bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral tolerance induction does not resolve allergic enteropathy due to residual IgE (125.7)
Authors: Toda Masako , Burggraf Manja , Nakajima-Adachi Haruyo , Hachimura Satoshi , Krause Maren , Kiyono Hiroshi , Hermann-Josef Gröne , Vieths Stefan 
Published: January 2023

Abstract
Oral immunotherapy (OIT) has gained attention as a therapy for food allergies. To investigate efficacy and safety of OIT pre-clinically, we established a murine model of allergic enteropathy. BALB/c mice were sensitised with ovalbumin (OVA, a major egg white allergen) plus ALUM and fed egg-white diet (EW-diet). The mice developed gastrointestinal symptoms (e.g. weight loss) and inflammation in the jejunum accompanied by a strong induction of IgE antibodies during the first 7 days of the allergenic diet. Importantly, the mice presented resolution of the symptoms and remarkable reduction of OVA-specific IgE levels in the sera if they were fed EW-diet more than 7 days. Reduced proliferation of T-cells from spleens and mesenteric lymph nodes of the mice on day 28 of EW-diet indicated that the continuous feeding of the allergenic diet induced oral tolerance. However, the inflammation in the jejunum of the mice was aggravated at this time point. We hypothesized that residual OVA-specific IgE antibodies promoted the intestinal inflammation, although oral tolerance against OVA was induced by the long-term EW diet. To verify it, we used mice deficient of FcϵRI, a high affinity IgE receptor. FcϵRI deficient mice presented intestinal inflammation on day 7 of EW-diet after OVA sensitisation. However, if EW-diet was continued, their intestinal inflammation was resolved. Our results suggest that residual IgE could be a poor prognostic factor for recovery from allergic enteropathy in OIT.
Anticipitated and Surprising effect of IL-17-producing CD4+ T Cells on chronic Graft-Versus-Host Disease after Unmanipulated Allogeneic Blood and Marrow Transplantation (126.17)
Authors: Zhao Xiang-Yu , Xu Ling-Ling , Lv Meng , Xu Lan-Ping , Liu Dai-Hong , Liu Kai-Yan , Huang Xiao-Jun 
Published: January 2023

Abstract
The aim of this study was to investigate the effects of Th17 cells on chronic graft-versus-host disease (cGVHD) in patients who had undergone allogeneic transplantation. Allograft from 41 patients were analyzed for Th17 with respect to cGVHD. Seven patients with cGVHD onset and after those achieved complete remission (CR) were monitored for the Th17 in the peripheral blood (PB). RNA was isolated from PB mononuclear cells to detect the transcript levels of STAT5, T-bet, Foxp3 and RORγ. There were significantly differences in Th17 dose in allograft between patients with and without cGVHD (p=0.012), especially with local or pure cGVHD (p=0.001). Patients received a higher Th17 dose in allograft (&gt;1.67×106/kg, p=0.018,n=20) exhibited a higher incidence of cGVHD compared to those received lower Th17 dose (n=21). Th17 cells were highly increased when cGVHD onset and decreased drastically following CR (p=0.018). Patients received a higher Th17 dose exhibited a trend to have the lower incidence of transplantation related mortality (p=0.084) and relapse (p=0.181), and achieved higher incidence of overall survival (p=0.082) and leukemia free survival (p=0.026). No differences in the transcript levels of STAT, T-bet, Foxp3 and RORγwere found between patients with cGVHD onset and after CR. These results suggested that Th17 cells contributed to cGVHD, especially skin cGVHD, and might account for the anti-leukemia effect, therefore increasing the leukemia free survival.
IL-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft vs. host disease (126.31)
Authors: Hanash Alan , Dudakov Jarrod , Hua Guoqiang , Liu Chen , Fouser Lynette , Kolesnick Richard , Blazar Bruce , van den Brink Marcel 
Published: January 2023

Abstract
Intestinal graft vs. host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (allo-BMT). Strategies to limit GVHD by selective promotion of epithelial regeneration in the absence of immunosuppression are largely unknown. We investigated the role of IL-22 in allo-BMT and found that IL-22 levels in small and large intestine were increased after BMT after radiation injury (RI) without BMT. IL-22 upregulation after RI was dependent on the presence of IL-23p40. Although intestinal IL-22 levels were increased after T cell-depleted (TCD) BMT, intestinal IL-22 was reduced by GVHD, as IL-22 production was mediated by host-derived innate lymphoid cells (ILC) that were eliminated by GVHD. Furthermore, host-derived IL-22 was critical for reduction of GVHD morbidity, mortality, and intestinal pathology. GVHD in IL-22 KO mice led to increased apoptosis in epithelial crypts where the intestinal epithelial stem/progenitor cell niche is located. Immunohistochemistry and immunofluorescence demonstrated IL-22 receptor expression on intestinal stem cells (ISC) and progenitors. Allo-BMT in Lgr5-LacZ reporter mice indicated that ISC were targeted by GVHD, and GVHD in IL-22 KO mice led to dramatic ISC depletion. IL-22 is thus critical for protection of host epithelium during GVHD and critical for protection of ISC. These findings may have broad relevance for protection of ISC and intestinal epithelium in clinical GVHD and other inflammatory intestinal diseases.
Pre-transplant administration of antithymocyte globulin increases its efficacy in inhibiting anti-donor memory T cell responses (126.9)
Authors: Ayasoufi Katayoun , Fan Ran , Yu Hong , Williams John , Valujskikh Anna 
Published: January 2023

Abstract
Antithymocyte globulin (ATG) is a lymphoablative agent used in transplant patients. In this study, we tested how murine analog of ATG (mATG)affects pre-existent donor-reactive memory T cells. mATG treatment of heart allograft recipients on d.-7 and -4 (pre-TP)led to better outcome than treatment on d.0 and d.4 (peri-TP). Pre-TP mATG resulted in lower frequencies of donor-specific IFNγ-secreting T cells than peri-TP mATG(72000 vs 12500spots/million CD44hi cells). Studies in recipients injected with tracer subsets of donor-reactive T cells showed that while both mATG regimens depleted naïve T cells equally well, pre-TP mATG was four times more efficient in depleting pre-existing memory T cells. IFNγ production by donor-specific memory T cell was diminished by 99% with pre-TP mATG and only by 70% with peri-TP mATG. Transfer of TCR transgenic Ld-reactive 2C memory CD8 cells into recipients of Ld+ or Ld- heart allografts showed that memory T cells resistance to peri-TP mATG depletion depended on the systemic inflammation after transplantation but not on their antigen specificity. In summary,pre-TP ATG is more efficient in targeting pre-existing alloreactive memory T cells and anti-donor T cell responses. Our findings may guide the future use of ATG in sensitized transplant patients.
Expression of Germinal Center B Cell Markers in Bortezomib-Resistant Multiple Myeloma Cells (127.11)
Authors: Baughn Linda , Stessman Holly , Mansoor Aatif , Van Ness Brian 
Published: January 2023

Abstract
Multiple myeloma (MM), the second most common hematopoietic malignancy, is an incurable plasma cell neoplasm. The proteasome inhibitor, bortezomib (Bz), has been widely used to treat MM. However, patients eventually relapse due to drug resistance. Identifying signatures that distinguish Bz sensitive from resistant cells is critical for the development of novel approaches to reverse resistance. We have utilized isogenic pairs of Bz sensitive and resistant lines derived from the iMycCα/Bcl-xL mouse model of MM. This highly robust model resembles human MM based on gene expression, chromosomal abnormalities and progression of disease and response to therapy. In populations with an acquired resistance to Bz, we observed increased expression of Pax5 and AID and reduced expression of CD93 compared to parental Bz sensitive populations. Although most parental cells are CD93+, we have isolated a subpopulation of CD93- cells that expresses 20x more AID and display an innate resistance to Bz, while the CD93+ population remains sensitive. Time course analysis following low-dose Bz treatment indicates that Bz increases the expression and promotes the stabilization of Pax5 and AID demonstrating drug-induced changes in markers associated with B cell differentiation relating to the ultimate emergence of the resistance phenotype. Targeting B cell differentiation may represent a rational therapeutic approach to overcoming drug resistance.
In vivo three dimensional MRI of GL261 syngeneic gliomas concurrently with analysis of CNS infiltrating tumor-specific killer T cell responses (127.15)
Authors: Johnson Aaron , Litterman Adam , Ohlfest John , Jin Fang , Hanson Lisa , Gamez Jeff , Chae Michael , Carlson Brett , Sarkaria Jann , Parney Ian , Pirko Istvan 
Published: January 2023

Abstract
Glioblastoma multiforme (GBM) is among the most lethal of cancers. Enhancing anti-tumor killer T cell responses via dendritic cell vaccines has correlated with a positive outcome in selected GBM patients. Nevertheless, the mechanisms by which killer T cell responses to GBM are inhibited or enhanced remain poorly defined. We therefore developed the GL261 “Quad Cassette” glioma cell line that expresses model T cell epitopes in the immunocompetent C57BL/6 mouse. Tumor size and inflammatory profiles observed in these animals was then compared to C57BL/6 mice administered the parent GL261 glioma cell line. Resulting tumors present with a tumor mass surrounded by considerable edema visible by gadolinium enhanced T1 and T2 weighted MRI. Both edema and tumor mass visible by MRI were quantified using Analyze 10.0 software which enables 3D volumetric analysis of MRI images. C57BL/6 mice with GL261 “Quad Cassette”, but not parent GL261 gliomas, presented with smaller tumor mass and significant brain infiltrating tumor specific Kb:ova specific CD8 T cells. We therefore conclude that the GL261 Quag Cassette system is suitable for studying tumor epitope specific CD8 T cell responses using the vast genetic and immunologic resources available for the C57BL/6 mouse background. Furthermore, incorporation of the first true 3D volumetric analysis of GL261 glioma size with small animal MRI will enable investigation of immunotherapeutic treatments in vivo without euthanizing the animal.
Activated mouse CD4+Foxp3- T cells facilitate melanoma metastasis via Qa-1-dependent suppression of NK cell cytotoxicity (127.17)
Authors: Gao Wenda , Wang Xiaojuan , Hu Jie , Cui Yanyan , Wang Qinghong , Luo Gaoxing , He Weifeng , Yuan Jun , Wu Yan , Sun Xiaofeng , Robson Simon , Li Xianchang , Tan Jiangling , Peng Yanmeng , Zhou Junyi , Xue Gang , Lu Linrong , Wu Jun 
Published: January 2023

Abstract
The regulatory activities of mouse CD4+Foxp3+ T cells on various immune cells, including NK cells, have been well documented. Under some conditions, conventional CD4+Foxp3- T cells are able to acquire inhibitory function on other T cells, but their roles in controlling innate immune cells are poorly defined. As a potential cellular therapy for cancer, ex vivo activated CD4+Foxp3- effector T cells are often infused back in vivo to suppress tumor growth and metastasis. Whether such activated T cells could affect NK cell anti-tumor function is unclear. We found that mitogen-activated CD4+Foxp3- T cells exhibited potent suppressor function on NK cell proliferation and cytotoxicity in vitro, and notably facilitated B16 melanoma metastasis in vivo. Suppression of NK cells by activated CD4+Foxp3- T cells is cell-cell contact dependent and is mediated by Qa-1:NKG2A interaction, as Qa-1-blocking antibody could completely reverse this suppression, and significantly inhibited otherwise facilitated melanoma metastasis. Moreover, activated CD4+Foxp3- cells from Qa-1-/- mice completely lost the suppressor activity on NK cells, and failed to facilitate melanoma metastasis when transferred in vivo. Taken together, our findings indicate that innate anti-tumor response is counter-regulated by the activation of adaptive immunity, and thus the regulatory role of activated CD4+Foxp3- T cells in NK cell activity must be taken into consideration in the future design of anti-tumor biotherapies.
Tumor-derived factors promote differentiation of immunosuppressive Gr-1+cDC through TLR2. (127.25)
Authors: Tang Michael , Diao Jun , Zhao Jun , Cattral Mark 
Published: January 2023

Abstract
Tumor cells secrete endogenous danger signals that modulate the tumor inflammatory microenvironment. We have found that the intra-tumor inflammatory milieu skews differentiation of DC precursors (pre-cDC) towards a novel immunosuppressive Gr-1+ subpopulation. Inhibition of this differentiation enhanced cytotoxic T cells expansion and suppressed tumor growth. We sought to identify signaling mechanisms that regulate Gr-1+DC development. Splenic Pre-cDC from wildtype and MyD88-/- mice were incubated with tumor-conditioned medium (TCM) derived from the Lewis lung carcinoma cell line or fibroblast control medium. Supernatants were collected to measure various cytokine levels and cell surface expression of Gr-1 was monitored by flow cytometry. We found that TCM, but not control medium induced IL-6, IL-10 & IL-1β production and Gr-1+DC development. These cells produced high amounts of IL-10 after secondary stimulation with LPS. MyD88-/- Pre-cDC stimulated with TCM did not produce cytokines or differentiate into Gr-1+DC. Tumors from MyD88-/- mice contained a significantly lower frequency of Gr-1+DC compared to wildtype mice (14.1% vs. 1.1%; p=0.001, n&gt;5). To determine whether Toll-like receptor 2 (TLR2) was involved in Gr-1+DC development, we stimulated Pre-cDC with different TLR agonists. We found that both Pam3CSK4 (TLR2/TLR1) and FSL-1 (TLR2/TLR6), but not LPS (TLR4) mimicked the activity of TCM. Together these data suggest that MyD88 and TLR2 are involved in Gr-1+DC development.
Targeting Tumor-Expressing CCR6 Inhibits Colorectal Cancer Progression in Mice (127.44)
Authors: Wang Honglin , Liu Jinlin 
Published: January 2023

Abstract
Background: CCR6/CCL20 expressed by colorectal cancer (CRC) cells. Although their interactions may play an essential role in proliferation and migration of CRC, the in vivo evidence is lacking. Methods: Expression of CCR6/CCL20 was evaluated in 130 primary tumor specimens from CRC patients. Mouse models was established by the injection of CMT93 transfected with luciferase in CCR6-/- mice, or by crossing CCR6-/- mice with APCmin/+ mice. Intratumor injection of anti-CCR6 was performed in CCR6-/- mice grafted luciferase-labeled CMT93. Luciferase intensity of CMT93 was monitored using the IVIS Imaging System. Intestinal tumor development in APCmin/+ mice was studied with a dissecting microscope. Migration of CMT-93 treated with anti-CCR6 was investigated by the Real-Time Cell Analyzer. Results: In contrast to paratumor tissues, CCR6/CCL20 predominantly expressed by tumor cells in CRC patients of all tumor stages. CCR6/CCL20 was consistently identified in CMT-93. Injection of anti-CCR6, significantly inhibited the growth of CRC in CCR6-/- mice. Knock-out of CCR6 resulted in a decrease in numbers and size of intestinal adenomas in APCmin/+ mice. Anti-CCR6 treatment markedly inhibited the migration of CMT-93 in vitro. Conclusion: The CCR6/CCL20 interaction plays an essential role in proliferation and migration of colorectal cancer cells via the autocrine mechanism in mice, and selectively targeting tumor-expressing CCR6 may harbor a novel therapeutic strategy for human CRC.
Circulating biomarker-IgM complexes in the serum of pediatric patients with osteosarcoma and Ewing tumor (127.9)
Authors: Savitskaya Yulia , Rico Genaro , Linares Luis , Delgado Ernesto , Martinez Elisa , Tellez Rene , Estrada Erendira , Marin Norma , Ibarra Clemente 
Published: January 2023

Abstract
Osteosarcoma (OS) and Ewing tumor (ET) together account for the majority of musculoskeletal sarcomas diagnosed in patients of all ages and nearly 90% of those occurring in children and adolescents. Natural IgM antibodies to tumor antigen have been reported in patients with early-stage cancer, and a panel of serum antibodies can detect cancer many years prior to imaging detection. Circulating immune complexes formed by tumor antigens and immunoglobulin M (IgM) represent a novel class of biomarkers with diagnostic value for early cancer detection. In the present study, we investigated the presence of ANG-IgM, VEGF-IgM, bFGF-IgM, PDGF-IgM in the sera of children with bone tumors. The study included 174 pediatric patients with newly diagnosed bone tumors. Express ELISA techniques have been developed to quantify immune complexes in INR. Serum samples from all patients were analyzed for the presence of biomarker-IgM immune complexes. We compared the serum level of angiogenic factors and immune complexes in children with different types of bone tumors. The highest concentration of VEGF-IgM was detected in ET patients and ANG-IgM in OS patients. The present study demonstrated increased ANG-IgM expression in the sera OS patients and a positive correlation between its expression levels and tumor vascularity evaluated by CTA. Our results have potential applications as biomarkers for controlling unwanted angiogenesis, early diagnosis and response to therapy in children with bone tumors.
Marginal zone B cells contribute to autoimmunity in the NZM2410 lupus prone mouse model. (159.13)
Authors: Zheng Ying Yi 
Published: January 2023

Abstract
Lupus is an autoimmune disease in which the affected individual generates antibodies (Abs) against nuclear antigens such as DNA. Our NZM2410-derived triple congenic (TC) model of lupus expresses 3 previously characterized lupus susceptibility loci. We have previously shown that the breach of follicular exclusion of TC MZB cells is associated with disease progression. The production of nuclear autoAbs occurred in tandem with a large influx of TC MZB cells in the follicles. We also found an expansion of MZB cells in TC mice as compared to non-autoimmune B6 mice that occurs prior to the production of anti-DNA autoAbs, further suggesting that MZB cells may contribute to autoimmunity. MZB cell expansion is associated with the upregulation of Notch2 signaling in these cells. Adoptive transfer of TC or B6 splenic B cells into B6.Rag1-/- recipients indicated no difference in the homeostatic expansion of MZB cells from either donor strain, whether the recipients were treated or not with CpG. However, CpG-treated recipients of TC B cells produced more anti-ssDNA IgM than recipients of B6 B cells. Our transfer results showed that although TC MZB cells do not expand more than B6 MZB cells in a lymphopenic host, TC splenic B cells produce higher level of anti-ssDNA IgM in response to CpG stimulation. Further characterization of the TC MZB cells will determine more precisely how they contribute to autoimmunity.
Genomic and functional characterization of the diverse immunoglobulin domain-containing protein (DICP) family (160.5)
Authors: Yoder Jeffrey , Haire Robert , Cannon John , O’Driscoll Marci , Ostrov David , Mueller M. , Turner Poem , Litman Ronda , Litman Gary 
Published: January 2023

Abstract
A heretofore-unrecognized multigene family encoding diverse immunoglobulin (Ig) domain-containing proteins (DICPs) was identified in the zebrafish genome. Twenty-nine distinct loci mapping to three chromosomal regions encode receptor-type structures possessing two classes of Ig ectodomains (D1 and D2). The sequence and number of Ig domains, transmembrane regions and signaling motifs varies between DICPs. Interindividual polymorphism and alternative RNA processing contribute to DICP diversity. Molecular models indicate that most D1 domains are of the variable (V) type; D2 domains are Ig-like. Sequence differences between D1 domains are concentrated in hypervariable regions on the front sheet strands of the Ig fold. Recombinant DICP Ig domains bind lipids, a property shared by mammalian CD300 and TREM family members. These findings suggest that novel multigene families encoding diversified immune receptors have arisen in different vertebrate lineages and effect parallel patterns of ligand recognition that potentially impact species-specific advantages.
Leukotriene B4 receptor BLT1 expression on CD8+ T cells is critical for antitumor immunity (161.5)
Authors: Sharma Rajesh , Jala Venkatakrishna , Chheda Zinal , Haribabu Bodduluri 
Published: January 2023

Abstract
Leukotriene B4 (LTB4) receptor, BLT1 is expressed on a verity of immune cells and has been implicated in diverse inflammatory disorders, including arthritis, atherosclerosis and asthma. In contrast, whether biological responses mediated via this receptor generate tumor promoting inflammation or anti-tumor immunity remains unexplored. Herein, we investigated the role of BLT1 in cancer progression using implantable TC-1 syngenic mouse cervical cancer model and observed accelerated tumor growth and decreased survival of BLT1−/− mice. Analysis of the tumor infiltrating leukocytes by flow cytometry and confocal microscopy revealed a significant decrease in T cells and NK cells in the tumors of the BLT1−/− mice compared to the BLT1+/+ mice. Expression profile of mRNA from the tumors of BLT1−/− mice confirmed the dramatic decrease in T and NK cell associated markers such as IFN-γ, granzyme-B and IL-2. Furthermore, depletion of CD8+ T cells enhanced the tumor growth in BLT1+/+ but not in BLT1-/- mice. Adoptive transfer of tumor educated CD8+ T cells from the BLT1+/+ but not BLT1-/- mice significantly decreased tumor growth and increased the survival in Rag2-/- mice. While the homeostatic proliferation of adoptively transferred BLT1+/+ and BLT1-/- CD8+ T- cells appears to be similar only the BLT1+/+ T-lymphocytes enter the tumors in greater numbers. These results suggest that BLT1 expression on CD8+ T cells is critical for generating effective anti-tumor immunity.
The G protein-coupled receptor mFPR2 promotes anti-tumor host defense (161.7)
Authors: Wang Ji Ming , Liu Ying , Chen Keqiang , Liu Mingyong , Gong Wanghua , Yoshimura Teizo , Ford Jill , McVicar Daniel 
Published: January 2023

Abstract
Abstract mFPR2 is a G protein-coupled receptor interacting with bacterial and host-derived chemotactic agonists. In vivo, mFPR2 plays a major role in innate and adaptive immune responses as shown by reduced severity of allergic airway inflammation in mFPR2-KO mice due to impaired trafficking of antigen presenting dendritic cells (DCs). The aim of this study is to examine the role of mFPR2 in anti-tumor host responses. We found that mFPR2-KO mice bearing subcutaneously implanted Lewis lung cancer (LLC) cells exhibited significantly shortened survival due to more rapidly growing tumors. In contrast, in mFPR2-transgenic (Tg) mice, subcutaneously implanted LLC tumors grew more slowly than those in wild type (WT) littermates. Mechanistic studies revealed an increased number of macrophages associated with tumors grown in mFPR2 KO mice and macrophages derived from mFPR2 KO mice showed a more potent chemotactic response to LLC-derived supernatant (LLC Sup), which could be neutralized by an anti-CCL2 antibody. In addition, macrophages from mFPR2 KO mice were more prone to assume an M2 phenotype after incubation with LLC Sup. These results suggest that mFPR2 plays an important role in host defense against tumor by sustaining macrophages in an M1 phenotype.