bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intestinal IL-25 signal and ILC2 regulates the susceptibility to IgE-mediated experimental food allergy (MUC8P.813)
Authors: Lee Jee-Boong , Chen Chun-Yu , Liu Bo , Burwinkel Karen , Hogan Simon P , Finkelman Fred , Wang Yui-Hsi 
Published: January 2023

Abstract
Food allergy is an IgE-mediated disorder manifested by uncontrolled type-2 immune response in the gastrointestinal tract. Little is known about the underlying mechanisms that drive the propensity to develop food-induced intestinal hypersensitivity. IL-25 is a distinct member of IL-17 inflammatory cytokine family, functioning at evoking type-2 inflammatory response. We aimed at investigating the involvements of IL-25 and its responding cells in the development of IgE-mediated experimental food allergy. We observed that IL-25 expression was rapidly elevated in the epithelium of inflamed duodenum before the onset of anaphylactic reaction to ingested allergens. Mice overexpressing intestinal IL-25 or deficient of IL-17RB displayed exacerbated or attenuated symptomatic features of IgE-mediated experimental food allergy, respectively. Subsequent analysis revealed that Lin-IL-17RB+ type-2 innate lymphoid cells (ILC2) that reside in the laminar propria of small intestine prior to the development of IgE-mediated experimental food allergy are the primary producers of Th2 cytokine, IL-5 and IL-13, in response to IL-25 stimulation. Furthermore, irradiated mice reconstituted with bone marrow cells that are deficient of RoRα or IL-17RB became resistant to developing IgE-mediated experimental food allergy. Our results suggest that intestinal ILC2 residents are poised to respond to induced IL-25 and function in promoting the development of IgE-mediated experimental food allergy.
Neonatal immunization with insulinoma-released exosomes induces humoral immune response that protects islets from autoimmune pathogenesis (THER5P.835)
Authors: Dai Yang , Rahman Muhammad , Bashratyan Roman , Regn Danielle 
Published: January 2023

Abstract
Exosomes (EXOs) are immunostimulatory microvesicles that can activate both innate and adaptive immunity. We have demonstrated that autoreactive B and T cells in prediabetic non-obese diabetic (NOD) mice can recognize EXOs released by insulinoma. In this study, we examined EXO-specific humoral immune response and its contribution to the islet-specific autoimmunity. We immunized NOD neonates with EXOs, in which mature T cells are rare, and then monitored antibody and B cell responses to EXOs in 4- or 8-week-old mice. At 4 weeks, the immunized mice showed increased B cells in pancreatic lymph nodes but not in spleen as compared with untreated mice. EXO-specific serum Ig titers remained higher than the controls. At 8 weeks, the immunized group had higher IgG1 but lower IgG2a and increased expression of FoxP3 and PD1 on Th cells, suggesting a Th1/Th2 shift and induction of regulatory T cells. As a result, the neonatal-immunized mice remained insulitis-free till 8-week old, whereas, age/gender-matched control mice developed insulitis. This effect can be partially explained by the induction of protective, EXO-specific antibodies, since the immunized sera were inhibitory for CD86 expression on activated B cells, more efficient than control sera and in vivo, the sera protected islets from insulitis caused by diabetogenic T cells. Thus, EXOs may contain unique antigen(s) that could be used as neonatal vaccine to prevent autoimmunity.
A targeted peptide controls and reverses type 1 diabetes. (THER5P.838)
Authors: Vaitaitis Gisela , Olmstead Michael , Waid Dan , Wagner David 
Published: January 2023

Abstract
CD40-CD154 interaction is decisive in directing autoimmune inflammation; therefore, controlling this interaction and hence destructive inflammation is a major goal in a number of autoimmune diseases including Type 1 Diabetes (T1D). Initial attempts to block CD40-CD154 interaction used antibody, random peptides, and small organic molecules, which all were problematic. Therefore an efficacious treatment remains a major goal. Here we reveal a unique targeted peptide, KGYY15, based on the domain of CD154 that binds to the CD40 receptor. Immunoprecipitation utilizing the peptide demonstrates that it binds directly to the CD40 receptor protein which in turn alters the CD40 signaling outcome. KGYY15 prevents T1D in 87% of non-obese diabetic (NOD) mice and histology reveals significant decreases in β-islet infiltration. Interestingly, KGYY15 treatment reverses overt hyperglycemia in 80% of new onset diabetic mice with significant improvement in β-islet insulin granule score. Structure-activity relationship studies demonstrate that the 15-mer peptide is optimal for efficacy and that five specific amino acids are critical in its activity. KGYY15 is well tolerated and functions to control the culprit Th40 effector T cells that are causative in T1D. The peptide sequence is 80% homologous to the human sequence suggesting an important candidate for translational studies.
Eradication of surface MHC class Ia expression in an insulinoma cell clone by TALEN-mediated gene deletion prevents recognition by diabetogenic CD8+ T cells (THER5P.843)
Authors: Hess Paul , Gojanovich Gregory , Holmes Jennifer 
Published: January 2023

Abstract
In type 1 diabetes, islet transplantation to replace β cells killed by pathogenic T cells is a promising means of attaining insulin independence; however, graft durability is limited by auto- & alloreactive responses. While autologous stem cells ultimately may circumvent the latter obstacle, the inciting CD8+ T-cell effectors are a threat to long-term engraftment. Islet cell manipulation to prevent expression of class Ia molecules could render them “invisible” to diabetogenic CTL, & we hypothesized that transcription activator-like effector nucleases (TALENs) could be used to engineer this modification. TALENs designed to flank a Bgl1 site in exon 1 of H2-Kd/Db were transfected into the NOD insulinoma line NIT-1, & cells with high nuclease activity were sorted using a GFP reporter plasmid encoding the target sequence. A clone isolated by limiting dilution (KG) was negative for H2-Kd/Db surface expression, & PCR amplicons were resistant to Bgl1 digestion. Genomic DNA sequencing showed biallelic modifications of both genes, with one Db sequence containing a 4 bp insertion. The remaining 3 alleles appeared to be repaired by gene conversion, causing frameshift mutations. When pulsed with cognate peptide, KG failed to stimulate diabetogenic CD8+ T cells purified from TCR-transgenic NOD.8.3 mice, as measured by CFSE dilution & IFN-γ production. These data demonstrate that TALEN-mediated genomic modification of insulin-producing cells can prevent recognition by autoreactive CTL.
CD354 in lupus nephritis (THER5P.825)
Authors: Du Yong , Wu Tianfu , Agac Didem , Zhou XinJin , Davis Laurie , Mohan Chandra 
Published: January 2023

Abstract
CD354, Triggering Receptor of Myeloid Cells -1 (TREM-1), is a potent amplifier of myeloid immune responses. Our goal is to determine the expression and function of TREM-1 in lupus nephritis. We used an anti-glomerular basement membrane antibody-induced nephritis (anti-GBM) model, which shares pathologic features with lupus nephritis (LN). 5 days after mice were sensitized with rabbit IgG in adjuvant, the mice received anti-GBM serum i.v. to induce disease. Anti-GBM treated 129x1/svJ mice developed severe nephritis and B6 mice did not. Anti-GBM disease induced elevated urine sTREM-1 levels in 129x1/svJ (dys 7-21) compared to B6 mice. TREM -1 blockade with an inhibitory peptide ameliorated renal inflammation compared to control peptide. TREM-1 blockade inhibited proteinuria and renal disease as measured by GN class, severity of tubulo-interstitial disease, crescent formation, and inflammatory cell infiltrates. Elevated sTREM-1 levels were detected in serum of spontaneous LN models and in their renal biopsies. Elevated TREM-1 levels were detected in serum of lupus nephritis patients and in SLE renal biopsies. We found that elevated TREM-1 expression in 129x1/svJ mice has importance pathologic consequences. TREM-1 is amenable to therapeutic targeting for nephritis. These studies could be important in understanding of pathogenic mechanisms driving SLE renal disease
Massive monoclonal expansion of functionally stable human regulatory T cells (THER5P.826)
Authors: Nowatzky Johannes , Manches Olivier , Bhardwaj Nina , Lafaille Juan 
Published: January 2023

Abstract
Adoptive Treg transfer is a promising therapeutic strategy for autoimmune diseases. Most current approaches rely on the enrichment and in vitro expansion of non-clonal, presumably thymus-derived Treg cells. Limitations include low expansion rates, contaminating effector cells, and unstable suppressive activity. Here, we hypothesized that cloning of human CD4+CD127lowCD25highFoxP3+HELIOS+ cells yields a highly pure cellular product with stable suppressor function throughout repeated re-expansion cycles. Cloning was performed through selection for CD4+CD127lowCD25+ cells by magnetic bead isolation and expansion in limiting dilution conditions. Suppressor function was tested in suppression assays of CD3/CD28-stimulated allogeneic Teff cells. Clonality was assessed by Vbeta staining. To demonstrate validity of our approach for a human autoimmune disease we also cloned Treg from a patient with Behcet's disease, a multisystem vasculitis. Cloning efficiency was 2-5/100 seeded cells. Treg clones were homogenously CD4+CD127lowCD25highFoxP3+HELIOS+, and clonality was confirmed by staining for a unique TCR Vbeta chain. Clones maintained at least 80% suppression at a 1:4 Treg:Teff ratio over 8 weeks in in vitro culture. Expansion rate was up to 9.8 billion-fold. Our results indicate that massive expansion of human antigen-specific Treg clones is a feasible approach for the generation of large numbers of functionally stable regulatory T cells for preclinical and clinical testing.
Impact of myeloid-derived suppressor cells on adoptive immunity in autoimmune arthritis (THER5P.827)
Authors: Liu Peng , Crook Kristen , Weeks Michael 
Published: January 2023

Abstract
Abnormal B- and T-cell recognition of self-antigens and autoantibody production result in autoimmunity. We previously showed that myeloid-derived suppressor cells (MDSCs) suppress T cell proliferation in autoimmune arthritis. To further explore the impact of MDSCs on B cells, we examined B cell functions in vitro and in vivo in collagen-induced arthritis. We found the proliferation of collagen-primed B cells was inhibited by autologous monocytic MDSCs, but not by Ly6G+ neutrophils. The production of both IgG and IgM was reduced in the supernatant of B cell and monocytic MDSC co-cultures as compared to the supernatant from B cells alone or the supernatant from B cell-Ly6G+ cell co-cultures. Mechanistically, the levels of iNOS and PGE2 increased in the B cell-MDSC co-cultures, and addition of either iNOS or PGE2 inhibitors abolished the MDSC suppression of B cell proliferation. While neutralizing IL-12 also reestablished B cell proliferation, blockade of IL-6 and TNFa did not show similar effect. Finally, adoptive transfer of monocytic MDSCs to collagen-immunized mice resulted in reduced autoantibody production and mitigated arthritis severity. In summary our data show that monocytic MDSCs suppress autoreactive B cell proliferation and antibody production. The suppressive function requires iNOS, PGE2 and IL-12, but is independent of IL-6 and TNFa. These MDSCs can potentially be used in cell-based therapy to treat autoimmune arthritis by limiting B cell functions.
Antigen-specific tolerance of diabetogenic T cells inhibits mTOR expression and function (THER6P.854)
Authors: Chen Weirong , Khairallah Marie-Therese , Miller Mindy , Ellis Jason , Ukah Tobechukwu , Zaghouani Habib 
Published: January 2023

Abstract
In prior studies we have shown that antigen-induced tolerance of diabetogenic Th1 cells leads to diminished expression of the transcription factor T-bet and downregulation of the chemokine receptor CXCR3. Consequently, the cells are retained in the spleen, can not traffic to the pancreas, and the mice are resistant to type 1 diabetes (T1D). Investigation of the molecular events underlying this form of Th1 tolerance indicates that expression of the mammalian target of rapamycin (mTOR), a conserved serine/threonine kinase involved in regulation of cell metabolism, is inhibited and its function is impaired. Specifically, phosphorylation of the ribosomal protein S6 kinase, a target of mTOR complex 1 (mTORC1) is decreased whereas mTORC2-dependent phosphorylation of AKTS473 is unaffected. In contrast, overexpression of mTOR or its positive regulator, Akt, by viral transduction nullifies antigen-induced tolerance and accelerates progression of T1D. Thus, mTOR plays a major role in the regulation of T cell activation and provides a useful target for modulation self-reactive T cells and suppression of autoimmune or type 1 diabetes.
The potent immunosuppressive role of Interleukin (IL)-37 in the pathogenesis of psoriasis (THER6P.846)
Authors: Li Jiong , Teng Xiu , Hu Zhonglan , Wang Zhen , Wei Xiaoqiong 
Published: January 2023

Abstract
IL-37 has emerged as a fundamental inhibitor of innate immune response. Psoriasis is thought to be initiated by abnormal interactions between cutaneous keratinocytes and systemic immune cells, triggering epidermal hyperplasia, increased inflammatory cells infiltration and high inflammatory mediator production. To research the presumed unique “cooling fires of inflammation” properties of IL-37 in psoriasis, we firstly found that IL-37 was abundantly distributed in human psoriatic plaques (mainly localized in effector memory T cells and macrophages not regulatory T cells). Further, we explored the possible immunomodulatory mechanism of IL-37 in psoriasis models in vitro and in vivo. IL-37 was effective in suppressing the production of chemokines, proinflammatory cytokines and antimicrobial peptides in human keratinocytes which recapitulated numerous features of psoriasis in vitro. IL-37 relieved the psoriatic symptoms of keratin14-VEGF Tg mice (widely-used psoriasis model) including thinner epidermis and diminished lymphocyte infiltration, and greatly dampened Th1 type cytokines production and mast cells recruitment in psoriatic lesions. Our results support the idea that the presence of IL-37 attenuates the inflammatory process in psoriasis by disrupting the linkage between innate immunity and adaptive immune response, indicating a hopeful therapeutic approach for immune-mediated disorders.
Targeting IL-6/STAT3 pathway with small-molecule compounds for multiple sclerosis therapy (THER6P.849)
Authors: Yang Yuhong , Li Chenglong , Nuro-Gyina Patrick , Lovett-Racke Amy , Racke Michael 
Published: January 2023

Abstract
Multiple Sclerosis is an immune-mediated chronic CNS disease where IL-6/STAT3 pathway plays a critical role in disease pathogenesis. Dysregulated IL-6/STAT3 signaling skews Teff/Treg balance toward an enhanced T effector response, favoring the development of CNS autoimmunity. Specifically, we previously showed IL-6 induces the development of highly encephalitogenic Th17 cells, suggesting IL-6/STAT3 pathway may serve as an innovative target. In support of this strategy, both IL-6-/- and STAT3-/- mice are completely resistant to EAE. Therefore, we designed four small-molecule lead compounds targeting IL-6/STAT3 pathway. MDL-5 and MDL-16 bind to the D1 domain of GP130, preventing the IL-6/GP130 interaction; while LLL-12 and LY-5 bind to the SH2 domain of STAT3, preventing STAT3 phosphorylation. All four lead compounds significantly inhibit IL-6 induced IL-17 production in myelin-specific CD4 T cells without significant toxicity. Furthermore, adoptive transfer of small-molecule treated myelin-specific CD4 T cells into naïve recipient mice show a significant reduction in EAE severity compared to control group, suggesting these compounds suppress the encephalitogenicity of CD4 T cells. More importantly, immunized small-molecule treated mice demonstrate delayed onset and reduced severity compared to control mice, suggesting in vivo treatment suppresses EAE development. Together, our data suggest that these four lead compounds have great potential to serve as an innovative therapy.
TGF-β-induced CD4+Foxp3+ T cells attenuate acute graft-verse-host disease via suppressing expansion and killing of effector CD8+ cells. (TRAN3P.875)
Authors: Zheng Song Guo , Gu Jian , Chen Dongdong , Wang Julie , Olsen Nancy 
Published: January 2023

Abstract
TGF-β-induced CD4+Foxp3+ T cells (iTregs) have been identified as important treating strategies for cell therapy to autoimmune diseases and other disorders. However, the prevention effect of these cells on acute graft-verse-host disease (GVHD) has been unsatisfied because these cells are unstable and less suppressive in the disease. Here we restudied the ability of iTregs to prevent acute GVHD in two different mouse models. Our results showed that iTregs, as long as an appropriate protocol is used, they displayed a strong and consistent ability to control acute GVHD development and increase the survival in two different types of acute GVHD animal models. iTreg infusion markedly suppressed the engraftment of donor CD8+ cells, the expression of Granzyme A and B and cytotoxic effect of donor CD8+ cells, production of cytokines in T cells in acute GVHD. We therefore conclude that iTreg cells are able to prevent acute GVHD as long as the right methods for generating iTreg cells have been employed.
Crosstalk of BAFF and TLRs after HCMV Infection in renal transplantation recipients (TRAN3P.878)
Authors: He Xiaozhou , Xu Haiyan , Dong Panpan , Xue Dong , Ma Xuyi , Zhang Yanyun , Zhang Xueguang 
Published: January 2023

Abstract
To investigate the correlation of BAFF signal and TLRs activtion after HCMV infection in renal transplant (RTx) recipients. Peripheral blood and urine of RTx recipients (113 cases) were collected. Urine HCMV DNA was detected by quantitative real-time PCR (qPCR); Sera anti-pp65 IgG /IgM antibody were detected with the use of HCMV pp65 antigen slide by indirect immunofluorescence assay; Soluble BAFF (sBAFF) was tested by ELISA; Sera anti-HLA&MICA was determined by single-antigen flow bead assays (One Lambda) on a Luminex platform; The concerned genes selected by Gene Ontology (GO) function classification and KEGG Pathway analysis were tested by qPCR chip assay. In RTx recipients with high copy of urine HCMV DNA (&gt;10,000 copy/ml, 12 cases, positive group), sBAFF, anti-pp65 antibody, and anti-HLA&MICA antibody also increased (P&lt;0.05); The correlation analysis indicated that HCMV DNA level was positively related with sBAFF, anti-pp65 antibody, and anti-HLA&MICA antibody. And the qPCR chip assay results showed that 46 genes were differentially expressed (&gt; 2 times) in all. In positive group BAFF-R and ICAM1 were upregulated, TLR9, NLRC5 and other 20 genes were downregulated, compared with negative group (with low copy of HCMV DNA); IFN-γ and ICAM1 were upregulated and 8 genes were downregulated in positive group, compared with healthy controls. So BAFF signal was enhanced after HCMV infection in RTx recipients, which involved in the decrease of renal allograft function.
Stem cell therapy to promote sensory and motor nerve function recovery in a limb transplant model (TRAN3P.863)
Authors: Fitzpatrick Emilie , DeHart Mary , Tercero Juan , Brown Tommy , Salgar Shashikumar 
Published: January 2023

Abstract
Introduction: Hand and leg transplantation (Tx) in military/civilian populations is increasingly needed to improve the quality of life. Our objective was to investigate whether Mesenchymal Stem Cell (MSC) therapy can improve nerve regeneration and function. Methods: We performed orthotopic syngeneic hind-limb transplants in Lewis (RT1.Al) rats. Following Tx rats received syngeneic MSC (5x106; passage ≤8) or vehicle intravenously and locally. Results: Ex vivo expanded Rat MSCs were CD29+, CD31-, CD34-, CD44+, CD45low, CD90+, MHC Class I+, Class II- and pluripotent. Limb Tx was highly successful (100% survival). Four weeks post-Tx sensory nerve function (determined by cutaneous pain reaction) was &lt;0.3 on a scale of Grade 0 to 3 (0=No function; 3=Normal function). By 8 weeks in vehicle group it was 2.2±0.7(tibial), 1.2±0.5(peroneal) and 1.7±0.9 (sural), and in MSC group it was 2.6±0.4(tibial),1.0±0.9(peroneal) and 1.7±0.9(sural). Overall sensory function was higher but not significant in MSC group compared to vehicle group at 4, 8, 16 and 24 weeks post-Tx. Walking track analysis (for motor nerve function) did not produce clear foot prints to calculate Sciatic Function Index (SFI), so a novel grading system was developed. Gastrocnemius muscle was atrophied (P&lt;0.05) and animals developed flexion-contractures in the transplanted limb. Conclusion: The limb Tx procedure was highly successful, sensory function was recovered (&gt;70%) and MSCs appear to promote nerve function recovery.
DAP12 deficiency in liver allografts results in enhanced donor DC migration, augmented effector T cell responses and abrogation of transplant tolerance (TRAN3P.883)
Authors: Yoshida Osamu , Kimura Shoko , Dou Lei , Matta Benjamin , Geller David , Thomson Angus 
Published: January 2023

Abstract
Liver interstitial dendritic cells (DC) have been implicated in immune regulation and tolerance induction. We found that the transmembrane immuno-adaptor DNAX-activating protein of 12kDa (DAP12) negatively regulated conventional liver DC maturation and their in vivo migratory and T cell allostimulatory ability. Livers were transplanted from B6 wild-type (wt) or DAP12-/- mice into wt C3H recipients. Donor DC (H2-Kb+CD11c+) were quantified in spleens by flow cytometry. Anti-donor T cell reactivity was evaluated by ex vivo CFSE-MLR and in vivo delayed-type hypersensitivity responses, while T effector and regulatory T cells were determined by flow analysis. A 3-4-fold increase in donor-derived DC was detected in the spleens of DAP12-/- liver recipients compared with those given wt grafts. Moreover, pro-inflammatory cytokine gene expression in the graft, IFNγ production by graft-infiltrating CD8+ T cells, and systemic levels of IFNγ were all elevated significantly in hosts of DAP12-/- liver recipients. DAP12-/- grafts also exhibited reduced incidences of CD4+Foxp3+ cells and enhanced CD8+ T cell IFNγ secretion in response to donor antigen challenge. Unlike wt grafts, DAP12-/- livers failed to induce tolerance and were rejected acutely. Thus, DAP12 expression in liver grafts regulates donor DC migration to host lymphoid tissue, alloreactive T cell responses and transplant tolerance.