bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hem-1 is essential for hematopoietic cell development and function by regulating the actin cytoskeleton (138.8)
Authors: Park Heon , Staehling-Hampton Karen , Appleby Mark W , Brunkow Mary E , Habib Tania , Ramsdell Fred , Liggit Denny , Freie Brian , Tsang Mark , Chan Maia , Carlson George , Friend Sherree , Iritani Brian 
Published: January 2023

Abstract
Hematopoietic protein-1 (Hem-1) is a hematopoietic cell-specific member of the Hem-family of cytoplasmic adaptor proteins. Orthologs of Hem-1 in flies and worms are essential for cytoskeletal reorganization, embryonic cell migration, and morphogenesis. However, the in vivo functions of mammalian Hem-1 are not known. Using a chemical mutagenesis strategy in mice to identify novel immune function genes, we positionally-cloned a nonsense mutation in the Hem1 gene. Loss of Hem-1 results in defective F-actin polymerization and actin capping in T lymphocytes and neutrophils, due to loss of the Rac GTPase-controlled actin-regulatory "WAVE" complex. T cell development and activation are impaired. Hem1-/- neutrophils are deficient in migration and phagocytic capacity. Conventional "B2" B cell development is inhibited at the pro-B and transitional T1 cell stages, and "B1" B cell development is also impaired. ELISA and ImageStream flow cytometric analyses reveal that NF-¿B-dependent transcription of proinflammatory cytokines, proceed normally in Hem1-/- mice, while TH17 differentiation is enhanced. These results demonstrate that Hem1 is essential for hematopoietic cell development and function by controlling cytoskeletal reorganization.
REGULATION OF SAPK/JNK PHOSPHORYLATION BY HISTAMINE IN SPLENOCYES (139.11)
Authors: Khan Manzoor M , Dandekar Radhika 
Published: January 2023

Abstract
Histamine is an inflammatory mediator in allergic disease and asthma. A number of histamine-mediated effects result from cytokine interactions and through their signal transduction mechanisms. SAPK/JNK are stress activated kinases which are stimulated by a variety of factors including cytokines and play a role in inflammation, cell proliferation and differentiation. This study was designed to study the effects of histamine on the phosphorylation of SAPK/JNK in splenocytes. Splenocytes were isolated from C57/BL 6 mice and after treatment with various agonists and antagonists phosphorylated SAPK/JNK levels were analyzed by Western Blot Analysis. While histamine at 10-4 inhibited the phosphorylation of SAPK/JNK , all histamine receptor subset agonists, H1, H2, H3, and H4 upregulated SAPK/JNK phosphorylation suggesting a complex interaction of histamine receptors in this process. Splenocytes from TNF-á knockout mice were employed to determine the role of TNF-á in histamine-mediated effects. Histamine further suppressed not only the effects of histamine but also that of histamine H1, H2, and H3 agonists but not that of H4 agonist. The effects of H4 agonists were further pronounced in TNF-á knockout splenocytes. Our studies demonstrate a role of TNF-á in histamine H1, H2 and H3 receptor- mediated regulation of SAPK/JNK phosphorylation. Other proinflammatory cytokines may be involved in mediating the effects of histamine on SAPK/JNK, via H4 receptors. In conclusion, the effects of histamine on SAPK/JNK phosphorylation involve complex interaction of its receptor subsets and cytokines which may have relevance in allergic disease.
SHIP is a repressor of mast cell hyperplasia, cytokine production, and allergic inflammation in vivo (139.12)
Authors: Haddon David James , Antignano Frann , Hughes Michael R , Blanchet Marie-Renée , Zbytnuik Lori , Krystal Gerald , McNagny Kelly Marshall 
Published: January 2023

Abstract
Src homology 2-containing inositol 5'-phosphatase (SHIP) inhibits immune receptor signaling through hydrolysis of the phosphatidylinositol-3 kinase (PI3K) product PI-3,4,5-P3, forming PI-3,4-P2. SHIP represses FcεRI- and cytokine-mediated mast cell activation in vitro, but little is known regarding the function of SHIP in mast cells in vivo, or the susceptibility of Ship-/- mice to mast cell-associated diseases. In this study, we found that Ship-/- mice have systemic mast cell hyperplasia, increased serum levels of IL-6, TNF, and IL-5, and heightened anaphylactic response. Further, by reconstituting mast cell-deficient mice with Ship+/+ or Ship-/- mast cells, we found that the above defects were due to loss of SHIP in mast cells. Additionally, we found that loss of SHIP in mast cells alone resulted in increased allergic asthma pathology. In summary, our data show that SHIP represses allergic inflammation and mast cell hyperplasia in vivo, and that SHIP exerts these effects specifically in mast cells.
PGI2, and its analog iloprost, regulate CD4+ Th2 lung inflammation and B cell production of IgE (140.11)
Authors: Ferrini Maria , Girtsman Teri , Jaffar Zeina , Roberts Kevan 
Published: January 2023

Abstract
Our previous findings have shown that PGI2 plays an important role in regulating Th2-mediated lung inflammation. Here, we have examined the mechanism by which PGI2, and its analog iloprost, limit allergic inflammation and the IgE response. Effector DO11.10 CD4+ Th2 cells, generated in the presence of the iloprost, produced normal levels of IL-4 and IL-5, but expressed higher levels of ICOS and CD62L than untreated Th2 cells. Adoptive transfer of iloprost-treated Th2 cells into BALB/c mice caused a markedly reduced airway inflammation following OVA inhalation, compared to untreated Th2 cells. CFSE labeling of CD4+ Th2 cells prior to injection revealed that the iloprost-treated cells proliferated less effectively in vivo in response to inhaled OVA. Moreover, intranasal instillation of FITC-OVA showed that iloprost-treated Th2 cells were less effective at promoting dendritic cell migration to the draining lymph nodes and subsequent expansion OVA-specific T cells. These effects were confirmed using mice lacking the IP receptor for PGI2 (IPKO). Following OVA aerosol challenge, primed IPKO mice developed increased eosinophilic inflammation, with elevated levels of airway CD4+ T cells and serum levels of OVA-specific IgE, compared to WT mice. Collectively, these data demonstrate that generation of PGI2, during allergic lung inflammation serves to limit both Th2 cell expansion and IgE production by B cells. A critical role for IL-4 in promoting expression of PGI2 receptor, IP, on Th2 cells and B cells that produce IgE is proposed.
Streptococcus pneumoniae vaccine, Prevenar, utilises Tregs to suppress Asthma (140.2)
Authors: Hansbro Philip M , Thorburn Alison N , Foster Paul S , Gibson Peter G 
Published: January 2023

Abstract
Our recent finding that exposure to Streptococcus pneumoniae may suppress pro-asthmatic responses led us to investigate whether the current human S. pneumoniae vaccines may be used to suppress asthma using mouse models of ovalbumin-(OVA)-induced allergic airways disease (AAD).
AAD was induced by intraperitoneal sensitisation and intranasal challenge with OVA. At the time of OVA sensitisation, Prevenar or Pneumovax were delivered intranasally either with or without CpG.
Prevenar, but not Pneumovax, suppressed hallmark features of AAD, including eosinophil influx, OVA-specific T helper (Th) 2 cytokine release, mucus hypersecretion, total serum IgE and airways hyperresponsiveness. We then investigated whether regulatory T cells (Tregs) were important in the suppression of AAD. Prevenar increased the number of CD4+CD25+FoxP3+ expressing Tregs in the lungs, lymph nodes and spleens. The release of immuno-suppressive cytokines IL-10 and TGF-â from lymph nodes was reduced. However, Prevenar increased expression of CD103 and CTLA-4 on CD4+CD25+FoxP3+ cells. Proliferation assays demonstrated that Tregs suppressed allergic effector T cell proliferation regardless of Prevenar treatment.
In conclusion, a currently available human vaccine increases the infiltration of Tregs and suppresses AAD, and may be useful as a novel therapy for asthma.
Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft versus host disease (141.13)
Authors: Yi Tangsheng , Chen Ying , Wang Lin , Du Gong , Huang Daniel , zhao Dongchang , young James , Todorov Ivan , Lieping Chen , Iwakura Yoichiro , Stephen Forman , Zeng Defu 
Published: January 2023

Abstract
In acute graft versus host disease (GVHD), donor CD4+ T cells recognize alloantigens on host antigen-presenting cells and differentiate into T helper (Th) subsets (i.e. Th1, Th2, and Th17), but the role of Th subsets in GVHD pathogenesis is still elusive. We found in an MHC-mismatched model of C57BL/6 donor to BALB/c recipient, wild-type donor CD4+ T cells predominantly differentiate into Th1 and preferentially mediate GVHD tissue damage in gut and liver. However, lack of IFN-γ in donor CD4+ T cells results in augmented Th2 and Th17 differentiation and exacerbated tissue damage in lung and skin; lack of both IL-4 and IFN-γ results in augmented Th17 differentiation and exacerbated tissue damage in skin; and lack of both IFN-γ and IL-17 leads to further augmentation of Th2 differentiation, expansion of TNF-α -producing proinflammatory Th2, and idiopathic pneumonia. The organ-specific GVHD mediated by differential Th subsets is associated with differential expression of chemokine receptors by different Th subsets and different chemokines released by various organ tissues. Furthermore, lack of tissue expression of IFN-γ -inducible co-inhibitory molecule B7-H1 play a critical role in augmenting the Th2-mediated idiopathic pneumonia. These results indicate that donor CD4+ T cells reciprocally differentiate into Th1, Th2, and Th17 in acute GVHD recipients; different Th subsets mediate organ-specific tissue damage.
The PD-L1 Signal is Important to Liver Dendritic Cells in Induction of Foxp3+CD4+CD25+ Treg and Liver Transplant Tolerance (141.33)
Authors: Li Wei , Bakthavatsalam Ramasamy , Meng zihui , Perkins James D , Latchman Yvette , Reyes Jorge D 
Published: January 2023

Abstract
Our previous studies have demonstrated that Foxp3+CD25+CD4+ regulatory T cells (Treg) play an important role in the induction of murine liver spontaneous transplant tolerance. How Treg are induced and what their mechanisms are in the regulation of liver transplant tolerance remain undefined. Here, we investigated the role of liver dendritic cells (DCs) on the induction of Treg and liver graft tolerance in vivo and in vitro. Fms-like tyrosine kinase 3 ligand (Flt3L) mutation mice, which have severe reduction in all types of DCs, and PD-L1 deficient mice were used to examine the role of liver DCs and the PD-L1 signal in Treg induction and liver transplant tolerance. Our results showed that liver DCs, which expressed a high number of PD-L1 molecules, induced more Foxp3+CD25+CD4+ Treg in vitro compared to spleen DCs. However, DCs from PD-L1 deficient mice failed to expand Foxp3+CD25+CD4+ Treg in vitro. Adoptive transfer of Foxp3+CD25+CD4+ Treg expanded from liver DCs prolonged heart allograft survival significantly more than in the CD4 treated controls. The liver grafts from Flt3L-/- and PD-L1-/- mice were rejected acutely in the C3H recipients. Foxp3+ cells were reduced, but IL-2, IL-10, and IFN-γ producing cells were significantly increased in the liver graft and recipient spleen sections of Flt3L-/- and PD-L1-/- donors. Thus, liver DCs play a critical role in the induction of Treg, which underpin spontaneous acceptance of liver allografts. The function of DCs on Treg induction appears to depend on the PD-L1 signal.
Epstein-Barr Virus Latent Membrane Protein 1 Modulates Host MicroRNAs in B Cell Lymphomas. (141.37)
Authors: Harris Aleishia , Lambert Stacie , Krams Sheri , Martinez Olivia M 
Published: January 2023

Abstract
Epstein-Barr Virus (EBV) infection is usually benign but immunosuppression can promote post-transplant lymphoproliferative disease (PTLD) and B cell lymphomas in transplant recipients. Latent membrane protein 1 (LMP1) is an important EBV-encoded oncogene that usurps cellular pathways to drive B cell transformation. MicroRNA (miRNA) are tiny, non-coding RNA that regulate cellular gene expression. Since aberrant expression of miRNA has been observed in a variety of malignancies, we hypothesized that modulation of cellular miRNA expression by EBV may play a role in the development of EBV+ B cell lymphomas. Infection of B cell lymphoma lines with EBV significantly modulated expression of miRNA-7, -15b, -221, and -222. Importantly, a similar pattern of microRNA expression was observed in an EBV+ B cell line derived from a patient with PTLD. Activation of a chimeric LMP1 signaling system in EBV negative B lymphoma cell lines also led to induction of miRNA-221 and -222 expression. These mRNA target the cell cycle regulators p27 and p57. Thus, LMP1 can promote cell cycle progression in B cells through miRNA expression. Modulation of miRNA may be a novel mechanism by which EBV drives lymphomagenesis.
Interleukin-10 delivery via mesenchymal stem cells (MSC) to prevent ischemia/reperfusion injury in lung transplantation (141.46)
Authors: Salgar Shashikumar K , Manning E , Li S , Vazquez-Padron R , Mathew J , Ruiz P , Pham S 
Published: January 2023

Abstract
Ischemia-reperfusion injury (IR) is an important cause for lung graft loss (~30%). In this study, MSC & viral interleukin-10 (vIL-10) engineered MSC were tested for their ability to prevent lung IR injury. Bone marrow derived MSC from Lewis rat were transduced with rvIL-10-retrovirus & selected on neomycin. Following 120 min of left lung ischemia induction, Group A, rats received vIL-10-MSC (~15 x 106; i.v.); Group B, empty vector engineered MSC; Group C, MSC; Group D, saline; and Group E, no ischemia or MSC. Mean blood oxygenation (PaO2/FiO2 ratio, mmHg) was reduced (P&lt;0.05) at 24h post-IR injury in Group B (138±86; n=9) & Group D (87±39; n=10), compared to MSC-vIL10 (353±105; Group A; n=10) group. By days 3 & 7 with MSC-vIL10 oxygenation was normal (475±55 & 435±33; n&gt;9); by 4h it was 319±94 (n=7). MSC (passage ≤6) increased PaO2/FiO2 (454 ± 59; n=5) by 24h post-IR. Bronchoalveolar lavage at 24h post-MSC-vIL10 therapy reduced (P&lt;0.05) granulocytes, CD4 & CD8 T cells. Lung injury score (histopathology) was higher (P&lt;0.05) with no treatment (3.5 ± 1.3; n=5) compared to MSC-vIL10 (1.21± 0.6; n=7) & MSC (1.6±0.9; n=6) treated groups. Lung microvascular permeability & wet:dry ratio were lower (P&lt;0.05) in MSC-vIL10 group. IL-1α, MCP-1α, MIP-1α, & IL1-β were increased in IR injured lung. ISOL (in situ staining for DNA fragmentation) & CASPACE-3 demonstrated reduced (p&lt;0.05) number of apoptotic cells in MSC-vIL10 treated lungs. Ex vivo, expanded MSC were CD34-, CD31+ & CD45+ (5-10%), CD29+, CD90+ & CD44+ (65-95%), CD80 (0%), CD 86 (8%), MHC Class I+ (23-57%), & MHC Class II-. MSC & IL-10 delivery via MSC to prevent lung transplant IR injury seems promising.
Islet Allograft Protection by Low Levels of Circulating Transgenic Lung-Specific Human Alpha-1-Antitrypsin (141.49)
Authors: Shahaf Galit , DeFelice Nathaniel , Ficek Chad , Friedman Frida , Lewis Eli C 
Published: January 2023

Abstract
Alpha-1-antitrypsin (AAT) exerts anti-inflammatory activities during islet allograft transplantation in several diabetes mouse models. We sought to examine inflammatory pathways in the previously described lung-specific human AAT (hAAT) transgenic mice, and establish whether transgenic circulating hAAT is sufficient to protect islet allografts from acute rejection. Homozygote mice exhibited circulating hAAT levels that were unaffected by age and by inflammatory stimuli (50-200 ng/ml). Transgene expression was limited to lung epithelia and was absent from macrophages and islets. Homozygote mice exhibited marked anti-inflammatory serum and lung tissue cytokine profiles (high IL-1 receptor antagonist and low IL-6 levels). In vivo, 48 hours after streptozotocin challenge (STZ, 225 mg/kg), blood glucose levels were 50% lower then those elicited in wild-type mice (n = 3). In islet allograft transplantation model, grafts were accepted in homozygote mice and rejected in wild-type mice (n = 4). We conclude that as low as 50-200 ng/ml transgenic circulating hAAT is sufficient to generate an anti-inflammatory cytokine milieu, improve islet viability and induce islet allograft immune protection. These low levels of the transgenic product are below its physiological anti-protease inhibitory threshold, suggesting that AAT may contain anti-inflammatory activities independent of protease inhibition.
Memory B cells and Alloantibodies Synergistically Prevent Anti-CD154-Mediated Cardiac Allograft Acceptance (141.5)
Authors: Troutman Audrea M , Ma Lianli , Xu Jing , Li Yijin , Chong Anita S. 
Published: January 2023

Abstract
The impact of memory B cells and preformed antibody in tolerance induction has yet to be elucidated. We have developed a heart transplant model that specifically generates allospecific memory B-cells and not memory T cells. 3.83 BCR (BALB/c) knock-in mice harboring 3.83 B-cells with dual-specificity for H-2Kk and H-2Kb were used as recipients of C3H hearts. To test whether memory 3.83 B-cells could prevent tolerance induction, C3H-primed-3.83 recipients (60d post-Htx) received a 2nd heart and α-CD154(MR1). Second B/6 hearts were acutely rejected (MST 12d). To confirm the importance of memory B cells in facilitating α-CD154-resistant rejection, we transferred memory B-cells from C3H-presensitized 3.83 mice into naïve BALB/c treated with α-CD154 and rejection occurred in only half of recipients. Surprisingly, transfer of low doses of serum from C3H-presensitized 3-83 recipients could not overcome α-CD154 therapy; however, transfer of low dose serum alloAbs with memory 3-83 B cells elicited rejection in one 100% of BALB/c recipients treated with α-CD154. In conclusion, memory B cells and alloAbs synergize to induce CD40-CD40L-independent activation of allo-T cells, which prevent graft tolerance.
Human memory FOXP3+ Treg secrete IL-17 ex-vivo and constitutively express the TH17 lineage specific transcription factor RORγt (33.14)
Authors: Ayyoub Maha , Deknuydt Florence , Raimbaud Isabelle , Dousset Christelle , Leveque Lucie , Bioley Gilles , Valmori Danila 
Published: January 2023

Abstract
Recent studies have suggested a close relationship between CD4+FOXP3+ regulatory T cells (Treg) and pro-inflammatory IL-17-producing T helper cells (TH17) expressing the lineage-specific transcription factor RORγt. We report here the unexpected finding that human memory Treg secrete IL-17 ex-vivo and constitutively express RORγt. IL-17 secreting Treg share some phenotypic and functional features with conventional TH17 cells, expressing high levels of CCR4 and CCR6 and low levels of CXCR3. However, at variance with conventional TH17 cells, they express low levels of CD161 and mostly fail to co-secrete IL-22 and TNF-α ex-vivo. Ex-vivo secretion of IL-17 and constitutive expression of RORγt by human memory Treg suggest that, beside their well known suppressive functions, these cells likely play additional yet un-described pro-inflammatory functions.
Dynamic equilibrium of B7-1 dimers and monomers is important for regulation of TCR/CD28 – mediated T cell activation (33.28)
Authors: Bhatia Sumeena , Almo Steven C , Nathenson Stanley G , Hodes Richard J 
Published: January 2023

Abstract
Under steady state conditions, B7-1 is present as a mixed population of non-covalent dimers and monomers on the cell surface. Here we have examined the physiological significance of this unique dimer-monomer equilibrium state of B7-1. We demonstrate that altering B7-1 to uniformly covalent dimeric state results in increased frequency of CD28 mediated T cell-APC conjugates. This augmented T cell-APC conjugate formation correlates with persistent concentration of signaling molecules, PKC-θ and lck, at the immunological synapse (IS) and with a higher calcium flux in T cells. In contrast, B7-1 acquisition by T cells, an event that occurs as a consequence of CD28 engagement with B7-1/B7-2, is highly reduced when B7-1 is present in covalently dimeric state. The ability of covalently dimeric and wild type B7-1 to costimulate antigen-specific T cell proliferation was also assessed. In contrast to the enhanced ability of dimeric B7-1 to support proximal T cell activation events, sensitivity to competitive inhibition by soluble CTLA-4:Ig indicated that the covalent dimeric form of B7-1 is in fact less efficient in costimulating T cell proliferation. These findings suggest a novel model in which optimal T cell costimulatory function of B7-1 requires CD28 engagement by B7-1 in a non-covalent dimeric state, followed by dissociation of these B7-1 dimers, facilitating downregulation of CD28 and internalization of B7-1.
The lifespan of dendritic cells (DC) affects DC-mediated regulation of B cells (34.16)
Authors: Ma Daphne Y , Draves Kevin E , Clark Ed A 
Published: January 2023

Abstract
DCs can directly regulate B cells without T cell help. We investigated the physiological properties of DCs that dictate their ability to prime and direct B cell responses. We used DCs lacking the pro-apoptotic molecule Bim (Bim-/-). Bim-/- DCs survive longer than DCs from wildtype (WT) control mice. Also, CD8α+DEC205+ DCs are elevated in Bim-/- mice. This suggested that Bim-/- DCs may be functionally distinct from WT DCs in regulating B cells. We thus examined effects of WT and Bim-/- DCs on α-IgM-induced proliferation of WT splenic B cells. LPS-matured DCs from Bim-/- mice are less effective than WT DCs in their ability to promote α-IgM-induced B cell proliferation. As with α-IgM, DCs from Bim-/- mice pulsed with chicken gamma globulin conjugated to (4-hydroxy-3-nitrophenyl)acetyl hapten (NP-CGG) were less capable of promoting proliferation in B cells with an NP-specific-Ig heavy chain "knock-in" (B1-8hi) B cell receptor. Finally, we transferred congenically marked CFSE-labeled B1-8hi B cells into C57BL/6 recipients by i.v. injection. 24 hours later, we transferred NP-CGG pulsed DCs from WT or Bim-/- mice into B1-8hi B cell recipients. 7 days later, B1-8hi B cells had proliferated less in recipients that had received antigen-pulsed Bim-/- DCs versus WT DCs. Together this illustrates a functional difference between WT and Bim-/- DCs in regulation of B cell activation and proliferation. We are currently investigating whether antibody responses are also altered by the effects of Bim-/- DCs.
(This work is supported by NIH grants 5 T32 CA009537 and DE16381.)