bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prolonged Survival of Vascularized Skin Grafts Across a Full MHC Mismatch Using Donor Antigen-Pulsed Tolerogenic GM+Rapa Dendritic Cells (102.22)
Authors: Feili-Hariri Maryam , Horibe Elaine , Sacks Justin , Unadkat Jignesh , Wang Zhiliang , Raimondi Giorgio , Ikeghchi Ryosuke , Thomson Angus , Lee WP , Marsteller Douglas 
Published: January 2023

Abstract
We compared the tolerogeneic properties of BM-derived GM+IL-4 and GM+Rapa host DCs and their potential to induce long-term acceptance of vascularized skin allograft in rats across a full MHC mismatch with transient immunosuppression. Results show that both DCs were CD11b+ and expressed low levels of CD86 and produced low levels of IL-12p70 following TLR activation. GM+Rapa DC produced lower levels of anti- and pro-inflammatory cytokines in response to LPS. Both DCs had low T cell stimulatory capacity in vitro. Interestingly, donor Ag-pulsed GM+Rapa DC (GM+Rapa DCp) induced long-term survival of the vascularized skin grafts and this was significant compare to GM+IL-4 DC and control groups. PBMC from long-term graft survivors that were previously treated with donor Ag-pulsed GM+Rapa DC were hyporesponsive to donor Ag, but proliferated in response to the third-party Ag and produced IL-10 in addition to IFN-gamma. Recipients of the long-term surviving allografts were challenged with full-thickness tail skin grafts. While the third-party grafts were rejected fast the donor graft had delayed rejection, suggesting that this treatment induced a regulatory mechanism that prevented the acute rejection of donor skin grafts. Further experiments demonstrated presence of CD4+ Foxp3+ T cells in the vascularized skin and secondary lymphoid tissues. Taken together, these results demonstrate that the donor Ag-pulsed tolerogenic GM+Rapa DC have ability to induce regulatory T cells and prevent vascularized skin graft rejection across a full MHC mismatch.
The Superdominant Minor Histocompatibility Antigen (MHAg) H60 Recognized by CD8 T Cells Fails to Elicit Lethal Graft Versus Host Disease (GVHD) Regardless of Its Tissue Expression Pattern (102.26)
Authors: Al-Awwami Moheeb , Sproule Thomas , Al-Khabbaz Hana , Roopenian Derry 
Published: January 2023

Abstract
Studies both in mice and humans have argued that immunodominant MHAg eliciting CD8 T cells cause increased risk for GVHD. We have shown that the H60 MHAg is remarkably immunodominant in that an overwhelmingly predominant CD8 T cell response developed after the transfer of T cells and bone marrow (BM) into MHAg-mismatched lethally irradiated recipients is directed against H60. Here we address whether H60 is a barrier to lethal (L) GVHD. Matching of donor cells and recipients for H60 while remaining disparate for all other MHAg failed to result in improved survival, indicating that H60 is not a barrier for LGVHD. Expression of H60 is normally limited to hematopoietic tissues, possibly explaining H60’s inertness in LGVHD. To broaden its expression, we produced transgenic mice expressing H60 driven by a tissue-ubiquitous cassette. We then evaluated whether H60 expressed broadly in recipients resulted in GVHD. Naïve B6 T cells transferred into B6-H60 transgenic or congenic mice failed to show any evidence of GVHD regardless of a robust anti-H60 CD8 T cell response. Augmentation of the response to H60 by preimmunization, resulting on over 50% of the CD8 T cell compartment being H60-specific in GVHD target organs, an failed to result in LGVHD. The overall results are inconsistent with a recent report (B. Kappel, et al. Blood, 2006.107:2045) and clearly indicate that potent CD8 T cell responses to MHAg are remarkably inert in GVHD.
Host conditioning is not required for generation of fibrotic graft-versus-host disease (102.5)
Authors: Askew David , Zhou Lixin , Gilliam Anita 
Published: January 2023

Abstract
Graft versus host disease (GVHD) is a major complication of hematopoietic cell transplant. One major form of GVHD is manifested by destruction of epithelial tissue in skin, liver and gut. This cytotoxic GVHD is thought to be initiated by the conditioning regimen (irradiation and/or chemotherapy) that is required to ablate the host immune system. In a model of GVHD that occurs in a minor histocompatability mismatch (B10.D2 → Balb/c), instead of cytotoxic GVHD, fibroblasts are stimulated to overproduce collagen resulting in fibrosis in the skin and lung. In earlier studies we found cutaneous TNFα-producing CD4+ T cells could be found in mice undergoing cytotoxic GVHD, but not in fibrotic GVHD.
To determine the relationship between host conditioning, TNFα production and type of GVHD generated, we used Balb/c Rag 1 knockout mice (Balb/c Rag1−/−) as recipients to generate GVHD in the absence of host conditioning. We found fibrotic GVHD in both B10.D2 → Balb/c Rag1−/−, and C57BL/6 → Balb/c Rag1−/−. This was surprising as C57BL/6 → Balb/c generates cytotoxic GVHD using standard BMT. Cutaneous TNFα-producing CD4+ T cells were again absent in the skin during GVHD. Thus, in some mouse strain pairs, while host conditioning may influence the development of TNFα-producing T cells that target skin and other organs leading to cytotoxic GVHD, other triggers promote the development of fibrotic GVHD.
Dendritic Cells Modified by Interleukin-10 Gene-Loaded Nanoparticles Expand Allogeneic Foxp3+ T Cells In vitro (102.9)
Authors: Kovacs Jeffrey Ryan , Jia Liang , Zheng Ying , Gawalt Ellen S , Shen Hongmei , Meng Wilson S 
Published: January 2023

Abstract
Interleukin-10 (IL-10) has been used to downregulate allogeneic T cell response in vivo. Herein we investigated two particulate systems to deliver a plasmid encoding murine IL-10 (pIL-10) into dendritic cells (DC). The hypothesis is IL-10 gene-modified DC can expand regulatory T (Treg) cells in allogeneic settings. The carriers were formed by coating on poly-(d, l-lactide-glycolide) (PLGA) or polystyrene (PS) particles pIL-10 condensed with the cationic peptide O10H6 (designated PLGAO10H6-pIL-10 and PSO10H6-pIL-10). These particles have a diameter below 300 nm and the DNA is protected from enzymatic degradation. DC transfected with either particles exhibited a 2-fold increase in IL-10 mRNA (RT-PCR, n=2). Compared to controls, DCs (H-2b) modified by the particles upregulated allogeneic CD4+ T cells (H-2d) Foxp3 mRNA by 1.5 fold (n= 3, p &lt; 0.05). This expansion was not due to changes in CD80 and CD86 expression on DCs for these markers were expressed at similar levels on modified (69.9±2%, 74.3±2%; n=3) and control DCs (68±5%, 71±5%; n =3). In cocultures of IL-10-modified H-2b DC and H-2d T cells, production of IFN-γ and TNF-α were suppressed by 40.1±4% and 43.3±2% respectively compared to those with control DC (n=2). Taken together, these data demonstrate that pIL-10 complexed PLGAO10H6 and PSO10H6 can promote tolerogenic phenotypes in vitro and should be further investigated in allograft transplant therapy.
GM-CSF expanded tolerogenic CD11c+CD8a− dendritic cells can induce autoantigen specific CD4+ CD25+ Foxp3+ T regulatory cells (128.11)
Authors: Ganesh Balaji Baskaran , Cheatem Donald , Vasu Chenthamarakshan , Prabhakar Bellur S 
Published: January 2023

Abstract
Treatment of CBA/j mice with Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), a potent growth factor for dendritic cells can prevent and suppress ongoing experimental autoimmune thyroiditis (EAT). GM-CSF treatment causes expansion of CD11c+CD8a− myeloid dendritic cells (DCs) with a consequent increase in CD4+CD25+ T regulatory cells (Tregs) in an EAT model. In this study, we investigated the significance of the expansion of CD8a− myeloid DCs by GM-CSF and its direct role in inducing CD4+CD25+Foxp3+ T regs. Co-culture of CD4+ T cells with CD8a-ve DCs from GM-CSF treated mice in the presence of mouse thyroglobulin (mTg) induced an increase in the number of CD4+CD25+Foxp3+ T cells. These Foxp3+ T cells produced high levels of IL-10. These T regs could suppress the mTg specific proliferation of effector CD4+CD25− T cells, which was reversed upon addition of anti-IL10R antibodies. In contrast, GM-CSF treated CD8a+ lymphoid DCs failed to show a significant suppression of mTg specific T cell proliferation. In vivo experiments in a SCID mouse model revealed that GM-CSF treated SCID mice could induce increased numbers of Foxp3 and IL-10 expressing CD4+ T cells that were adoptively transferred from wild type CBA/j mice. These results indicate that GM-CSF acts directly on CD8a− myeloid DCs in the absence of T cells and renders them tolerogenic in that they cause expansion of CD4+Foxp3+ Tregs, which suppress mTg specific proliferation in an IL-10 dependent manner. NIH 1RO1AI058190
CD11c+ hepatic dendritic cells induce strong innate immune response with reduced capacity to activate allogeneic T cells (128.14)
Authors: Shu Shang-An , Lian Zhe-Xiong , Chuang Ya-Hui , Yang Guo-Xiang , Moritoki Yuki , Comstock Sarah S , Gershwin Eroc 
Published: January 2023

Abstract
Splenic and bone marrow dendritic cells (DCs) and their subsets have been shown in multiple studies to play a critical role in maintaining tolerance and also in select differentiation of pathways responsive to infectious agents. Comparable studies in the liver have been lacking primarily due to difficulty in isolation and contradictory data. We have taken advantage of our ability to identify and isolate relatively pure DC populations and have compared the phenotype and function of select subsets of DCs in liver compared to spleen in C57BL/6 mice. Importantly, freshly isolated NK1.1−CD11c+ liver DC subsets (conventional and plasmacytoid DCs) can efficiently endocytose dextran as well as induce significant levels of TNF-α, IL-6 and IL-12 p40 in response to toll-like receptor ligand stimulation. These responses are higher than comparable studies of isolated splenic DCs from the same animals. In addition, there is a relatively higher frequency of pDC populations in liver. Our results suggest that hepatic DCs has differential capability in response to innate signals and that in fact CD11c+ hepatic DCs have a greater capacity to respond to innate stimulation but less capable of inducing CpG activated-allogeneic T cells. Our data emphasize not only the critical difference in hepatic DC subsets, but also highlight the need to study individual DC subsets in understanding the modulation of the immune response in the liver.
Th1 and Th17 in tumor Immunity versus autoimmunity (128.15)
Authors: Jacob Jennifer B. , Kong Yi-chi M. , Nalbantoglu Ilke , Snower Daniel P. , Wei Wei-Zen 
Published: January 2023

Abstract
To determine the role of Th1 and Th17 T cells in the reactivity to self antigens in tumor vs autoimmunity, IFN-γ and IL17 secreting T cells to rat neu and mouse thyroglobulin (mTg) were measured in neu transgenic BALB/c (NeuT) and NeuTxDR3 mice, which expressed neu and HLA-DR3. HLA-DR3 is associated with susceptibility to some autoimmune diseases in humans and experimental autoimmune thyroiditis (EAT) in mice. BALB/c and BALBxDR3 served as controls. α-neu response was induced by vaccination with pneuTM encoding neu ECD and TM & pGM-CSF, or by TC-1/neu, heterologous tumor cells transfected with neu, and LPS. α-mTg response was induced by mTg & LPS, i.v. Regulatory T cells (Treg) were depleted by CD25 mAb 9 d before mTg. In BALBxDR3 & NeuTxDR3 mice, pneuTM & pGM-CSF vaccination induced 59 & 1 ug/ml Ab and 592 & 217 IFN-γ secreting cells. Vaccination with TC-1/neu & LPS induced 18 & 41 ug/ml neu Ab and 241 & 187 IFN-γ cells. Neu+ tumors can be regressed, yet no IL-17 was detected in any group. In BALBxDR3 mice depleted of Treg and immunized with mTg/LPS, 51400 U/ml mTg Ab, 119 IFN-γ secreting cells, and 64 IL-17 secreting cells were present, with 40–60% thyroid destruction. Hence, Th1 but not Th17 were activated by neu vaccination in normal or NeuT mice. Both Th1 and Th17 were activated in mTg-induced EAT. Since Neu vaccination & LPS did not induce IL-17 secretion, Th17 activation is unrelated to LPS. Elucidating the precise roles for Th1 and Th17 in tumor immunity and thyroiditis is critical when both are present in an individual. (CA 125680, CA76340, DK45960, St. John Hosp)
Embryonic-like stem cells and mesenchymal cell precursors expand in the bone marrow of lupus mice (128.17)
Authors: Wang James , Chen James Y , Vazquez Brenda , Singh Ram Raj 
Published: January 2023

Abstract
Autoimmune diseases such as lupus are characterized by inflammation and fibrosis in multiple organs. Development of inflammation in these diseases is preceded by abnormal development and functions of various immune cells. These immune aberrations may represent secondary immune changes or intrinsic abnormalities of their precursors, i.e., stem cells (SC). The impairments of SC and how they contribute to these diseases remain unclear. Here, we analyzed SC characteristics and differentiation in autoimmune-prone (NZB/NZW F1, MRL-Faslpr/lpr and MRL-Fas+/+) mice and MHC-matched normal controls. We found that BM cells expressing ScaI, a marker on mesenchymal SC and HSC, expand with age in all mice. Strikingly, the proportion of Sca1+ cells and Sca1 mRNA levels in fresh BM are markedly higher in autoimmune mice than in controls. However, surface expression and mRNA levels of c-Kit, a marker of HSCs, in the fresh BM are not different between normal and autoimmune mice. The expansion of Lin–cKit–Sca1+ cells occurs long before the onset of disease in lupus mice. Interestingly, the bone marrow of lupus mice had a 3-fold increase in the embryonic-like stem cells (ELSC, Lin–CD45–Sca1+ cells) as compared to normal bone marrow. In long-term cultures, BM cells from young mice differentiated into adherent cells, which is dramatically higher in autoimmune mice than in controls. These adherent cells exhibit structural characteristics of adipocytes, stain for oil red O (adipocytes), and express fatty acid binding protein (a marker of mesoderm cell adipocyte), but not nestin (an ectoderm marker), osteocalcin (a bone formation marker) or AFP (an endoderm marker). Thus, BM cells in young autoimmune mice exhibit expansion and preferential differentiation of mesenchymal stem cell lineage cells. The pathogenetic potential of these stem cell abnormalities is under investigation.
Tolerance induction for immature anti-insulin B cells involves impaired calcium mobilization (128.20)
Authors: Henry Rachel A. , Acevedo-Súarez Carlos A. , Thomas James W. 
Published: January 2023

Abstract
B cells that recognize small self proteins are presumed to escape tolerance and reside in a non-tolerant state of “clonal ignorance”. In contrast to this assumption, B cells that harbor anti-insulin Ig transgenes (125Tg) are not clonally ignorant; rather they are maintained in a novel anergic state. Anti-insulin B cells do not proliferate to BCR cross-linking and show impaired Ca2+ and NFAT responses, but unlike the anti-HEL/HEL model, they are not developmentally arrested and show intact tyrosine phosphorylation. To understand the genesis of this novel form of anergy, IL-7 was used to generate naïve anti-insulin B cells from bone marrow cultures. Naïve anti-insulin B cells mobilize Ca2+ upon acute antigen exposure. However, continuous antigen exposure decreased surface IgM expression and lead to impaired Ca2+ mobilization following BCR-dependent and BCR-independent stimuli. These data show that anti-insulin B cells are not clonally ignorant; rather, continuous BCR signals initiate tolerance early in development and maintain anergy in the mature repertoire. This highlights the therapeutic potential of targeting developing B cells in the bone marrow for functional silencing.
Support provided by 5T32 HL069765, 5T32 GM08554, AI051448, and JDRF.
Apoptotic cells: a source of autoantigens for antiphospholipid antibodies. (128.32)
Authors: Kang Sun-Ah , Khan Salar N. , Radic Marko Z. , Monestier Marc 
Published: January 2023

Abstract
Antiphospholipid antibodies (APAs) are detected in various autoimmune diseases, such as antiphospholipid syndrome (APS) and systemic lupus erythematosus. In addition to their binding to negatively charged phospholipids, APAs often cross-react with other molecules. Their biological effects are not fully understood.
Apoptotic cells are a potential source of auto-antigens during systemic autoimmunity. Inefficient clearance of apoptotic cells results in the development of autoimmune manifestations and intracellular antigens such as nucleosomes become accessible during apoptosis.
We examined a panel of monoclonal APAs generated from NZW/BXSB F1, a strain which spontaneously develops autoimmune symptoms reminescent of APS. These APAs did not bind to live cells, but reacted strongly with different structures within apoptotic cells. Further analysis with various inhibitors indicated that the binding of APAs to apoptotic cells depends on specific caspase activities and on the modification of auto-antigens by reactive oxygen species (ROS).
Therefore, apoptotic cells provide a potential source of APA antigens that may not be limited to phospholipids. Our data also indicate that physical accessibility and apoptosis-specific modification of auto-antigens by caspases or ROS are crucial factors for APA-antigen interactions.
NIH, AHA, Lupus Research Institute
Regulation of TLR9 dependent DNA Immune complex mediated cell activation by High Mobility Group Box Protein 1 (HMGB1) and Receptor for Advanced Glycation End products (RAGE) (128.35)
Authors: Tian Jane , Avalos Ana Maria , Chen Bo , Fitzgerald Katherine A. , Sirois Cherilyn , Golenbock Douglas , Marshak-Rothstein Ann , Crow Mary K. , Audoly Laurent , Kiener Peter A. , Latz Eicke , Coyle Anthony J. 
Published: January 2023

Abstract
Stimulation of endosomal associated TLR9 by DNA plays an important role in activation of plasmacytoid dendritic cells (pDCs) and autoreactive B cells and may contribute to the pathogenesis of systemic lupus erythematosus (SLE). HMGB1 is a DNA binding protein that is liberated either from cells undergoing necrosis or following cytokine stimulation. Here we show that HMGB1 forms a high affinity complex with CpG-A oligodeoxynucleotides and augments the production of IFN-a from murine pDCs. We also show that HMGB1 is indeed a component of naturally formed DNA containing chromatin complexes. IFNa induced by either the exogenously formed HMGB1/CpG-A complex or naturally formed complex is TLR9 dependent and is inhibited by HMGB1 and RAGE antagonists. The complex without HMGB1 induces significantly less IFNa. HMGB1-RAGE interactions are required for activation of autoreactive B cells following stimulation with DNA immune complexes and are critical in the regulation of type I interferon gene induction by DNA complexes present in lupus plasma. Our data provide a novel mechanism by which HMGB1 confers potent stimulatory activity to DNA through a RAGE dependent mechanism and may contribute to the pathogenesis of lupus.
A Destabilizing Di-nucleotide Deletion in 3’-Untranslated Region of Human CD24 mRNA Confers Protection against Multiple Sclerosis (129.1)
Authors: WANG LIZHONG , LIU RUNHUA , ZHENG XINCHENG , LIN SHILI , ZHENG PAN , LIU YANG 
Published: January 2023

Abstract
Single-nucleodie polymorphism (SNP) has a profound impact upon one’s susceptibility to autoimmune diseases such as multiple sclerosis (MS). Although it is well established that 3’UTR play a major role in regulating RNA stability, the contribution of SNP in the 3’UTR to the risk of autoimmune diseases has not well characterized. We have proviously reported the contribution of mouse CD24 3’UTR to its mRNA stability, so we investigated the significance of SNPs in the hCD24 3’UTR to MS susceptibility.
Our analysis of the 316 MS patients and 342 controls revealed that a di-nucleotide deletion at position 1580 (P1580) of hCD24 mRNA is associated with significantly reduced risk (odds ratio OR = 0.53 with 95% confidence interval = 0.34–0.81) and delayed progression (p = 0.016). More importantly, using 150 families from two independent cohorts, we have found that the P1580del allele is preferentially transmitted to unaffected individuals (p = 0.003). In heterozygous individuals, the mRNA levels for the the di-nucleotide-deletion allele is 2.5-fold less than that of the wild-type allele (p = 0.004). Our transfection studies revealed that the di-nucleotide deletion dramatically reduced the stability of hCD24 mRNA (p &lt; 0.001).
Our results demonstrate that a destabilizing di-nucleotide deletion in the 3’UTR of hCD24 mRNA substantially reduces the risk and delays the progression of MS.
Visualizing mechanisms of peripheral tolerance against autoreactive T cells (129.35)
Authors: Divekar Rohit D. , Haymaker Cara , Jain Renu , Ellis Jason , Tartar Danielle , Yu Ping , Lee Hyun-Hee , Hardaway John , Hoeman Christine , Guloglu Betul , Franklin Craig , Miller Mark , Zaghouani Habib 
Published: January 2023

Abstract
Where and how T cell tolerance happens remains largely undefined. Here, we used an established in vivo model and investigated the site and the mechanisms that govern APC-mediated inactivation of autoreactive T cells.
Fcγ receptor-deficient (FcγR−/−) mice were induced for experimental allergic encephalomyelitis (EAE), with a myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide and when the disease became apparent the mice were given FcγR+/+ APCs and treated with Ig-MOG, a tolerogenic Ig expressing MOG peptide. Under this regimen the mice were able to reverse their EAE only when given FcγR+/+ APCs that can present Ig-MOG and carry out T cell tolerance. This system was then used to visualize encounter of the APCs with the pathogenic T cells. The results indicate that tolerance occurs in a time dependent fashion when both the T cells and APCs have accumulated in sufficient number at the encounter site but unlike immunity, can take place in the non-draining lymph nodes. Two-Photon microscopy analysis revealed that tolerized T cells exhibit organ-specific changes in motility, pattern of migration and trafficking which could be related to functional matters as tolerance manifest the form of Th2 deviation in the lymph node and anergy in the spleen.
Research supported by grant NS37406 from NIH.
Critical roles of Bcl-3 in type 1 diabetes (129.43)
Authors: Ruan Qingguo , Carmody Ruaidhri , Zheng Shijun , Chen Youhai H. 
Published: January 2023

Abstract
Bcl-3 (B cell leukemia-3) is a member of the inhibitor of nuclear factor kappa B (NF-κB) family. In contrast to other members of this family, Bcl-3 is localized primarily in the nucleus, and selectively interacts with the p50 and p52 homodimers but not their heterodimers. To explore the roles of Bcl-3 in models of type 1 diabetes, we studied cyclophosphamide-induced diabetes in NOD mice and low-dose streptozotocin-induced diabetes in C57BL/6 mice that did or did not express Bcl-3. We found that Bcl-3-deficient mice were more susceptible to autoimmune diabetes and were defective in Th2, but not Th1 responses. Additionally, we found that chemokine production in Bcl-3-deficient mice was significantly enhanced as compared to the control mice. Mechanistic studies reveal that in the absence of Bcl-3, the inhibitory p50 homodimer of the NF-κB family is ineffective in suppressing gene expression because it is rapidly ubiquitinated and degraded upon binding to DNA. Bcl-3 effectively inhibits p50 polyubiquitination and stabilizes its interaction with DNA through the formation of a stable Bcl-3:(p50)2:DNA complex. These results indicate that Bcl-3 is a critical transcriptional inhibitor of autoimmune diabetes.