bluuebunny/crossref_metadata_2025_split huggingface dataset:
An adenosinergic loop contributes to the generation of a microenvironment favoring growth and expansion of CLL cells (165.39)
Authors: Serra Sara , Horenstein Alberto , Tripodo Claudio , Vaisitti Tiziana , Audrito Valentina , Rossi Davide , Gottardi Daniela , Gaidano Gianluca , Malavasi Fabio , Deaglio Silvia 
Published: January 2023

Abstract
CD39 and CD73 are surface enzymes with extracellular catalytic sites. CD39 hydrolyses ATP/ADP to AMP, which is then converted to adenosine (ADO) by CD73. ADO may re-enter the cell or engage different types of purinergic receptors, eliciting potent immunosuppressive responses. The working hypothesis is that CD39+/CD73+ leukemic cells from chronic lymphocytic leukemia (CLL) patients produce ADO, generating environmental conditions favoring growth, through the inhibition of the host immune response. Results indicate that while CD39 is constantly expressed, CD73 is present in 30% of a cohort of 300 CLL patients, where it associates with markers of aggressive disease. Differential CD73 expression is confirmed by immunohistochemical analyses of BM and LN biopsies, with the highest intensity scored by cells within the lymph nodes, where the proliferative core of the leukemia resides. Furthermore, CD73 is expressed at high levels in proliferation centers and by CLL cells surrounded by CD3+ T lymphocytes. CD39+/CD73+ CLL cells produce ADO from ADP, in a time- and dose-dependent way. RT-PCR data indicate that T and CLL lymphocytes express higher levels of a functional A2A receptor, as compared to age-matched healthy controls. These results suggest the existence of an adenosinergic loop, active in selected CLL patients, which likely contributes to determining conditions that favour the development, maintenance and progression of the leukemia.
Low dose irradiation reduces lipid uptake in tumor resident dendritic cells which in combination with tumor specific CD8 T cells induces regression and prevents relapse (165.43)
Authors: Lerret Nadine , Rogozinska Magdalina , Jaramillo Andres , Marzo Amanda 
Published: January 2023

Abstract
Total body irradiation has been shown to enhance the efficacy of adoptively transferred tumor cells. The mechanisms responsible for this have largely been attributed to removal of cytokine sinks, suppressive cells and increase in danger signals. We now show that irradiation results in the down regulation of the macrophage scavenger receptor 1 on dendritic cells within the tumor and as a consequence reduces lipid uptake by tumor resident dendritic cells. The tumor antigen targeted in our model is Mammaglobin-A, expressed by approximately 80% of human breast tumors. We show that only the adoptive transfer of Mammaglobin-A2.4 specific CD8 T cells leads to long-term tumor regression and in combination with low-dose irradiation prevents tumors from reoccurring. These data demonstrate that irradiation reduces lipid uptake by dendritic cells and increases the efficacy of adoptively transferred Mammaglobin-A specific CD8 T cells providing a potential therapy for the treatment and/or prevention of breast cancer.
Oncogenic role for miR-17-92 paralog clusters in AIDS-related non-Hodgkin’s lymphomas (165.45)
Authors: Thapa Dharma , Martinez-Maza Otoniel 
Published: January 2023

Abstract
HIV infected individuals are at an increased risk for developing non-Hodgkin’s lymphomas (AIDS-NHL). Two key factors, immune deficiency, which allows the outgrowth of Epstein-Barr virus (EBV) infected cells, and chronic B cell activation, which promotes the development of oncogenic molecular lesions, are thought to contribute to the development of AIDS-NHL. Recently, microRNAs (miRNA) have been shown to play critical roles in cancers, including in B cell NHLs. miRNAs are small noncoding RNA molecules that can bind to mRNAs and inhibit protein expression. We hypothesized that miRNAs are deregulated in AIDS-NHLs, that these deregulated miRNAs serve as useful biomarkers, and also provide insights into the molecular mechanism of NHL pathogenesis, especially in the setting of immune deficiency. We did a microarray based miRNA profiling of 26 primary cases of AIDS-NHLs from four lymphoma subtypes, Burkitt’s lymphoma (BL, n=6), primary central nervous system lymphoma (PCNSL, n=6), diffuse large B cell lymphoma (DLBCL, n=9), and primary effusion lymphoma (PEL, n=5) and compared the miRNA profile to each other and to normal B cells subsets (naïve, germinal center, and memory) isolated from tonsils. We show that: (1) normal tonsillar B cells exhibit a differentiation stage specific miRNA profile; (2) AIDS-BL and DLBCL overexpressed miRNAs from the miR-17-92 paralog clusters; and (3) members of miR-17-92 paralog clusters target the cell cycle inhibitor p21/CDKN1A.
Growth and constitutive expression of CCL2 and CCL5 by murine mammary carcinomas are dependent upon Myd88 function (165.6)
Authors: Kurt Robert , Egunsola Adetutu , Zawislak Carolyn , Akuffo Afua , Chalmers Samantha , Ewer Jason , Vail Caroline , Lombardo Jeffrey , Perez Dana 
Published: January 2023

Abstract
Previously we reported that lipopolysaccharide (LPS) treatment of murine mammary carcinomas resulted in decreased growth of the tumors in vivo, but not in vitro. Here we explored whether the effects of LPS were dependent upon TLR4 and Myd88 using RNA interference. Two clones with reduced TLR4 mRNA and protein expression and two clones with reduced Myd88 mRNA and protein expression were generated, as well as a clone expressing shRNA specific for lacZ as a control. Significantly, tumors with reduced TLR4 or Myd88 expression no longer exhibited decreased growth rates in vivo following LPS treatment indicating that the decreased growth rate of the 4T1 tumor following LPS treatment was mediated through effects downstream of TLR4 and Myd88. Perhaps more significantly, tumor cells with reduced levels of TLR4 or Myd88 exhibited slower growth rates in vitro and in vivo relative to the parental 4T1 and lacZ controls, and reducing Myd88 expression was sufficient to decrease CCL2 and CCL5 expression. To determine whether inhibiting Myd88 function was enough to alter tumor growth and CCL2 and CCL5 expression we used a Myd88 homodimerization inhibitory peptide. The data revealed that inhibiting Myd88 function was sufficient enough to impair growth of the tumor cells, and decrease constitutive expression of CCL2 and CCL5. These data imply that Myd88 is necessary for growth of murine mammary carcinomas, and expression of at least two proinflammatory chemokines.
Regulatory B10 cells within the peritoneal cavity delay colitis onset by altering local T cell-specific IFNγ production (166.1)
Authors: Maseda Damian , Smith Susan , Poe Jonathan , Tedder Thomas 
Published: January 2023

Abstract
B cells mediate multiple functions that influence immune and inflammatory responses. A rare subset of splenic CD1dhiCD5+ B cells with capacity to produce IL-10 (B10 cells) has been found to regulate T cell responses, inflammation and autoimmunity. Relative to the spleen, higher frequencies of B cells produce IL-10 in the peritoneal cavity (PC) upon a combined in vitro LPS, PMA and Ionomycin stimulation for 5 hours. In this study, the phenotypic and functional characteristics of IL10-competent B10 cells within the PC (PC B10 cells) were characterized. PC B10 cells share several phenotypic markers with splenic B10 cells, and were found within the phenotypically defined B1a (46%), B1b (28%) and B2 (5%) subsets. Adoptive transfer of PC B10 cells significantly delayed disease onset and severity in both the IL10-/- mouse model of spontaneous colitis and the model of induced colitis through transfer of CD4+CD25-CD45RBhi into Rag-/- mice. Overall, when PC B10 cells were transferred i.p. into both disease model recipient mice, the number of activated and IFNγ-producing CD4+ cells significantly decreased in the PC and mesenteric lymph nodes. Thereby, PC B10 cells significantly modulate T cell pathogenicity during colitis.
Changes in T cell subsets in 12 patients enrolled in a tolerance induction protocol with combined kidney and hematopoietic cell transplantation (169.34)
Authors: Dejbakhsh-Jones Sussan , Takahashi Kazuhiro , Jensen Kent , Busque Stephan , Scandling John , Shizuru Judy , Lowsky Robert , Engleman Edgar , Strober Samuel 
Published: January 2023

Abstract
The goal of the study was to determine the changes in T cell subsets for up to 3 years in12 patients given HLA matched combined kidney and hematopoietic cell transplants using total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) as posttransplant conditioning. Eight of the 12 patients were successfully withdrawn from their immunosuppressive drugs. After the completion of the conditioning regimen the absolute number of CD3+T cells in the blood fell 10 by 100 fold in all patients as compared to the pretransplant levels. The greatest reduction was among the naïve CD4+ and CD8+ T cells. Among the CD4+ T cells the percentage of the naïve cells fell from about 40% pretransplant to about 2% at the nadir with a gradual increase thereafter to pretransplant levels during the end of the second year. In contrast, the percentage of Treg cells among CD4+ T cells increased about 3 fold after conditioning, and the ratio of Treg:naive CD4+ cells increased about 20 fold at that time. The change in the ratio approached the pretransplant value at about 6 months as the percentage of Treg cells declined and naive cells rose. During this period, there was upregulation of the expression of the PD-1 activation marker on both Treg and CD4+ Tcon cells, and transient increase in the ratio of NK T cells to naive T cells. Although T cell subsets returned to the pretransplant levels in the patients completely withdrawn from immunosuppressive drugs, no rejections were observed.
Inhibition of STAT1 modulates GVHD after allogeneic BMT through induction of S100A8/A9 (169.38)
Authors: Nasholm Nicole , Bouchkouj Najat , Fry Terry , Capitini Christian 
Published: January 2023

Abstract
T cell depletion (TCD) of donor bone marrow (BM) reduces graft-versus-host-disease (GVHD) after allogeneic blood and marrow transplantation (alloBMT), but can result in poor T cell reconstitution and relapse. We have shown that transplantation of TCD BM deficient in the gamma interferon (IFNγ) receptor allows delayed donor lymphocyte infusions (DLI) without GVHD. We have replicated these results with TCD BM deficient in STAT1, which mediates IFNα and IFNγ signals, and demonstrated expanded plasmacytoid dendritic cells (pDCs). In this study, we further characterized the mechanism of GVHD resistance. After MHC-matched, minor histocompatibility antigen-mismatched alloBMT, TCD STAT1-deficient BM prevents DLI-induced GVHD. Treatment of wild type BM donors and recipients with the glucagon-like peptide-1 analog, Exenatide, which mediates off-target inhibition of STAT1, attenuates GVHD and increases splenic B220+ cell recovery. TCD IRF9-deficient BM, which lacks IFNα signaling, does not prevent GVHD, confirming that IFNγ signaling via STAT1 is the primary pathway of GVHD resistance. Selective deletion of STAT1 using CD11c cre/STAT1flox BM is sufficient to attenuate GVHD-associated weight loss, further implicating a DC subset. Although S100 proteins are not typically found in pDCs, pDCs from TCD STAT1-deficient BM recipients express increased S100A8. Finally, TCD S100A8/A9-deficient BM causes more severe weight loss after DLI, confirming the relevance of S100 proteins in GVHD.
Regulatory dendritic cell mediated allo-antigen specific tolerance for acute graft versus host disease in young and older mice (169.42)
Authors: Scroggins Sabrina , Legge Kevin , Schlueter Annette 
Published: January 2023

Abstract
Graft-versus-host disease (GVHD) occurring after allogeneic bone marrow transplant (BMT) is often fatal. When compared to younger recipients, older BMT recipients experience increased morbidity and mortality. Following BMT, in our model, older (≥14 month) and young (3-4 month) mice succumb to GVHD, but older mice experience faster onset of weight loss and earlier mortality. Prophylactic treatment with syngeneic regulatory DC (DCreg) has been shown to decrease mortality of GHVD and maintain the graft vs. tumor response. DCreg were generated as previously described from age-matched bone marrow. In vitro analysis of young and older DCreg revealed no difference in co-stimulatory or inhibitory marker expression following culture. Following BMT and DCreg treatment most young DCreg treated BMT mice exhibited a brief period of weight loss and survived at least 45 days post-BMT with no evidence of GVHD; older mice had increased morbidity and decreased long-term survival than young mice. Analysis of inhibitory molecules on DCreg one day following adoptive transfer showed significantly lower expression of PD-L1 and PIR B on older DCreg than younger. To assess the donor immune system’s capacity to respond to infection while remaining free of GVHD, DCreg treated BMT mice were challenged with influenza. DCreg treated BMT mice displayed similar morbidity to control mice and GVHD relapse was not observed. Future studies will continue to investigate the mechanisms of DCreg mediated tolerance.
Th1 memory cells induce lethal allogeneic disease in recipient bone marrow and spleen (169.43)
Authors: Chewning Joseph , Zhang Weiwei , Schoeb Trenton , Weaver Casey 
Published: January 2023

Abstract
Graft versus host disease (GVHD) represents a major cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). We sought to determine if Th1 memory CD4 cells were capable of inducing disease in allogeneic recipients. Studies were performed using the murine MHC Class II-disparate HSCT model, C57BL/6 (B6) to B6.C-H-2bm12 (B6→bm12). Initial studies using naïve CD4 cells in the B6→bm12 model revealed bone marrow aplasia present in diseased mice, in addition to classic GVHD tissue findings. FACS CD4 phenotyping of the transferred cells isolated directly from diseased tissues revealed a marked increase in IFN-γ in the allogeneic mice compared to syngeneic recipients. Using a previously described transgenic Ifng reporter mouse containing the Thy1.1 gene knocked in-frame into the first exon of the Ifng gene, we were able to isolate IFN-γ-producing Th1 cells with magnetic bead separation. Adoptive transfer studies of allogeneic Thy1.1-positive cells into bm12 allogeneic mice resulted in fatality in a dose-dependent fashion. FACS phenotyping of Thy1.1-expressing cells in mice demonstrating illness revealed persistence of the Th1 phenotype and tissue histology showed severe disease of bone marrow and spleen in the absence of classic GVHD findings. Serial blood counts confirmed decreases in all hematologic parameters in allogeneic Th1 recipients. These results have important implications for future studies in graft manipulation for human HSCT.
A repertoire independent and cell intrinsic defect in murine GVHD induction by effector memory T cells (169.6)
Authors: Juchem Kathryn , Anderson Britt , Zhang Cuiling , McNiff Jennifer , Demetris Anthony , Caton Andrew , Shlomchik Warren , Shlomchik Mark 
Published: January 2023

Abstract
Graft versus host disease (GVHD) is a major complication of allogeneic stem cell transplantation (alloSCT). In murine models of alloSCT, naïve T cells (TN) cause GVHD, while effector memory T cells (TEM) do not. Why TEM fail to cause GVHD is unknown and whether central memory T cells (TCM) are also unable to cause GVHD is controversial. It has been proposed that a more-restricted T cell receptor repertoire within the memory T cell (TM) pool may limit the ability of TM to recognize alloantigens. To address the role of repertoire, we developed a novel T cell receptor transgenic (Tg) GVHD model in which naive CD4+ TS1 Tg T cells, which recognize an epitope of influenza hemagglutinin (HA), are transferred, along with syngeneic bone marrow, into irradiated transgenic recipients that ubiquitously express HA. We then converted TS1 TN to TM and tested these for GVHD induction. TEM caused minimal, transient GVHD whereas TN and TCM caused potent GVHD. TEM engrafted and accumulated in the spleen to the same extent as TN, but failed to accumulate in the colon. Within the colon, TEM were dividing less actively than TN, and in co-transfer experiments TN out-competed TEM. TEM induced GVHD in recipients that lack expression of PD-L1 and PD-L2, indicating that PD-1, which is unregulated on TS1 cells post transplant, limits the ability of TEM to induce GVHD. Thus, cell intrinsic properties independent of repertoire explain the impairment of TEM while TCM clearly can cause GVHD.
Swine leukocyte antigen diversity in commercial breeding boars: molecular characterization and potential implications on animal health (170.1)
Authors: Ho Chak-Sum , Galina-Pantoja Lucina , Mellencamp Martha , Lee Jun-Heon , Smith Douglas 
Published: January 2023

Abstract
The highly polymorphic swine MHC antigens (SLA) are among the most important determinants of swine immune responses to disease and vaccines, yet their diversity in commercial swine breeding stock has not been studied at the molecular level. Using PCR-based typing assays, diversity of the class I (SLA-1, -2, -3) and class II (DRB1, DQB1, DQA) genes was surveyed in ten pure-line, pedigreed boar populations (n = 413) of a major commercial pig breeder. Of a maximum possible of 623 SLA haplotypes of these loci, 44 class I and 30 class II haplotypes were identified. The three most common class I and class II haplotypes constituted a combined frequency of 33% and 36%, respectively. Half of the studied animals (48% and 53%, respectively) had at least a copy of either of these class I or class II haplotypes. Prevalence of SLA homozygosity varied significantly among boar lines, ranging between 5-70%; overall one in five animals was homozygous for all six SLA loci surveyed. Limited MHC diversity, which has been associated with poor disease outcomes in other species, may result from unintentional selection of the SLA region which links closely to many favorable production traits. Molecular breeding techniques, including the assessment of SLA, may allow breeders to unlink SLA from production traits and reduce its negative pressure. Monitoring SLA diversity in breeding and commercial herds (produced by 2, 3, or 4-way crosses of breeding stock) will ensure robust immune response.
Comparing immune response times and pathogen replication rates across vertebrate host species: a case study in West Nile Virus (170.17)
Authors: Moses Melanie , Banerjee Soumya 
Published: January 2023

Abstract
The vast majority of biological rates and times decrease systematically with increasing animal body size. For example, circulation times, a range of developmental times, and life span are systematically slower in larger animals. We use empirical data and ordinary differential equation (ODE) models of disease progression to show that immune response is independent of host body size, but that viral pathogen replication rates in vivo are systematically slower for larger animals. The models focus on West Nile Virus, but we suggest that this pattern holds more generally. We examine how the sizes and numbers of lymph nodes and the size of the lymphocyte repertoire enable immune responses that are similar across animals with vast differences in body size. We discuss how body size influences pathogenesis, epidemic spread of multi-host pathogens and the metabolic cost of immunity. Comparative studies of immune response and pathogen replication have implications for human health and animal disease.
Innate immune responses differ in baboons, chimpanzees and humans. (170.18)
Authors: Brinkworth Jessica , Pechenkina Kate , Silver Jack , Goyert Sanna 
Published: January 2023

Abstract
Innate immunity is the first host defense against invading pathogens and involves the activation of immune cells via Toll-like receptors (TLRs). As close human relatives sharing genomic identity, chimpanzees (98.6%) and baboons (~92%) are important biomedical models. Despite strong genetic relatedness, all three species very differently manifest infectious diseases characterized by strong innate immune activation (HIV-1, hepatitis). To examine potential differences in innate immune responses to TLR-detected pathogens, fresh whole blood from humans, chimpanzees and baboons was stimulated for 90 minutes with Pam3CSK4, Lipomannan from Mycobacterium smegmatis, LPS from E. coli, and LcrV from Yersinia pestis. Immune activation was assessed by measuring cytokine/chemokine induction using real-time PCR. Major differences in cytokine/chemokine induction patterns were observed between species. Baboons preferentially express the chemokine CXCL2, whereas chimpanzees and humans preferentially express CCL3 in response to all agonists. In contrast, chimpanzees initiate a strong IL-8 (CXCL8) response to all agonists while humans and baboons minimally respond with IL-8. Anti-inflammatory responses also differ between species; baboons more strongly induce IL-10 and humans and chimpanzees preferentially induce IL1RN in response to challenge. These observations suggest inter species differences in cell activation and trafficking that may impact the use of these animals as biomedical models.
Identification of myeloid-derived suppressor cells in dogs (170.2)
Authors: Goulart Michelle , Pluhar Elizabeth , Husbands Brian , Ohlfest John 
Published: January 2023

Abstract
Approximately six million dogs are diagnosed with cancer each year in the United States.Naturally occurring malignances in dogs share many features with human cancers that make dogs an excellent outbred spontaneous tumor model. The accumulation of myeloid derived suppressor cells (MDSCs) in tumor-bearing mice and in humans with cancer is known to be a key mechanism of tumor escape from immune surveillance and antitumor immunity. Due to their remarkable ability to downregulate the immune response against cancer cells in mice and in humans, we hypothesized that MDSCs would also play important role in tumor-induced immune suppression in dogs with cancer. Peripheral blood mononuclear cells of dogs with a variety of cancers and of age-matched healthy control dogs were analyzed by flow cytometry. Immunophenotyping revealed that dogs with cancer exhibited a significantly higher percentage of CD11b+ CD14- MHCII- cells compared with healthy dogs. More importantly, these cells have polymorphonuclear granulocyte morphology and demonstrated an ability to suppress T-cell proliferation in a dose dependent manner. Therefore, according to these results, canine MDSCs do exist and can be a potential target for therapeutic interventions in dogs with cancer. Furthermore, the study of MDSCs in dogs can be used to address underlying questions of resistance and evasion of malignant tumors that comprise an important target for translation cancer immunotherapy.