenesis of Autoimmune Diabetes (131.28)
Authors: Zekavat Ghazal , Migone Thi-Sau , Roses Robert E , Cancro Michael P , Naji Ali , Noorchashm Hooman 
Published: January 2023

Abstract
NOD B cell development is characterized by a defective homeostatic checkpoint in B cell maturation and selection. Having demonstrated that the progression of autoimmune diabetes requires antigen presentation by B-lymphocytes, we hypothesized that B cell depletion may prevent diabetes progression in NOD mice. Here, we employed two distinct approaches for in vivo B lymphocyte depletion:
a cohort of adult hCD20 Tg NOD mice were treated with the B lymphocyte depleting mAb, Rituximab (anti-CD20) anda cohort of adult NOD mice were treated with a neutralizing Hamster anti-mouse mAb specific for the B cell survival factor, BLyS/BAFF.
Treatment with both Rituximab (2mg/injection x3doses) and anti-BLyS mAb (100?g/injection x2 doses) led to B cell depletion within 10 days. BLyS/BAFF neutralization, using anti-BLyS, caused a profound depletion of mature/recirculating B cells in these mice and lasted for &gt;30 days. Diabetes occurred within 2 weeks in all Rituximab treated female hCD20 Tg NOD mice (n=4); despite their early backcross generations (i.e., N4-6F1) onto the NOD genetic background. Conversely, adult female NOD/LtJ mice (n=20), B cell depleted using anti-BLyS/BAFF did not progress to diabetes for &gt;30 days following treatment. Collectively, these results indicate that BLyS/BAFF neutralization may be required for the prevention of autoimmune diabetes following B lymphocyte depletion.
MHC polymorphism translates T cell tolerance into B cell autoimmunity. (131.29)
Authors: Ellis Jason Scott , Bell J. Jeremiah , Khapli Shruti , Divekar Rohit D. , Haymaker Cara L. , Yu Ping , Lee Hyun-Hee , Jain Renu , Tartar Danielle M. , Hoeman Christine M. , Guloglu F. Betul , Zaghouani Habib 
Published: January 2023

Abstract
Experimental allergic encephalomyelitis (EAE) is a mouse model for human multiple sclerosis (MS). While effective treatments of EAE have been developed, adapting these for use in human MS has proven difficult and therefore investigations into this model continue. Here, we examine the effects of MHC polymorphism on the control of tolerance. Our previous studies have shown that treatment of EAE with immunoglobulins (Ig) containing proteolipid protein (PLP) or myelin oligodendrocyte glycoprotein (MOG) epitopes reverses ongoing disease in both SJL/J and C57Bl/6 mice. We used F1(SJL/J x Bl/6) mice to test Ig-PLP and Ig-MOG for reversal of compatible as well as “in trans” EAE wherein disease induced by MOG epitope is treated with Ig-PLP and EAE induced by PLP epitope is treated with Ig-MOG. The findings indicated that EAE induced in F1 mice by PLP is successfully treated with Ig-PLP or Ig-MOG. However, an asymmetrical effect was observed for the treatment of MOG EAE whereby Ig-MOG reverses MOG EAE while Ig-PLP exacerbated MOG induced EAE. The mechanism underlying disease exacerbation correlated with a cytokine-induced Ig class switch among anti-MOG antibodies during treatment with Ig-PLP.
Research supported by grant NS37406 from NIH.
Follistatin Like Protein-1 is a Marker of Inflammation (131.31)
Authors: Clutter Suzanne Davis , Marinov Anthony D , Wilson David C , Vilaiyuk Soamarat , Hirsch Raphael 
Published: January 2023

Abstract
Follistatin-like protein-1 (FSTL-1) is a poorly characterized gene which we have recently shown to be a novel proinflammatory molecule. FSTL-1 is overexpressed in mouse paws during early arthritis, especially at the interface of synovial pannus and eroding bone. In this study we evaluated FSTL-1 expression following inflammation in both mice and humans in order to characterize the role of FSTL-1 in inflammation. Mice inoculated with complete Freunds’ adjuvant in paws, LPS in the peritoneal cavity, or pseudomonas aeruginosa in the lungs displayed an elevation of FSTL-1 protein, similar to that found in arthritic mice. In addition, utilizing quantitative PCR and ELISA specific for FSTL-1, we demonstrated increased FSTL-1 expression in the heart and brain following LPS peritoneal injection. Finally, FSTL-1 is increased in sera of patients with juvenile rheumatoid arthritis and Kawasaki Disease, compared to normal aged-matched control patients. These observations suggest that FSTL-1 is a potential biomarker of inflammation and may be a novel target for therapy.
This work was supported in part by National Institutes of Health grants AI44566 and T32AR052282.
Endogenous Nitric Oxide Carrier S-nitrosoglutathione Attenuates Experimental Autoimmune Encephalomyelitis by Maintaining a Fine Balance between Th1/Th2 Immune Responses (131.32)
Authors: Nath Narender , Giri Shailendra , Morinaga Osamu , Singh Avtar K , Singh Inderjit 
Published: January 2023

Abstract
The carrier of nitric oxide S-nitrosoglutathione (GSNO) is an antioxidant and neutralizes oxidative stress, here we have evaluated its efficacy in EAE and T cell functions. Oral administration of GSNO (0.5 or 1.0 mg/kg) reduced the disease progression in chronic models (SJL or C57BL/6) of EAE induced with PLP(139-151) or MOG(35-55) peptides. The attenuation of EAE was mediated by less infiltration of CD4 T cells in CNS and a balance between Th1/Th2 immune responses. Recall responses and production of Th1 (IFNgamma&#61481; cytokine was not affected by GSNO treatment in antigen specific T cells however under these condition myelin specific IL4 secreting Th2 cells were present. GSNO treatment neither induces apoptosis nor hampers T cell activation. Consistent with myelin specific T cells, production of IFN from naïve T cells were unaffected whereas IL4 was induced. Further, the phosphorylation of STAT4 or 6 and expression of Tbet or GATA3 were not inhibited suggesting that both Th1/Th2 cell mediated immune responses were intact with GSNO. The 2D2 MOG(35-55) TCR transgenic T cells in naïve host following immunization and GSNO (0.5 or 1.0 mg/kg) treatment differentiated into Th1 and Th2 clones. Further, GSNO (0.5mg/kg) treatment efficiently reduced the clinical severity of EAE in MOG transgenic mice without affecting the production IFNgamma from myelin CD4 cells. These results suggest the efficacy of GSNO in attenuation of EAE by maintaining a balance between Th1/Th2 cell immune responses which can be exploited in the treatment of autoimmune diseases.
This work was supported in parts by grants NS-22576, NS-34741, NS-37766, NS-40810 and NS-40144 from NIH.
Migration inhibitory factor modulates experimental autoimmune encephalomyelitis through a novel combination of suppressive mediators (131.34)
Authors: Kithcart Aaron P , Powell N , Williams J , Gatson N , Papenfuss T , Gienapp I , Shawler T , Satoskar A , Whitacre C C 
Published: January 2023

Abstract
Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), is more prevalent in women than men. Recent studies suggest that the cytokine migration inhibitory factor (MIF) plays a role in the progression of MS and experimental autoimmune encephalomyelitis (EAE). We have shown that MIF−/− mice have decreased EAE severity relative to wt controls. Here, we evaluate the role of MIF in the context of known suppressive hormones. Serum levels of corticosterone (CORT) and testosterone (TEST) were measured prior to and following EAE induction in the presence and absence of MIF. Basal levels of TEST in MIF−/− mice were notably higher than controls; basal levels of CORT were low and similar between groups. Following EAE, there was little change in CORT and TEST in wt mice; however, TEST decreased and CORT increased in MIF−/− mice following immunization. To evaluate the role of TEST, we removed the testes of male MIF−/− mice and induced EAE. We found no difference in disease severity whether MIF−/− mice were gonadectomized or not; control mice had significantly more severe EAE in the absence of TEST. These findings suggest that CORT plays a larger role than TEST in disease progression, although both hormones appear to be influenced by MIF. Further study of the mechanism of MIF could lead to improved therapies for a variety of autoimmune diseases.
(Supported by NIH grant AI 064320 and National MS Society grant RG3272)
Ingestion of lactobacilli delays lupus development by stimulating APC in (NZBxNZW)F1 mice (131.35)
Authors: Manirarora Jean N. , Kosiewicz Michele M. , Parnell Sarah A. , Alard Pascale 
Published: January 2023

Abstract
Various defects in T cells and APC have been associated with lupus in (NZBxNZW)F1 (BWF1) mice. We and others have found that BWF1 mice exhibit lower number of CD4+CD25+ regulatory cells and impaired APC function. Lactobacilli have been shown to prevent colitis and diabetes in autoimmune-prone mice and are used to treat intestinal inflammation and allergic disease in humans. Since viruses and parasites can prevent lupus in BWF1 mice, we examined whether lactobacilli ingestion would have a similar effect. After feeding BWF1 mice with three different strains of lactobacilli, we found that both anti-dsDNA antibody production and lupus severity were delayed. Next, we tested the effect of lactobacilli ingestion on APC in vivo. We found that lactobacilli upregulated B7.1 on both macrophages and dendritic cells (DC) in the LN of BWF1 mice. Finally, we characterized the effect of lactobacilli and lipoteichoic acid (LTA), a bacterial cell wall component, on bone marrow-derived DC in vitro. Interestingly, we found that lactobacilli and LTA restored the expression of all costimulatory molecules and triggered production of high levels of IL-10 vs IL-12. Together, these data suggest that lactobacilli-mediated lupus prevention is associated with induction of IL-10 producing APC which may ultimately restore immune regulation in BWF1 mice.
Supported by the Lupus Research Institute.
Induced Organ-Specific T Regulatory (Treg) Cells Prevent Autoimmunity by Reducing the Ability of Dendritic Cells (DC) to Present Self-Antigen. (131.4)
Authors: DiPaolo Richard J , Davidson Todd S , Andersson John , Brinster Carine , Shevach Ethan M 
Published: January 2023

Abstract
Foxp3− T cells can be converted to Foxp3+ T reg cells by T cell stimulation in the presence of TGFb. TGFb-induced Tregs (iTregs) have been shown to prevent the induction of autoimmunity although little is known about their mechanism of action in vivo. Here we demonstrate that naïve CD4+Foxp3− T cells specific for the gastric parietal cell antigen, H+/K+ ATPase, can be converted to Foxp3+ T regulatory cells following TCR activation in the presence of TGFb. The iTregs were anergic to TCR stimulation, failed to produce effector cytokines, and were suppressive in vitro. When co-transferred with disease inducing CD4+ T cells, the iTreg were long lived in vivo and were able to prevent organ-specific autoimmunity. iTregs prevented the initial activation and expansion of autoreactive T cells in response to H+/K+ ATPase presented by DC in the gastric lymph node. Gastric lymph node DC from animals that were treated with iTreg had a markedly reduced ability to stimulate H+/K+ ATPase-specific T cells in vitro. When stimulated by peptide in vitro, iTregs mediated the downregulation of the costimulatory molecules CD80 and CD86, but not MHC class II or CD40, on the surface of DC. These data demonstrate that the autoantigen presenting DC is the major target for Treg mediated suppression in vivo, and raise the possibility of using TGFb to generate large numbers of organ-specific Tregs to prevent and possibly treat autoimmunity.
How PPARγ Mediates Immunoregulation: An Integral Role for PPARγ in Regulatory T cells (131.6)
Authors: Wohlfert Elizabeth A , Clark Robert B 
Published: January 2023

Abstract
Ligands for the nuclear hormone receptor PPARγ, which are used to treat human type 2 diabetes, also down-regulate APCs and pathogenic T cells. While these effects may underlie the recent demonstration of the efficacy of PPARγ ligands in treating autoimmunity, a role for PPARγ in CD4+CD25+ natural regulatory T cells (TR) has not yet been examined. Strikingly, we found that murine ex-vivo TR express 10-fold higher levels of PPARγ than naive CD4+CD25− T cells (Teff). To examine whether the immunotherapeutic effects of the synthetic PPARγ ligand Ciglitazone (Cgl) involve TR we used the C57BL/6 (WT) Teff → bm12 model of GVHD. Neither ex-vivo TR alone nor Cgl alone was capable of preventing disease. However, Cgl administered with TR significantly ameliorated GVHD. We generated mice with PPARγ-null T cells (T-PPAR) and found that T-PPAR TR were unable to mediate Cgl’s effect. Thus, PPARγ-expressing TR are required for Cgl’s immunotherapeutic effect. We next asked if PPARγ signaling via endogenous ligands, in the absence of synthetic ligands, might also play an important role in TR function. Transfer of in-vitro activated WT TR significantly ameliorated GVHD, with 90% of bm12 mice surviving the disease. In contrast, activated T-PPAR TR were significantly less effective in suppressing disease, with only 40% of bm12 mice surviving. Overall, our results demonstrate for the first time an integral role for PPARγ in TR function.
MHC variant peptide control of experimental autoimmune encephalomyelitis (131.8)
Authors: Rosenthal Kristen M , Evavold Brian D 
Published: January 2023

Abstract
Experimental autoimmune encephalomyelitis is a CD4+ T cell mediated disease of the central nervous system used as a rodent model to study multiple sclerosis. Epitope spread, or reactivity to epitopes distinct from the disease-inducing antigen, in the CNS correlates to relapses in the relapsing-remitting form of both MS and EAE. Treatments specific to the initiating epitope in EAE have been successful in inhibiting the response to that epitope, but not to subsequent epitopes. We have previously shown inhibition of EAE induction, as well as treatment of symptoms, using variants of the initiating peptides with mutations in the MHC contact residues to decrease stability of the peptide:MHC complex. Here, we demonstrate that pre-immunization with an MHC variant of the first epitope results in a significant reduction of disease induced with both the first and second epitope but not the second epitope alone. Using the R-EAE mouse model in SJL mice, an MHC variant of the initiating antigen is able to inhibit subsequent relapses upon treatment during the primary phase of disease symptoms. This data implies that inhibiting one epitope with an MHC variant peptide may also inhibit subsequent epitope-reactivity, suggesting that antigen specific treatment need not include all possible antigens associated with MS to stimulate a response to treatment.
This work is supported by NIAID (R01 AI56017) and NMSS (RG 3683)
Label-free dectection of cytotoxic antigen-specific T cells with semiconductor Nanowires: (132.10)
Authors: Fahmy Tarek M , Stern Eric , Reed Mark 
Published: January 2023

Abstract
Detection of T cell mediated disease and vaccine-induced immunity has been made possible by the discovery of MHC restricted recognition of peptide by T cells. Current approaches for detection of antigen-specific T cells rely on the use fluorescently labeled-soluble forms of multivalent MHC-peptide complexes or functional assays. We have developed a solid-state semiconductor nanowire technology for label-free direct detection of antigen-specific T cell subsets reactive to their specific antigens. The approach is simple, fast, sensitive and integratable into clinical settings. We describe this technology and demonstrate its feasibility in the in vitro detection of 100–1000 murine antigen-specific T cells in a label-free fashion.