bluuebunny/crossref_metadata_2025_split huggingface dataset:
AIM2 and NLRP3 inflammasome activation provide dual surveillance to confer protection against Aspergillus infection (MPF4P.728)
Authors: Karki Rajendra , Man Si Ming , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
Pulmonary aspergillosis is a leading cause of infection-associated mortality in immunocompromised individuals. Recognition of Aspergillus by pattern recognition receptors drives innate immune responses in the host. However, the role of cytosolic receptors in inflammasome activation during Aspergillus infection is unclear. Here, we showed that two different inflammasome receptors, AIM2 and NLRP3, play redundant roles in inflammasome activation in response to A. fumigatus infection. While mice deficient in AIM2 or NLRP3 alone showed similar susceptibility compared to WT mice, mice doubly deficient for both AIM2 and NLRP3 receptors were highly susceptible to Aspergillus infection. The increased susceptibility in AIM2 and NLRP3 DKO mice was associated with significantly higher Aspergillus burden and concomitantly reduced inflammatory responses in the lungs. Bone marrow chimera study further confirmed that AIM2 and NLRP3 play vital role in both stromal and hematopoietic compartments during Aspergillus infection. Mechanistically, activation of these receptors initiates assembly of ASC, caspase-1 and caspase-8, for effective processing of IL-1β and IL-18. In agreement, mice lacking caspase-8, IL-1β or IL-18 were highly susceptible to Aspergillus infection in comparison to WT controls. Together, these findings reveal that dual surveillance system provided by both AIM2 and NLRP3 inflammasome receptors is required to provide anti-fungal host responses against A. fumigatus.
Role of plasma high-molecular-weight-kininogen in the pathogenesis of inflammatory bowel disease (MUC5P.748)
Authors: Wang Bo , Wu Yi 
Published: January 2023

Abstract
High-molecular-weight kininogen (HK) is a major component of plasma kallikrein-kinin system (KKS), its cleavage products bradykinin and HKa are proinflammatory. Clinical observations have shown that KKS activation and HK cleavage are involved in inflammatory bowel disease (IBD). However, the pathogenic role of HK in IBD have never been characterized using a genetic approach. Our goal is to characterize the role of HK in the pathogenesis of IBD，using HK-deficient (Kng1-/-) mice we recently generated. Dextran sulfate sodium (DSS)-induced colitis in mice were induced by 2.5% (wt/vol) DSS in drinking water for 7 days. Plasma bradykinin level in wild-type (WT) mice was elevated on day 7 (p&lt;0.001). Weight loss index and disease activity index (DAI) of DSS-treated Kng1-/- mice were significantly lower than those of WT mice (p&lt;0.05). Kng1-/- mice had a decrease in colonic cytokines (TNF-α, IL-1β, IL-6 and INF-γ) and myeloperoxidase (MPO) levels (p&lt;0.001). As indicated by H&E staining, Kng1-/- mice exhibited a reduced colonic tissue damage and neutrophil infiltration in colonic lamina propria (p&lt;0.001). Similar with Kng1-/- mice, the mice lacking double bradykinin receptors (B1RB2R-/-) exhibited an amelioration of DSS-induced colitis, including the amelioration of weight loss, DAI, colonic tissue damage, and colonic cytokine levels. This study provides the first genetic evidence demonstrating that HK and its cleavage product bradykinin play a critical role in the pathogenesis of IBD.
Intrathymic transplantation of young, engraftable thymic epithelial cells promotes the growth and regeneration of the aging thymus (TRAN1P.932)
Authors: KIM MIJEONG , Miller Christine , Shadrach Jennifer , Wagers Amy , Serwold Thomas 
Published: January 2023

Abstract
The thymus reaches its maximum size early in life and then begins to shrink, producing fewer T cells with increasing age. This thymic decline is thought to contribute to age-related T cell lymphopenias and hinder T cell recovery following bone marrow transplantation. While several cellular and molecular processes have been implicated in age-related thymic involution, their relative contributions are not known. Using heterochronic parabiosis, we observe that young circulating factors are not sufficient to drive regeneration of the aged thymus. In contrast, we find that resupplying young, engraftable thymic epithelial cells to an aged or defective thymus leads to thymic regrowth and renewed T cell production. Intrathymic transplantation and in vitro colony forming assays reveal that the engraftment and proliferative capacities of thymic epithelial cells diminish early in life, whereas the receptivity of the thymus to thymic epithelial cell engraftment remains relatively constant with age. These results support a model in which thymic growth and subsequent involution are driven by cell intrinsic changes in the proliferative capacity of thymic epithelial cells, and further show that young thymic epithelial cells can directly drive aged thymic regeneration.
Acute graft-versus-host disease impairs anti-viral immunity and leads to fulminant CMV disease (TRAN1P.937)
Authors: Degli-Esposti Mariapia , Wikstrom Matthew , Kuns Rachel , Fleming Peter , Tey Siok-Keen , Andoniou Christopher , Hill Geoffrey 
Published: January 2023

Abstract
Viral infection is a common, life-threatening complication of allogeneic bone marrow transplantation (BMT), particularly in the presence of graft-versus-host disease (GVHD). The inability to mount protective anti-viral immunity is well recognized, yet the defects remain unclear. Using cytomegalovirus (CMV) as the prototype pathogen, we delineated the cause of the disease that arises following infection, as well as the mechanisms that lead to the inability to mount effective anti-viral immunity in this setting. While infection was self-limiting after syngeneic BMT, CMV infected mice with GVHD developed a fulminant necrotizing hepatitis directly associated with extensive CMV cytopathy. GVHD induced profound defects in dendritic cells (numerical and resistance to infection) that profoundly impaired viral antigen presentation, preventing the priming of CMV-specific CD8+ T cells. Changes indicative of T cell exhaustion were also observed. The transfer of virus-specific CD8+ T cells pre-infection circumvented the priming defect and provided protective immunity. Notably, efficacious anti-viral immunity could still be generated when T cells were transferred at the time of BMT, a month prior to infection, despite concurrent GVHD. These data demonstrate the importance of avoiding GVHD when reconstructing anti-viral immunity after BMT, and highlight the mechanisms by which the adoptive transfer of virus-specific T cells overcome the endogenous defects in priming invoked by GVHD.
Stem cell and novel biologic therapies to enhance functional recovery in vascular composite allotransplantation (TRAN1P.922)
Authors: Kniery Kevin , DeHart Mary , Brown Tommy , Salgar Shashikumar 
Published: January 2023

Abstract
Introduction: Vascular composite allotransplantation (VCA) such as limb and face require successful nerve regeneration and reinnervation of graft motor and sensory targets for optimal clinical outcome. Methods: Lewis (RT1.Al) rat was anesthetized and individual sciatic nerve branches (tibial, peroneal and sural) of the right hind-limb were transected. After one hour the epineurium of the transected nerves were approximated by 10-O sutures. Mesenchymal Stem Cells (MSC; 5x106; passage ≤6), G-CSF (50 µg/kg), Dihexa (2 mg/kg) or Vehicle were administered locally and intravenously. Results: Rat MSC expanded ex vivo were CD29+, CD90+, CD34-, CD31-, CD45low, MHC Class I+, and Class II-; and were pluripotent. At two weeks post nerve repair, total sensory nerve function in all groups was ~1.5 on a scale of Grade 0-3 (0=No function; 3=Normal function). By 8 weeks sensory function was ≥ 2.5 in all groups studied (n≥6); slightly lower in the vehicle group. Peroneal sensory function appeared as early as one week (≥2) but not tibial or sural function (~0.5). At five weeks, the sciatic nerve function index (SFI) a measure of motor function (0=Normal function; -100=Nonfunctional) was ~ -50 in G-CSF, and ~ -80 in MSC, Dihexa, and Vehicle treated groups (n≥6). By 12 weeks SFI in G-CSF group was markedly improved (-25). Histology and molecular studies are ongoing. Conclusions: MSC and G-CSF appear to promote both sensory and motor nerve functions in nerve transection repair model.
Nrf2 is a critical regulator of allogeneic T cell function and acute graft-versus-host disease (TRAN1P.923)
Authors: Tsai Jennifer , Dudakov Jarrod , Velardi Enrico , Shono Yusuke , Smith Odette , Wertheimer Tobias , Jenq Robert , Hanash Alan , Van Den Brink Marcel 
Published: January 2023

Abstract
Nuclear factor erythroid-derived 2-like 2 (Nrf2) is an ubiquitously expressed transcription factor, well-known as a master regulator of cellular redox pathway. A recent paper showed that Nrf2 can modulate Th1/Th2 axis in vitro. Here, we evaluated the relative contribution of Nrf2 to alloreactive T cells in the context of allogeneic bone marrow transplant (allo-BMT). We found that Nrf2-deficiency in donor T cells led to significantly less acute graft-versus-host disease (GVHD) in both MHC-mismatched and MHC-matched, minor antigen mismatched murine models. Surprisingly, Nrf2-/- T cells demonstrated comparable levels of proliferation, activation, and similar sensitivity to apoptosis during both early expansion and contraction phase of acute GVHD. However, Nrf2-/- T cells showed markedly reduced infiltration and tissue damage in the intestines, in keeping with their significantly lower expression of α4β7 integrin. Serum cytokine analysis on day 7 of allo-BMT showed increased IFNγ, IL-4 and IL-5 levels in the recipients of Nrf2-/- allo-T cells without a concomitant rise in TNFα, IL-13 or IL-17 production, while intracellular staining showed a marked increase in the proportion of CD25+Foxp3+ regulatory T cells in Nrf2-/- donor T cells. Taken together, we identified a novel role of Nrf2 in T cell function in the context of allo-BMT. Our findings suggest that targeted manipulation of Nrf2 activities in alloreactive T cells may offer a useful clinical strategy to mitigate GVHD.
Imprime PGG, a yeast β-glucan immunomodulator has the potential to modulate the subtypes of immunosuppressive M2 macrophages (TUM6P.962)
Authors: Bose Nandita , Qiu Xiaohong , Jonas Adria , Chan Anissa , Kangas Takashi , Graff Jeremy 
Published: January 2023

Abstract
Imprime PGG (IPGG) is a yeast β-1,3/1,6 glucan that, when complexed with endogenous anti-β-glucan antibodies, binds and primes neutrophils and monocytes to exert cytotoxic activity against antibody-targeted cancer cells via a complement receptor 3-dependent mechanism. Randomized Phase 2 clinical trials of IPGG in the 1st-line treatment of stage IV non-small cell lung cancer have shown promising efficacy in terms of both objective tumor response and survival. Recent in vitro human mechanistic work revealed that IPGG inhibits the polarization of immunosuppressive M2 macrophages. These studies used macrophage-colony stimulating factor (M-CSF) as the polarizing cytokine. Given that the macrophages undergo specific differentiation depending on the cytokine milieu in the local tissue microenvironment, the objective of the current study was to further evaluate the effect of IPGG on the other subsets of M2 macrophages, including M2a (elicited by M-CSF and IL-4) and M2c (elicited by M-CSF and IL-10). The results demonstrated that IPGG induced phenotypic changes on both type of macrophages, including upregulation of PD-L1. In terms of functional activity, IPGG enhanced the ability of M2a macrophages to enhance CD4 T cell proliferation, and the ability of M2c macrophages to phagocytize tumor cells. These results, along with previous results, demonstrate that IPGG has a strong potential to downmodulate the immunosuppressive tumor microenvironment shaped by tumor-associated macrophages.
Alteration in immuno-suppressive macrophage responses is associated with inhibition of vacuolar ATPase activity in breast cancer (TUM6P.968)
Authors: Katara Gajendra , Kulshrestha Arpita , Jaiswal Mukesh , Gilman-Sachs Alice , Beaman Kenneth 
Published: January 2023

Abstract
Vacuolar ATPases (V-ATPase) are important for tumor growth and metastasis. A novel, peptide of a2 isoform of V-ATPase (a2V) has been shown to have an immunoregulatory role in the tumor microenvironment by controlling the maturation of monocytes towards a TAM phenotype. This activity caused us to further investigate the role of a2V in cancer progression. Our results showed that inhibition of a2V in tumor cells have a significant growth reducing effect on the tumor and its associated microenvironment. Tumor volume analysis revealed that tumor growth in mice inoculated with a2V knocked down (sh-a2) 4T-1 cells was delayed up to ten fold compared to control (mean±SD: 1.3 ± 1.15 vs 13.96 ± 4.06, P&gt;0.01) at day 8 after inoculation. When compared by flow cytometry and immuno-histochemistry, a decreased number (60%) of TAM (F4/80+CD206+) in cell suspensions from sh-a2 generated tumors and an increase in macrophage with anti-tumor activity (F4/80+CD11c+) was observed. Further, The expression of TAM associated molecules (mannose receptor-1 or CD206, IL-10, Arginase-1, matrix metalloproteinase and vascular endothelial growth factor) were significantly down regulated in tumors from sh-a2 inoculated mice compared to control (P&lt;0.01). These findings demonstrate that the a2V from tumor cells can directly alter the resident TAM population and immune responses in the tumor microenvironment and hence may constitute novel target to control tumor growth through host immune system.
SOCS3 deficiency in myeloid cells promotes tumor development: involvement of STAT3 activation and myeloid-derived suppressor cells (TUM6P.1000)
Authors: Yu Hao , Benveniste Etty , Qin Hongwei 
Published: January 2023

Abstract
Suppressor Of Cytokine Signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway, and generally function as tumor suppressors. The absence of SOCS3 in particular leads to heightened activation of the STAT3 transcription factor, which has a striking ability to promote tumor survival while suppressing anti-tumor immunity. We report for the first time that genetic deletion of SOCS3 specifically in myeloid cells significantly enhances tumor growth, which correlates with elevated levels of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, and diminished CD8+ T-cell infiltration in tumors. Furthermore, SOCS3-deficient bone-marrow-derived cells exhibit heightened STAT3 activation and preferentially differentiate into the Gr-1+CD11b+Ly6G+ MDSC phenotype. Importantly, we identify granulocyte-colony stimulating factor (G-CSF) as a critical factor secreted by the tumor microenvironment that promotes development of MDSC via a STAT3-dependent pathway. Abrogation of tumor-derived G-CSF reduces the proliferation and accumulation of Gr-1+CD11b+ MDSC and inhibits tumor growth. These findings highlight the critical function of SOCS3 as a negative regulator of MDSC development and function, via inhibition of STAT3 activation.
Antibody blockade of semaphorin 4D promotes infiltration of activated tumor infiltrating leukocytes and inhibits tumor growth. (TUM7P.1030)
Authors: Klimatcheva Ekaterina , Evans Elizabeth , Bussler Holm , Torno Sebold , Mallow Crystal , Winter Laurie , Reilly Christine , Veeraraghavan Janaki , Jonason Alan S. , Scrivens Maria , Kirk Renee , Giralico Susan , Howell Alan , Leonard John , Paris Mark , Fisher Terrence , Smith Ernest , Zauderer Maurice 
Published: January 2023

Abstract
Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 are broadly expressed in cancer and expression correlates with invasive disease. A novel function of SEMA4D, regulating immune cell infiltration and activity in the tumor microenvironment (TME), is described. Antibody neutralization of SEMA4D enhances recruitment of activated antigen presenting cells and lymphocytes into the TME, shifting the balance of cells and cytokines toward increased Th1 and reduced immunosuppression. This orchestrated change in the tumor architecture was associated with durable tumor rejection and immunologic memory in several syngeneic tumor models. The immunomodulatory activity can be enhanced by combination with other immunotherapies. Strikingly, in some models, the combination of anti-SEMA4D antibody with immune checkpoint blockade acts synergistically to reverse tumor growth. Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the tumor and inhibit tumor progression. A humanized antibody, VX15/2503, has completed a Phase I prospective multiple ascending dose trial in 42 adult patients with advanced refractory solid tumors, in which the highest doses were well tolerated. Patients with the longest duration of treatment, 48-55 weeks, included colorectal, breast, and a papillary thyroid patient, who had a partial response by RECIST. A phase 1b/2a trial of combination therapy is planned.
Increased expression of anti-oxidant molecule Thioredoxin-1 on T cells improves immunotherapeutic control of tumors (VAC7P.1039)
Authors: Kesarwani Pravin , Thyagarajan Krishnamurthy , Soloshchenko Myroslawa , Chatterjee Shilpak , Maulik Nilanjana , Mehrotra Shikhar 
Published: January 2023

Abstract
Adoptive transfer of tumor epitope reactive T cells is a promising strategy to control tumor growth. However, chronically stimulated T cells expanded for adoptive cell transfer (ACT) are susceptible to cells death in an oxidative tumor microenvironment. Since oxidation of cell surface thiols (c-SH) also alters functionality of proteins, we hypothesized that increased level of thioredoxin, an anti-oxidant molecule that facilitates reduction of proteins by cysteine thiol-disulfide exchange, in T cells will result in sustained anti-tumor function. We thus crossed Trx1 transgenic mice with gp100 reactive TCR (Pmel) to generate Pmel/Trx mice. The Trx overexpressing transgenic T cells expressed higher thiols that inversely correlated with ROS, and susceptibility to TCR restimulation or H2O2 mediated cell death. These Trx1 expressing T cells showed CD62Lhi central memory-like (TCM) phenotype with reduced effector function (IFNglo2-NBDGlo), and were less effective in controlling tumor upon adoptive transfer. However, adoptive transfer of Pmel cells mixed with Pmel/Trx1 cells in 1:1 ratio markedly improved tumor control as compared to the mice that were transferred Pmel or Pmel/Trx T cells alone. It is likely that Pmel immediate effectors and Pmel/Trx cells with T-stem cell memory phenotype (i.e. CD62LhiCD44loCD122+Sca1hi), contributed to the improved tumor control. Thus, strategies to increase anti-oxidant capacity of anti-tumor T cells could have immunotherapeutic implications.
BscF as a vaccine candidate for Bordetella pertussis infection (“Whooping Cough”) (VAC9P.1064)
Authors: Alvine Travis , Ganske Alec , Nilles Matthew , Bradley David 
Published: January 2023

Abstract
Bordetella pertussis, a Gram- bacterium, causes pertussis (“Whopping Cough”). Despite widespread vaccination, 48 million cases of pertussis occur annually worldwide. The resurgence of pertussis is linked to antigenic divergence of circulating pertussis and waning and/or ineffective immunity induced by the current acellular vaccine. YscF, a Yersinia protein that, in multimeric form, makes up the Type III Secretion System (T3SS) needle, has been shown to be both an excellent protective antigen for Y. pestis, as well as a strong adjuvant via TLR signaling. We characterized here immune responses induced by BscF, the Bordetella homolog of YscF. BscF activated NF-κB through both TLR-2 and TLR-4 in vitro. Moreover, BscF induced IL-1β and IL-12 secretion in human THP-1 cells and bone marrow-derived macrophages. In vivo, BscF immunization in alum induced both a Th1 and Th17 response, with stimulated CD4+ T cell secreting both IFN-γ and IL-17A. Interestingly, in vivo BscF (in alum) also induced significant titers of BscF-specific antibody of all IgG isotypes (1, 2a, 2b, 3), suggesting the induction of both Th1 and Th2 responses. In toto we demonstrated that BscF induces a strong humoral and cell-mediated protein-specific immune response. This, along with the adjuvant characteristic and external structural location of BscF, suggests that BscF may provide an excellent addition to the current acellular vaccine to yield a stronger and/or more persisted protection against pertussis.
Influenza-A virus specific Epstein-Barr virus lytic memory CD8 T cells in EBV sero-negative middle age adults (VIR5P.1147)
Authors: Mishra Rabinarayan , Watkin Levi , Aslan Nuray , Gil Anna , Luzuriaga Katherine , Selin Liisa 
Published: January 2023

Abstract
For unknown reasons 5-10% of middle-aged adults (&gt;35 years) remain EBV-sero-negative when the virus infects the vast majority of people, and is actively shed at high titers during chronic infection. Here we show that EBV-sero-negative (EBV-SN) HLA-A2+ middle-aged adults possess a unique IAV-M158-66(GIL) memory CD8 T cell response that cross-reacts with EBV lytic epitopes. The five tested HLA-A2+ EBV-SN middle-aged adults had a significantly increased IAV-M158-66(GIL) tetramer+ CD8 frequency compared to adult EBV sero-positive donors. Upon exposure to EBV antigens in vitro both IAV- M1(GIL) /EBV-BMLF1280-288(GLC) and IAV- M1(GIL) /EBV-BRLF1109-117(YVL), functionally cross-reactive CD8+ responses could be detected in the peripheral blood of middle-aged EBV-SN donors, while only weakly IAV-(M1)/EBV-(YVL) cross-reactive responses were detected in 4 out of 6 teenage EBV-SN donors. These IAV-M1-GIL-specific CD8 T cells in middle-aged EBV-SN adults expanded dramatically to EBV lytic antigens and produced cytokines at high functional avidity. They lysed EBV-infected targets. Additionally, these cross-reactive cells had an oligo-clonal T cell receptor repertoire different than EBV sero-positive donors. Taken together these data suggest that an altered cross-reactive T cell repertoire could mediate protective immunity against viral infection. Our results imply that sero-negative adults might have the ability to resist viral infection via heterologous immunity.
Molecular regulation of host inflammation during influenza A virus infection (VIR5P.1155)
Authors: Yager Eric , Reid Bethany , Visconti Rachel , Harton Jonathan 
Published: January 2023

Abstract
The innate immune system recognizes influenza A viruses through multiple mechanisms, with recent studies revealing a critical role for the cytoplasmic NLRP3 inflammasome complex which promotes the maturation of the pro-inflammatory cytokine interleukin 1-β (IL-1β). Virus-induced NLRP3 inflammasome activation is critical for host defense and tissue repair during flu infection. Conversely, it is also evident that excessive NLRP3 inflammasome activity, especially during infection by highly pathogenic or pandemic strains of virus, can result in dysregulated inflammation that is detrimental to the host. Recent studies have identified a small molecule (pyrin-only protein 2 or POP2) that blocks the formation and activation of inflammasome complexes in humans. Because POP2 can interact with the pyrin domain of NLRP3, we hypothesize that POP2 functions to regulate the robust NLRP3-dependent IL-1β responses elicited during human IAV infection. Data from our continuing studies indicate that POP2 gene expression and function “cycles” with the expression of pro-IL-1β in PMA-differentiated human THP-1 monocytic cells exposed to seasonal and pandemic strains of influenza A viruses. Additionally, POP2 gene expression was found to be up-regulated in human donor PBMCs exposed to influenza A viruses. These findings support our notion that POP2 plays a critical role in ensuring a controlled, inflammatory response during human influenza A virus infection to favor protection over pathology.