bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of Adenovirus Vectors Encoding Rat Complement Regulators for Use in Therapy in Rodent Models of Inflammatory Diseases
Authors: McGrath Yvonne , Wilkinson Gavin W. G. , Spiller O. Brad , Morgan B. Paul 
Published: December 2022

AbstractC activation has been implicated in the pathogenesis of numerous inflammatory human diseases and disease models. A therapy based on C inhibition might therefore be of benefit to reduce inflammation and ameliorate disease. C inhibition in vivo can be accomplished by the delivery of soluble recombinant C regulators either systemically or directly to a target site, but effects are transitory. We have developed a strategy for the efficient delivery of the membrane-bound rat C inhibitors, CD59, Crry, and decay-accelerating factor (DAF), using replication-deficient adenovirus vectors with the intention of treating rat models of disease in which C is implicated. The adenovirus recombinants(RAd), RAdCD59, RAdCrry, and RAdDAF, respectively, have been tested for expression and function of the transgene in vitro. Infection of human fetal foreskin fibroblasts resulted in high levels of expression of each of the rat inhibitors. The constructs were also tested for inhibition of rat C-mediated cell lysis and C3b deposition. In a cell lysis assay, each inhibited to varying degrees of efficiency in the order RAdCD59 = RAdDAF &gt; RAdCrry. In a C3b deposition assay, RAdDAF caused a greater reduction in C3b deposition than RAdCrry and RAdCD59 was ineffective. These agents, individually or in combination, provide the tools for testing the effects of prolonged inhibition of C at a target site on the progress of experimental models of disease.
In Vivo Administration of Recombinant IL-2 to Individuals Infected by HIV Down-Modulates the Binding and Expression of the Transcription Factors Ying-Yang-1 and Leader Binding Protein-1/Late Simian Virus 40 Factor
Authors: Bovolenta Chiara , Camorali Laura , Lorini Alessandro L. , Vallanti Giuliana , Ghezzi Silvia , Tambussi Giuseppe , Lazzarin Adriano , Poli Guido 
Published: December 2022

AbstractLeader binding protein-1 (LBP-1)/late SV40 factor (LSF) and ying yang-1 (YY1) transcription factors are involved in the regulation of HIV expression. In particular, YY1 and LBP-1 have been shown to cooperate in repressing HIV-1-long terminal repeat reporter gene expression by in vitro cotransfection experiments. However, no information is available on the levels of expression and activation of these transcription factors in PBMC of HIV-infected individuals. Therefore, we have evaluated the expression and DNA binding activity of YY1 and LBP-1 (LSF) in PBMC of HIV-infected individuals before, during, and after administration of IL-2 in association with antiretroviral therapy (ART), a regimen under consideration for broad clinical use in this disease based on its ability to stably raise the absolute number of circulating CD4+ T lymphocytes. Both YY1- and LBP-1 (LSF)-DNA binding were profoundly down-modulated during administration of IL-2/ART, and a proteolytic activity probably responsible for the reduced expression of the two cellular transcription factors was found activated in PBMC of individuals receiving the immunotherapeutic regimen. This study is the first evidence of modulation of cellular transcription factors following IL-2/ART administration and provides a potential correlate of the transient raises in plasma viremia early reported in patients receiving IL-2 in the absence of ART, thus underscoring the importance of always administering this cytokine to HIV-infected individuals together with potent antiretrovirals.
I. Isoagglutinins in the Blood of Cattle
Authors: Little Ralph B. 
Published: December 2022

Abstract
Introduction Since the identification by Landsteiner of the four definite human blood groups numerous workers have attempted to group the blood of mammals with varying results. In 1907, Hektoen (1) was unable to find any isoagglutinins in the serum of rabbits, guinea pigs, dogs, horses, and cattle. In each instance 0.1 cc. of 10 or 20 different sera was tested upon 0.1 cc. of 2.5 per cent suspension of washed corpuscles from as many animals. Ottenberg and Friedman (2), in 1911, were able to divide by agglutination the blood of steers into three definite groups, as follows.
Group I. Agglutinative but not agglutinable.
Group II. Agglutinable but not agglutinative.
Group III. Neither agglutinative nor agglutinable.
The authors assume that in the blood of steers there is one isoagglutinin and one isoagglutinable substance. They also thought that the examination of a large number might reveal the existence of a second agglutinin and a second agglutinable substance.
Hypersensitiveness to Diphtheria Bacilli
Authors: Neill James M. , Fleming William L. 
Published: December 2022

Summary
The present example of diphtheria bacterial hypersensitiveness agrees with the previous examples in that it is manifested by an immediate skin reaction and in that the capacity for the reaction can be passively transferred. It differs, however, in that the individual is particularly reactive with a heat (60°C.) labile product not involved in the reactions of the previous diphtheria-sensitive persons. This product is apparently contained in effective concentration only in the unheated culture filtrates of toxicogenic diphtheria bacilli and not in the filtrates of nontoxicogenic strains nor in solutions of material derived from the washed bacterial cells. If it is not toxin, it is a hitherto unrecognized diphtheria bacterial product that possesses a degree of lability not usually encountered among the bacterial substances associated with hypersensitive reactions.
The results are discussed in respect to the possibility that the described reactions may represent an example of true hypersensitiveness of man to diphtheria toxin.
The Influence of Blockade of the Reticuloendothelial System on the Formation of Antibodies
Authors: Cannon Paul R. , Baer Raymond B. , Sullivan F. L. , Webster J. R. 
Published: December 2022

Summary and Conclusions
The liberation into the blood stream of hemolysins to sheep's red corpuscles following blockading procedures depends upon the manner of administration of the blockading material and the amount of antigen injected. Repeated injections of suspensions of India ink, particularly when given intravenously and continued after the injection of a small quantity of “test-antigen,” are followed by a significant decrease in the liberation of antibody into the blood stream, this liberation apparently varying inversely with the extent to which the phagocytic cells are blocked. This decrease in output of antibody is independent of individual variation of animals, loss of weight or of depression by fluids alone. Evidence is presented that small amounts of blockading material stimulate the liberation of antibody whereas large amounts tend to depress such a liberation. These experiments offer additional evidence that antibodies, at least hemolysins, are formed by the phagocytic cells of the mesenchymal tissues.
Development of CD8αβ+ iNKT cells in a humanized mouse model (APP3P.112)
Authors: Yuan Weiming , Wen Xiangshu , Kim Seil , Xiong Ran , Li Michelle , Lawrenczyk Agnieszka , Besra Gurdyal , Delabona Paolo , Casorati Giulia , Akbari Omid , Exley Mark , Rao Ping 
Published: December 2022

Abstract
Invariant NKT (iNKT) cells are innate-like T cells showing potent anti-tumor function in conventional mouse models. In sharp contrast, iNKT cell ligands have had limited efficacy in human anti-tumor clinics, mostly due to the profound differences in the properties and compositions of iNKT cells between human and mice, including the presence of CD8+ iNKT cells only in humans. To build more relevant in vivo models for studying human iNKT cells, we recently developed the first humanized mouse model (hCD1d-KI) with human CD1d knocked in (Proc. Natl. Acad. Aci. USA 110: 2963-8, 2013). To further humanize the mouse model, we introduced human invariant TCRα chain (Vα24Jα18) into the hCD1d-KI mice. Interestingly, we observed a substantial subset of iNKT cells expressing CD8αβ. The presence of these CD8αβ+ cells in the thymus suggested that they are developed in the thymus. Functionally these iNKT cells show a strong Th1-biased cytokine response and potent cytotoxicity upon activation. The low binding of iNKT TCRs to human CD1d/lipid complex and high prevalence of Vβ7 TCRβ among these CD8+ iNKT cells strongly suggested a novel low avidity-based developmental program for the ontogeny of these iNKT cells which includes the suppression of Th-POK and up-regulation of Eomes transcriptional factors. Our establishment of a near fully-humanized mouse model in CD1d/iNKT TCR system will greatly facilitate the future design and optimization of iNKT cell-based immunotherapies.
Effects of immunosenescence on professional antigen presenting cell immunogenicity in the context of Varicella zoster viral infection (APP3P.114)
Authors: Cheney Elizabeth 
Published: December 2022

Abstract
A protracted decline in immune system fitness occurs over one’s lifespan. Both the innate and adaptive immune systems exhibit numerous alterations with age. Despite these alterations, aged people often have robust responses to pathogens they encountered in child and adulthood. Memory lymphocytes that develop during these challenges are protective and remain largely intact. In contrast, protection against Varicella Zoster Virus (VZV) wanes with increasing age and results in viral reactivation known as Herpes Zoster (HZ) or shingles. This increased incidence correlates with a decrease in cell-mediated immunity (CMI) that is critical for protection against VZV. This is perplexing as most people are exposed to VZV when young, and have functional anti-VZV CMI in adulthood. Viral latency of both VZV and a closely related herpes virus, Herpes simplex 1 (HSV-1), is maintained by CMI. Importantly, maintenance of Tm cell responses is dependent on the recruitment of professional APC (pAPC) to the site of reactivation in HSV-1 infection. We hypothesize that increased incidence of HZ in the elderly is due to a deficit in pAPC function or numbers that then results in loss of tissue resident Tm responses. Specifically we predict that aging affects Ag processing and presentation in pAPCs. Data will be presented that examines the capacity of human pAPCs to process and present antigen as a function of age.
Quantitative expression analysis of rhesus macaque MHC alleles (APP3P.102)
Authors: Peng Xinxia , Pyo Chul-Woo , Thomas Matthew , Pyon Yoon Soo , Law Lynn , Wang Ruihan , Geraghty Daniel , Katze Michael 
Published: December 2022

Abstract
The relevance of MHC genes to HIV infection and disease progression is well established, and nonhuman primates are the most important model for AIDS vaccine research and development. However, due to the structural and sequence complexity of the macaque MHC, the expression changes across this complex region have not been determined accurately. We are developing a strategy for accurately quantifying rhesus MHC allele expression. Our strategy leverages a large collection of full-length rhesus MHC genomic sequences and a custom-developed computational pipeline, and only requires regular macaque RNA-seq data from users. We used this technique to analyze RNA-seq data collected from normal rhesus macaque tissue samples and PBMC samples from acutely infected rhesus macaques. We show that the expression of both MHC class I and class II genes was highly tissue specific, and multiple class I alleles were expressed within a single tissue. Compared to animal matched baseline PBMC samples, there was an overall increase in the expression of class I alleles in acutely infected rhesus macaques, as early as 3 days post infection. Both up-regulation and down-regulation of class II gene expression in PBMC samples was also observed during acute SIV infection. This study presents for the first time a systematic quantification of macaque MHC allele expression. The results may reveal limits in our understanding to fully account for the impact of MHC expression on immunological outcomes.
Identification of endogenous murine leukemia retrovirus antigens attributing to exosome-induced autoimmunity in NOD mice (BA6P.122)
Authors: Dai Yang , Bashratyan Roman , Regn Danielle , Binley James , Marquardt Kristi 
Published: December 2022

Abstract
Endogenous autoimmune triggers and antigens are required for initiating the innate and cellular immune responses in the islet of non-obese diabetic (NOD) mice. We found that secreted, nano-sized microvesicles or exosomes are potent inflammatory triggers that, importantly, stimulated autoreactive B and T cells. By performing proteomic analysis, we identified endogenous retrovirus (ERV) proteins, highly homologous to murine leukemia retrovirus (MLV), that are enriched in the exosomes. To study whether these ERV antigens attribute to the autoimmune induction, we produced exosomes lacking the ERV Gag protein and virus-like particles (VLPs), which are nano-sized microvesicles overexpressing Gag and Env proteins. We found that NOD mice spontaneously develop autoantibodies binding to the MLV Env, and also accumulate Env-specific B cells in periphery as compared with diabetes-resistant mice. Autoreactive T cells did not respond to the MLV antigens directly; however, immunization with the exosomes or VLPs induced Gag-specific T cells that inhibited the function of diabetogenic T cell clones in the pancreas. Therefore, ERV antigens may be the targets of autoreactive B and T cells in this T1D mouse model. Consistently, we detected endogenous MLV antigens expressed in the pancreas and by the islet stromal/stem cells in NOD mice. These data support that unique ERV antigens and/or altered formation of exosomes in islet cells may trigger tissue-specific autoimmunity in NOD mice.
Commensal microbiota regulate inflammatory cardiac remodeling (BA6P.126)
Authors: Barin Jobert , Diny Nicola , Gebremariam Elizabeth , Talor Monica , Bedja Djahida , Kass David , Peterson Daniel , Rose Noel , Cihakova Daniela 
Published: December 2022

Abstract
In this study, we sought to understand how the microbiota regulates inflammatory mechanisms underlying cardiac autoimmunity. We employ an autoimmunization model of heart disease in mice, termed experimental autoimmune myocarditis (EAM). This disease model depends on CD4+ T cells for pathogenesis, immediately implying a cytokine product of these cells as a critical mediator of disease pathogenesis, and an attractive target for therapeutic intervention. Our laboratory has previously reported that Th17 cells are critical for the disease process. In order to establish a role for the commensal microbiota in autoimmune heart disease, we treated animals with a comprehensive polyantibiotic cocktail to induce antibiotic dysbiosis. Treating BALB/cJ animals with antibiotic limited the development of myocarditis, and furthermore prevented their progression to later heart failure. Segmented filamentous bacteria (SFB) represent a clade of Clostridia that have been found to elicit intestinal Th17 differentiation upon colonization, and subsequently modulate susceptibility to Th17-associated autoimmune disease. We colonized BALB/cJ mice with SFB and observed that these animals progress to diminished cardiac function following the induction of EAM. Microbiota manipulations were associated with differences in canonical Th17-associated programs, pointing to these pathways as an important mechanism in coupling commensal sensing to the progression of heart disease.
Overexpression of Pbx1-d, a novel splice isoform of Pbx1, in CD4+ T cells promotes follicular helper T cell differentiation (BA6P.127)
Authors: Choi Seung-Chul , Morel Laurence 
Published: December 2022

Abstract
Pbx1 controls chromatin accessibility to a large number of genes. Pbx1-d is a Pbx1 dominant negative isoform lacking the DNA binding domain, and its expression is more frequent in the CD4+ T cells from lupus patients than in healthy controls. Pbx1-d is associated with the production of autoreactive CD4+ T cells in the Sle1a1 lupus susceptibility locus and lupus susceptibility in the B6.Sle1.Sle2.Sle3 mouse model. We have generated Pbx1-d Tg mice that specifically express Pbx1-d in CD4+ T cells. These Tg mice reproduce the phenotypes of Sle1a1 mice, with increased inflammatory functions of CD4+ T cells and impaired regulatory T (Treg) cell homeostasis. Pbx1-d Tg mice also present an increased number of follicular helper T (TFH) cells, which expand with age in naïve mice, and result in enhanced TH1-biased antibody production in response to T-dependent immunization. Interestingly, the relative distribution of TFH and regulatory T (TFR) cell populations is different in both Pbx1-d Tg and Sle1a1 mice as compared with wild-type mice. Adoptive transfers of OT-II.Pbx1-d Tg CD4+ T cells showed that Pbx1-d overexpression expands TFH cell differentiation in a cell-intrinsic and antigen-specific manner. Our results suggest that Pbx1-d impacts lupus development by regulating effector T cell differentiation by promoting TFH to the expense of Treg cell. In addition, our results identify Pbx1-d as a novel regulator of CD4+ T cell effector function.
Innate cells in autoimmune diabetes in mice and man (BA7P.150)
Authors: Bayer Allison , Umland Oliver , Fraker Chris 
Published: December 2022

Abstract
Donor Treg engraftment following immunomodulation is lower in recent diabetic compared to prediabetic NOD mice. This may be related to altered immune compartment that cannot fully support Tregs and represents an obstacle to successful therapy. Interplay of adaptive and innate immune cells is often overlooked and role natural killer cells (NKs) have only recently been appreciated. But NK subsets remain poorly understood in mice. The current study was aimed at identifying NK functional subsets with effector and regulatory properties using NOD mouse model. We found CD335+CD122+ cells among CD45+CD3- cells in lymph nodes (LN), pancreatic LN (pLN), spleen, and blood in young female non-autoimmune B6 and diabetes-prone NOD mice. Among bulk NKs, c-Kit+ and c-Kit+CD127+ were found in LN, pLN, and spleen, but c-Kit+CD127+ cells was considerably lower in NOD mouse. Interestingly, majority of CD127+ NKs were CD25+ and IL-18R++ compared to other NKs. Blood samples of long-standing diabetic and patients at-risk for diabetes in comparison to control subjects revealed majority of human NK (hNK) are NKeff (CD56+CD16+), but ratio NKeff:NKreg (CD56++CD16-) statistically decreases with disease progression resulting in a more regulatory environment. c-Kit+ hNKs are largely found in NKreg and express IL-18R with long-standing and at-risk having highest %c-Kit+ NKreg compared to controls. The challenge is to resolve the inflammatory roles of NK cells with their regulatory roles in autoimmunity.
Modulation of autoimmune diabetes by innate-like B cell derived antibodies specific for N-acetyl-D-glucosamine. (BA7P.148)
Authors: New James , Dizon Brian , King Rodney , Kearney John 
Published: December 2022

Abstract
The immunodominant epitope of Group A Streptococcus (GAS) is the cell wall associated N-acetyl-D-Glucosamine (GlcNAc) of Group A Carbohydrate (GAC). Previous reports in humans and rodent models have suggested a link between GAS exposure and protection from T1D. Through neonatal immunization with GAS and serum-transfer experiments we find that T1D protection elicited by neonatal GAS exposure is conferred by the antibody (Ab) response to GAC, and the differentiation of unique GlcNAc-specific clonotypes into long-lived plasma cells. Glycan microarray analysis of GAC-specific antibodies indicates they recognize aberrantly truncated mammalian glycans. GlcNAc-terminating glycans exist on a subset of insulin-containing granules and are generated as neoepitpoes during beta cell apoptosis. We find GAC-specific Abs directly block recognition of GlcNAc-modified autoantigens by innate lectins, dampen inflammatory complement activation, and reduce the capacity of dendritic cells to present beta cell antigen. Importantly, T1D patients are deficient in GAS-reactive IgM antibodies. These observations suggest that early exogenous antigen exposure in crucial for developing protective GlcNAc-specific natural antibodies and validate a role for the hygiene hypothesis in T1D. Subsets of GlcNAc-specific antibodies may serve as biomarkers for identifying at-risk patients with natural antibody deficits, and boosting these clonotypes may serve to suppress T1D development
Identification of immunogenic epitopes of β-adrenergic receptor 1 that induce heart autoimmunity in A/J mice (BA8P.164)
Authors: Basavalingappa Rakesh H , Massilamany Chandirasegaran , Arumugam Rajasekaran Rajkumar , Steffen David , Reddy Jay 
Published: December 2022

Abstract
Coxsackievirus B3 (CVB3) is one of the important infectious causes of myocarditis that may lead to dilated cardiomyopathy. To study the autoimmune events in this viral infection, various mouse models are commonly employed. In our studies with A/J mice, we recently demonstrated that the animals infected with CVB3 show the appearance of pathogenic T cells specific to cardiac myosin heavy chain (Myhc)-alpha 334-352, leading us to hypothesize that CVB3 infection might accompany with the generation of T cells with specificities for multiple antigens. To test this hypothesis, we sought to identify the immunogenic epitopes of one other putative cardiac antigen namely, β-adrenergic receptor 1 (BAR1) that has been previously implicated in the immune pathogenesis of CVB3 infection. Our data revealed that the peptides spanning the amino acids, 170 to 230 are capable of inducing epi/endocarditis by active immunization. We also noted that the disease induced by BAR1-peptides was associated with the induction of CD4 and/or CD8 T cell responses, with a skewed T helper (Th)1 and Th17 cytokine production. In conjunction with Myhc-alpha 334-352, identification of BAR1-peptides may thus permit us to determine the kinetics of the generation of autoreactive T cells with multiple antigen-specificities, which might be generated as a result of epitope spreading during the course of CVB3 infection.
Heterodimeric IL-15 regulates the balance of effector and regulatory cells, promoting anti-cancer tumor effects (CCR4P.213)
Authors: Felber Barbara , Bergamaschi Cristina , Ng Sin Man , Chen Stephanie , Bear Jenifer , Alicea Candido , Beach Rachel Kelly , Chertova Elena , Sowder Raymond , Pavlakis George 
Published: December 2022

Abstract
Interleukin-15 (IL-15) is a common γ-chain cytokine that plays a significant role in the activation and proliferation of T and NK cells and holds great potential in fighting infection and cancer. We have previously shown that bioactive IL-15 in vivo comprises a complex of the IL-15 chain with the soluble or cell-associated IL-15 receptor alpha chain that are together termed heterodimeric IL-15 (hetIL-15). HetIL-15 produced from engineered human cell lines showed favorable pharmacokinetics and bioactivity compared to monomeric IL-15 in both mice and macaques. We investigated the anti-tumor efficacy of hetIL-15, using the MC38 colon carcinoma mouse model. hetIL-15 resulted in a significant delay in tumor growth, when administered intraperitoneally every 2 days for 2 weeks. In addition, intratumoral delivery of hetIL-15 induced regression of established tumors and cured 50% of mice. Repeated injections of hetIL-15 resulted in an increased CD8+/Treg cells ratio in spleen, lymph nodes and tumor microenvironment. Preclinical cancer studies support the use of hetIL-15 in tumor immunotherapy approaches to promote the development of anti-tumor responses by favoring effector over regulatory cells.