bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of antigen transport from the female reproductive tract to the gastrointestinal tract
Authors: Howe Savannah E , Shillova Nita , Konjufca Vjollca H 
Published: January 2023

Abstract
One of the major functions of the female reproductive tract (FRT) is the establishment and maintenance of pregnancy, resulting in healthy offspring. Although many pathogens (e.g. Chlamydia spp.) infect the FRT, no vaccines against these pathogens have been licensed to date. This lack of success has been in part attributed to the inability of the FRT to efficiently internalize antigens. We showed that FRT epithelium of mice can internalize nanoparticles (NPs) &lt; 40 nm and that protein coated 20 nm NPs prime the intestinal mucosa for secretion of IgA. This finding led us to hypothesize that NPs reach the GI tract following per-vaginal (PV) instillation. Using multiphoton and fluorescence microscopy, we show that PV-instilled antigens (DAPI, Dextran, NPs) reach the stomach antrum and the small intestine within 1–3 h. It is proposed that Chlamydia spp. colonizes the GI tract following PV instillation by entering the circulation. We show that colonization of the GI tract by C. muridarum is dependent on cell transport. While within 7 days of PV infection Chlamydia colonizes the GI tract of controls, while no Chlamydia can be detected in iliac lymph nodes (ILNs) or GI tracts of CCR7−/− mice. Moreover, treatment of mice with FTY720 inhibits colonization of the GI tract, but it does not preclude infection of ILNs by Chlamydia. This finding indicates that Chlamydia transport from the ILNs to the GI tract depends on sphingosine 1-phosphate-mediated cell egress. Elucidation of mechanisms by which C. muridarum disseminates systemically to colonize the lymphoid tissues and the GI tract will be important for understanding both the immunity to and pathogenesis of Chlamydia spp.
Human CD39 overexpression or APT102 recombinant apyrase administration enhances Treg and Tr1 cell immunity in inflammatory bowel disease
Authors: Vuerich Marta , Robles Rene’ J. , Mukherjee Samiran , Xie Anyan , Harshe Rasika , Moss Alan C. , Robson Simon C. , Longhi Maria Serena 
Published: January 2023

Abstract
CD39/ENTPD1 is an ectonucleotidase that scavenges pro-inflammatory nucleotides to ultimately generate adenosine. Single nucleotide polymorphisms within the promoter region of the ENTPD1 gene are linked to higher rates of inflammatory bowel disease (IBD) in humans. Furthermore, decreased levels of CD39 expression are noted in Th17 cells purified from patients with Crohn’s disease, because of aberrant signaling by aryl-hydrocarbon-receptor (AhR) in response to endogenous ligands e.g. unconjugated bilirubin (UCB). Deletion of CD39 increases susceptibility to disease in experimental colitis while overexpression of human CD39 (hCD39) in transgenic mice results in protection from ischemia reperfusion injury and thromboembolism.
Here, we show that overexpression of hCD39 results in amelioration of dextran-sulfate-sodium (DSS)-induced experimental colitis and protects mice from the deleterious effects of systemic hypoxia, pharmacologically induced by deferoxamine. We further report that treatment with APT102, soluble recombinant apyrase, boosts Foxp3 expression in wild type Treg and renders Crohn’s-derived Treg and Tr1 cells more responsive to UCB-AhR stimulation in vitro. Further, APT102 enhances the beneficial regulatory effects of UCB in DSS colitic mice, in vivo.
We conclude that transgenic overexpression of hCD39 is beneficial in experimental colitis and ameliorates systemic hypoxic injury in vivo. Exogenous administration of APT102 promotes AhR-mediated regulatory effects in vivo while boosting the regulatory T-cell pool in Crohn’s disease ex vivo. Boosting endogenous CD39 or augmenting ectonucleotidase activity, as with pharmacological treatment with APT102, might represent therapeutic options in IBD.
B-cell specific duo-conjugates for therapy of autoimmune myasthenia gravis
Authors: Huda Ruksana , Bahauddin Afrin , Fang Xiang , Wu Xiaorong 
Published: January 2023

Abstract
We have prepared a unique set of monoclonal antibody-siRNA conjugates which will target two different subsets of pathogenic B cells in a mouse model of autoimmune myasthenia gravis (EAMG). At the optimum dose, our duo-conjugates significantly reduced two crucial receptors, CD268 and -269, of pathogenic B220 positive cells in PBMCs, lymph node cells and splenocytes in EAMG mice. Modifying the base-composition of the conjugate components further reduced adverse effects of the high dose and significantly decreased pathogenic autoantibody levels, which corresponded with improved clinical symptoms. Our ongoing works suggest a potential for further developing target specific conjugates as highly effective therapeutics for myasthenia gravis.
Blocking the Pro-Inflammatory Response Associated with Inflammatory Bowel Disease with 7-Ketocholesterol
Authors: Bamezai Anil K , Mallon Francine , Lawrence Audrey 
Published: January 2023

Abstract
Inflammatory bowel disease (IBD) affects more than one million people in the United States alone, and currently has no cure. IBD is a chronic inflammatory condition, perpetrated by dysregulation of the adaptive immune system’s response to nonpathogenic flora in the gastrointestinal tract. CD4+ T cells, critical components of the adaptive immune response, misperceive commensal microbiota in the gut as threats and persistent stimulators of CD4+ T cells, resulting in uncontrolled and episodic responses. Regulatory T cells, through secretion of interleukin 10 (IL-10) cytokine, suppress the pro-inflammatory environment in the gut. In the absence of this suppression a chronic inflamed state can be reached. Previous studies have shown that 7-ketocholesterol (7-KC), a natural metabolite of cholesterol, can successfully disrupt lipid raft-based membrane order in vitro, promoting a disordered state. This forces the question of whether pro-inflammatory responses can be disrupted through this method. We investigated the potential of 7-KC to suppress gut inflammation using the IL-10 KO animal model. Mice deficient in IL-10 have inflamed guts and symptoms of IBD as observed in humans. IL-10 knockout mice were orally gavaged twice daily, 3 days a week for 3 weeks to deliver 7-KC. Treated and control mice were observed for 4 weeks and necropsies were performed on day 27 to dissect their colons for immunohistochemistry. We observed a change in tissue constitution, stool quality, and fatty pockets in the treatment group in comparison with the controls receiving saline. These preliminary findings with IL-10 knockout mouse model reflect the potential of 7-KC as immunomodulatory agent for suppressing the inflammatory environment in the gut.
Development of a Novel Antigen-Specific Therapy for Autoimmune Diabetes Using an Insulin-ChgA Hybrid Peptide Neoantigen
Authors: Jamison Braxton , Beard K. Scott , Neef Tobias , Bradley Brenda , Baker Rocky , Gill Ronald G. , Miller Stephen D. , Haskins Kathryn 
Published: January 2023

Abstract
In Type 1 Diabetes (T1D) patients and non-obese diabetic (NOD) mice, autoreactive CD4 T cells contribute to destruction of insulin-producing β-cells in the pancreatic islets. Our lab has discovered that in NOD mice the endogenous ligand for the diabetogenic CD4 T cell clone BDC-2.5 is a hybrid insulin peptide (2.5HIP), consisting of a fragment from proinsulin fused to a peptide from chromogranin A (ChgA). The purpose of this study was to determine if tolerogenic poly(lactide-co-glycolide) (PLG) nanoparticles (NPs) coupled with 2.5HIP (2.5HIP-PLG) could be used to induce antigen-specific T cell tolerance. We have found that treatment with 2.5HIP-PLG NPs synergizes with a short course of low-dose recombinant IL-2, leading to robust induction of 2.5HIP-specific Foxp3+ regulatory T cells (Tregs) and prevention of spontaneous diabetes in 50% of NOD mice. In a disease reversal model, spontaneously diabetic NOD mice were transplanted with 500 syngeneic islets and recipients were infused with HEL-PLG (control) or 2.5HIP-PLG NPs pre- and post-transplant. In contrast to HEL-PLG treated mice that showed aggressive disease recurrence in around 2 weeks, graft destruction in 2.5HIP-PLG treated mice was significantly delayed up to an average of 8 weeks, indicating that targeting graft-infiltrating 2.5HIP-specific T cells dampens ongoing autoimmunity. Our current goal is to determine whether the therapeutic effects observed in the transplantation model are due to expansion of antigen-specific Tregs, induction of anergy in effector T cells, or both. This novel antigen-specific therapy using a disease-relevant neoantigen may have implications for development of an immune-modifying treatment for T1D patients.
Transplantation of MHC-mismatched Mouse Embryonic Stem Cell-Derived Thymic Epithelial Progenitors Prevents Autoimmune Diabetes
Authors: Su Min , Lin Yujun , Lai Laijun 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is an autoimmune disease results from the destruction of insulin-secreting islet β-cells by autoreactive T cells. NOD mice are the widely used animal model for human T1D. Autoimmunity in NOD mice is associated with particular MHC loci and impaired islet autoantigen expression and/or presentation in the thymus, which results in defects in both central and peripheral tolerance. It has been reported that induction of mixed chimerism with MHC-mismatched, but not MHC-matched donor bone marrow (BM) transplants prevents the development T1D in NOD mice. We have reported that mouse embryonic stem cells (mESCs) can be selectively induced in vitro to generate thymic epithelial progenitors (TEPs) that further develop into thymic epithelial cells (TECs) in vivo to support T cell development. We show here that transplantation of MHC-mismatched mESC-TEPs and MHC-matched donor BM prevents insulitis and T1D development in NOD mice. This is associated with higher expression of proinsulin 2, a key islet autoantigen, in the mESC-TECs, and an increased number of regulatory T cells. Our results suggest that embryonic stem cell-derived TEPs may offer a new approach to control T1D.
Neutralization of IL-2 prevents acute GVHD while preserving GVL activity via regulating PD-L1/PD-1 signaling
Authors: Song Qingxiao , Wang Xiaoning , Martin Paul J. , Chen Yuanzhong , Zeng Defu 
Published: January 2023

Abstract
Acute gut graft versus host disease (GVHD) has a critical impact on the outcome of allogeneic hematopoietic cell transplantation (allo-HCT). Our recent studies indicate that IL-2 from donor CD4+ T cells make infiltrating T cells resistant to host-tissue PD-L1-mediated tolerance (Ni & Song et al: JCI 2017), but the mechanisms remain unclear. To tested whether in vivo neutralization of IL-2 early after allo-HCT differentially regulates PD-L1/PD-1 signaling in GVHD target tissues and lymphoid tissues, spleen and BM cells from C57BL/6 (H-2b) donors were transplanted into lethally irradiated wild-type (WT) or PD-L1−/− BALB/c (H-2d) recipients in the presence or absence of BCL1 leukemia/lymphoma cells. Recipients were treated with neutralizing anti-IL-2 mAb or control IgG. Administration of anti-IL-2 completely prevented gut GVHD while preserving GVL activity in WT recipients but not in PD-L1−/− recipients. This effect was associated with expansion of donor T cells in the lymphoid tissues (i.e. spleen and MLN) but reduction of donor T cells in the GVHD target tissues such as the gut. Prevention of GVHD resulted from increased donor T apoptosis, with increased expression of Fas but reduced expression of Bcl-XL. Residual T cells showed evidence of enhanced anergy/exhaustion and upregulated expression of FR4, CD73, KLRG1 and Eomes. Finally, prevention of GVHD was associated with inhibition of pAKT/mTOR pathway in a donor T cell PD-1-dependent and host tissue PD-L1-dependent manner. These results indicate that neutralizing IL-2 early after allo-HCT augments tolerance-induction through PD-1 signaling mediated by host PD-L1 in GVHD target tissues but not in lymphoid tissues, thereby preventing gut GVHD while preserving GVL effects.
Ex vivo fucosylation promotes the GVL effect of NK cells after Allo-HSCT
Authors: Gong Huanle , Ma Shoubao , Wu Depei 
Published: January 2023

Abstract
Recent studies demonstrated that ex vivo fucosylation can increase the persistence and anti-GVHD potency of Treg cells. Fucosylation also improves human cord blood engraftment. However, the role of fucosylation in graftversus- leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains unknown.
Here, we established a murine GVL model by intravenously injecting luciferase (lus+)/yfp-expressing B-cell lymphoma (A20) cells and founded that adoptive transfer of fucosylated NK cells markedly prolonged the survival than control NK cells. Ex vivo fucosylation significantly upregulated IFN-γ production in NK cells and enhanced their cytotoxic activity. Flow cytometry analysis revealed that fucosylation promoted the infiltration of NK cells, which may be due to the elevated binding to CD62E. Further studies are needed to confirm the contribution of IFN-γ by using IFN-γ KO mice and investigate the detailed mechanisms of fucosylated NK cells in the regulation of GVL responses.
Profiling pre-existing autoantibodies for prediction of Primary Graft Dysfunction after lung transplantation (LT)
Authors: Li Quanzhen , Zhu Chengsong , Kaza Vaidehi 
Published: January 2023

Abstract

Background
Primary graft dysfunction (PGD) is acute allograft injury that results in increasing morbidity and mortality after LT. Pre-existing autoantibodies (autoAbs) targeting to self-antigens may play a major role for PGD.

Method
In this study, the effects of autoAbs and their specific patterns were comprehensively evaluated on serum samples collected from 51 patients before and after LT. The pre-existing AutoAbs in sera were measured using proteomic arrays bearing 375 autoantigens developed by UT Southwestern Microarray core. The score of each autoAb was compared between the patients who developed PGD (n=21) with those without PGD (n=30). Survival analysis was performed to investigate the effects of differential autoAbs upon the survival proportion. A machine learning program combined with lasso and elastic-net model was used to select the panel of AutoAbs with the best predict value for PGD.

Results
The patients who developed PGD had a lower survival rate compared with patients without PGD. The autoAbs against AchR3, AGTR1, FUCA1 and aldolase showed significant higher expression in patients with PGD compared with those without PGD (fold change &gt;1.5, p&lt;0.05). The levels of anti-AchR3 and anti-AGTR1 were significantly correlated with the survival rate in PGD group. A panel of 19 AutoAbs were selected by a machine learning program with the best predictive value for PGD. A receive operative curve was generated using the 19 autoAb panel with AUC 0.96 and CI 0.99–1.0.

Conclusion
Our study identified AutoAbs associated with PGD in LT patients. A prediction model developed with a panel of AutoAbs with high accuracy may make a significant impact in the management of LT recipients.
Expression of the Butyrate/niacin Receptor, GPR109a on T cells Plays an Important Role in a Mouse Model of Graft Versus Host Disease
Authors: Docampo Melissa D , Stein-Thoeringer Christoph , Lazrak Amina , da Silva Marina Burgos , van den Brink Marcel R.M. 
Published: January 2023

Abstract
The intestinal microbiota is essential for the fermentation of dietary fibers into metabolites, notably the short-chain fatty acids (SCFA) butyrate, acetate and propionate. SCFA can bind to G-protein-coupled receptors such as GPR109a to activate downstream anti-inflammatory effects. GPR109a is the main butyrate receptor and we have previously demonstrated that butyrate can ameliorate gastrointestinal injury during graft versus host disease (GVHD). Therefore, we hypothesized that GPR109a is important in the pathophysiology of intestinal GVHD. Using a MHC-mismatched model of GVHD, we demonstrated a lower incidence of disease when mice received wild type (WT) bone marrow (BM) and T cells from a GPR109a−/− mouse. It is known that GPR109a is highly expressed on myeloid cell populations such as dendritic cells and macrophages; however, expression on T cells is not entirely resolved. At baseline, we observed low expression of GPR109a on T cells, which increases upon T-cell receptor stimulation. T cell development in GPR109a−/− mice appears normal, however, 7 days after transplant, we found significantly fewer CD4+ and CD8+ T cells in the intestines of mice that received WT BM and GPR109a−/− T cells. While frequency of Th1 and Th17 cells were similar between the groups, we saw significantly more regulatory T cells in the intestines and spleen of GPR109a−/−T cell recipients. This reduction of GVHD was accompanied by maintenance of the gut commensal Clostridium and increased butyrate, which is known to protect the intestinal epithelium and increases the regulatory T cell pool. Thus, we propose a novel role for GPR109a in the expansion and activation of T cells during GVHD.
Role of Akt Isoforms in Hyperlipidemia induced changes to Regulatory T cells
Authors: Hyde Michael , Bagley Jessamyn , Iacomini John 
Published: January 2023

Abstract
Hyperlipidemia is a common health condition in the transplant patient population. This condition causes end-stage heart disease in approximately 40% of all patients requiring a heart transplant, developing in 50% of heart transplant recipients after the first year and 95% of patients within 5 years of transplant. A history of ischemic heart disease resulting from coronary artery disease due to hyperlipidemia is also a major predictor of heart transplant rejection. In spite of its prevalence in the transplant population and the observation that it appears to be a significant risk factor in rejection, the role of hyperlipidemia in transplant rejection remains poorly understood. We have recently shown that hyperlipidemia promotes an aggressive rejection response that results in accelerated rejection of allogeneic heart transplants and resistance to tolerance induction. Hyperlipidemia causes a variety of systemic immune system changes including increased production of IL-17, and regulatory T cell dysfunction. Here we examined how activation of Akt alters regulatory T cells phenotype and metabolism. In mice, Akt has three isoforms, two of which play a critical role in regulatory T cells, Akt1 and Akt2 which have non-overlapping roles in cellular functions. Here we examine the mechanism of Akt activation, activation of downstream targets of Akt1 and Akt2, and modification of metabolic pathways in regulatory T cells derived from hyperlipidemic mice.
The Ocular Immune Response in a Rodent Model of Whole Eye Transplantation
Authors: Li Bing , Zhang Wensheng , Wang Yong , Banaee Touka , Chen Wendy , Su An-Jey , Owens Charles , Miller Maxine , Komatsu Chiaki , Washington Kia 
Published: January 2023

Abstract

Introduction
Approximately 36 million people are totally blind globally. Using a rodent whole eye orthotopic transplant model (WET), we are investigating a potential clinical treatment to restore vision. Typically, clinical transplantation involves allogeneic individuals and immune rejection is the first obstacle after surgery. Her--e, we use an MHC class I and II mismatched transplant model without immunosuppression to describe for the first time the features of the immune reaction in WET.

Methods
14-wk old male Brown Norway (BN) rats served as donor and recipient in the syngeneic group. 14-wk old male BN rats served as donors with age/sex matched Lewis rats used as recipient in the allogeneic group. Both groups underwent WET, subsequently the transplanted eye blood supply and structure were evaluated on post-operative day (POD) 2 by optical coherence tomography (OCT). Skin and cornea rejection at POD 2,4,5,6,8 were assessed separately by a scoring system. The progressive infiltration of immune cells into the eye was evaluated by flow cytometry and histology.

Results
At POD5 allogeneic corneas had transparency changes that coincided with skin rejection and Cornea thickness dramatically increased by 150% over syngeneic eyes. Also, the allogeneic group had significant CD4+, CD8+ T cells and NK cell infiltration in aqueous humor, iris, retina and choroid with no difference in cornea.

Conclusion
These preliminary results indicate that acute rejection in WET is T cell mediated and the blood ocular barrier is compromised post-operatively, where immune cells can access the eye. Rejection after WET can be potentially monitored by noninvasive measurement of the cornea thickness or easily accessible aqueous humor.
A longitudinal analysis of TCRβ repertoire diversity in immune tolerance of pediatric patients post-UCBT: T cell clonal deletion over clonal anergy
Authors: Chen Xiaohua , Szabolcs Paul 
Published: January 2023

Abstract
The mechanisms of long term immune tolerance after successful hematopoietic stem cell transplantation are not fully elucidated. We set up serial experiments to test central and peripheral mechanisms sustaining tolerance after HLA-mismatched unrelated cord blood transplant (UCBT) in the GvH direction. TCRβ ImmunoSEQ® (Adaptive Biotechnology®) was applied for tracking and characterizing host-reactive T cell clones from graft or patient samples.
Seven UCBT recipients with non-malignant diseases were studied. All patients enrolled on the same reduced intensity conditioning trial (NCT01852370). Patients achieved tolerance if discontinued immunosuppression, exhibited immunocompetence without GvHD or graft rejection. Purified T cells responses to host APCs were measured by mixed lymphocyte reaction, cytokine bioplex, and micro CTL assays. T cells clones expanding &gt;0.1% frequency in response to host APC were tracked and characterized with TCRβ ImmunoSEQ®.
ImmunoSEQ® revealed the disappearance of host-reactive clones that expanded from an aliquot of the infused cord blood graft by 7 days of stimulation with purified host APC. Most of these allo-reactive T cell clones were not identifiable even in the presence of IL2 supplementation to break anergy. Serial experiments post-UCBT revealed novel host-reactive clones that were not identifiable within the alloreactive pool of the graft pre-UCBT.
In summary, the acquisition of immune tolerance in the GvH direction post-UCBT is characterized by hypo-reactivity in all assays employed towards host APC. The disappearances of most host-specific clones in the graft indicate that deletion is a major mechanism of long term tolerance with possibly a small degree of anergy in contribution.