bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipoxygenase-derived lipid mediators effectively regulate influenza-induced immunopathology.
Authors: Pernet Erwan , Downey Jeffrey , Coulombe François , Allard Benoit , Martin Jim , Divangahi Maziar 
Published: January 2023

Abstract
Despite the worldwide application of vaccination and other antiviral interventions, influenza A virus (IAV) infection still remains a serious threat to humans. The success of IAV infection is linked to its ability to cause lower airways infections, which activates alveolar macrophages and often leads to a cytokine storm, pneumonia and respiratory failure. At this stage, uncontrolled host inflammatory response is the major cause of death. Therefore, understanding the mechanisms of immune regulation during IAV infection is critical in preventing IAV-induced immunopathology and mortality. Although cytokines have been extensively studied in immunity to IAV infection, little is known about the role of eicosanoids. We have recently demonstrated that cyclooxygenase-derived PGE2 plays a deleterious role in protection against IAV infection by inhibiting antiviral type I interferon (IFN). Herein, we aimed to investigate the potential contribution of lipoxygenase (LOX)-derived lipid mediators in IAV-immunity using the 5-LOX (Alox5−/−) deficient mice. Our data indicate that despite reduced pulmonary IAV titers, Alox5−/− mice are more susceptible to infection and exogenous administration of stable lipoxin A4 restore protection to IAV in Alox5−/− mice. This increased susceptibility was coupled with enhanced immunopathology and decreased pulmonary function. Remarkably, the production of type I IFN and IL-10 were significantly reduced in the lungs of IAV-infected Alox5−/− mice as well as IAV-infected Alox5−/− macrophages. Collectively these findings identified a protective role of the LOX-derived lipids against IAV-induced immunopathology and may pave the way for novel anti-influenza treatments using stable bioactive lipids.
PDZ-bm of influenza virus NS1 protein increases host susceptibility to super-infection via inhibition of IFNβ production
Authors: Rynda-Apple Agnieszka , Huber Victor C , Shepardson Kelly M. , Klonoski Joshua M. , Kyle Larson , Morton Rachelle 
Published: January 2023

Abstract
Type I interferon (IFN) signaling is a known contributor to increased host susceptibility to deadly bacterial super-infections (BSIs) following influenza A virus (IAV) pandemics. However, many IAV infections never develop secondary bacterial complications, suggesting that viral-derived factors can influence host susceptibility to BSIs. Utilizing reverse genetics we found that a natural variation in IAV nonstructural protein (NS1) could directly affect the duration of IFNβ signaling, which in turn affected susceptibility of mice to BSIs. Specifically, the presence of PDZ-binding motif (PDZ-bm) on the C terminus of PR8 IAV NS1 was responsible for suppression of IFNβ after day 3 post-PR8, which resulted in transition from reduced (day 3) to increased (day 7) BSI susceptibility determined by increased morbidity, mortality and lung bacterial burden. Introduction of stop codon in the position 220 of PR8 NS gene resulted in PDZ-bm deletion mutant (PR8-Trunc) that sustained production of IFNβ up to day 7 and protected WT mice from S. pnuemoniae BSI. We determined that IFNβ was required for this protective effect as unlike WT mice, IFNβ−/− mice were susceptible to BSI at day 7 post PR8-Trunc infection. Furthermore, treatment of WT mice at day 6 after WT PR8 infection with exogenous IFNβ reduced their susceptibility to BSI on day 7. Through utilization of both blocking antibodies and cell-specific type I IFN receptor −/− mice we found that reduced susceptibility to BSI required IFNβ signaling in both CD11c and Ly6G cells. Conversely, the increased susceptibility to BSIs at day 7 of PR8 infection resulted from IFNα signaling in Ly6G cells in the absence of IFNβ. Thus IAV-regulated duration of IFNβ signaling directly affects host susceptibility to BSIs.
Role of PD-1 in regulatory T cells during chronic virus infection
Authors: Ha Sang-Jun , Park Hyo Jin , Park Joon Seok , Jeong Yun Hee , Son Jinmin , Ban Young Ho , Chang Jun , Chung Doo Hyun 
Published: January 2023

Abstract
Regulatory T (Treg) cells act as terminators of T cell immunity during acute phase of viral infection; however, their role and suppressive mechanism in chronic viral infection are not completely understood. In this study, we compared the phenotype and function of Treg cells during acute or chronic infection with lymphocytic choriomeningitis virus. Chronic infection, unlike acute infection, led to a large expansion of Treg cells and their upregulation of programmed death-1 (PD-1). Treg cells from chronically infected mice (chronic Treg cells) displayed greater suppressive capacity for inhibiting both CD8+ and CD4+ T cell proliferation and subsequent cytokine production than those from naive or acutely infected mice. A contact between Treg and CD8+ T cells was necessary for the potent suppression of CD8+ T cell immune response. More importantly, the suppression required cell-specific expression and interaction of PD-1 on chronic Treg cells and PD-1 ligand on CD8+ T cells. Our study defines PD-1 upregulated on Treg cells and its interaction with PD-1 ligand on effector T cells as one cause for the potent T cell suppression and proposes the role of PD-1 on Treg cells, in addition to that on exhausted T cells, during chronic viral infection.
Tbet suppresses TH17 differentiation during viral infection
Authors: Hale J Scott , Mohammed Ata Ur Rasheed , Ahmed Rafi 
Published: January 2023

Abstract
Lineage-specifying transcription factors such as Tbet, GATA3, RORγt, and Bcl6 play critical roles in directing T helper lineage differentiation in response to various types of infections to orchestrate protective immune responses. Following acute LCMV infection, antigen-specific CD4 T cells differentiate to become either Tbet-expressing Th1 cells, or Bcl6+Tbet(low) T follicular helper cells. However, virus-specific CD4 T cells do not generate Th2 and Th17 responses. To determine whether Tbet plays a role in suppressing these alternative T helper differentiation programs in CD4 T cells during viral infection in a cell-intrinsic manner, we adoptively-transferred Tbet-deficient (Tbx21 knockout) SMARTA TCR transgenic CD4 T cells and then infected recipient mice with LCMV. Tbet deficient CD4 T cells generated 2 types of effector T helper cells: IL-17+CXCR5- Th17 cells and Bcl6+CXCR5+ Tfh cells. Tbet deficient Th17 effector cells expressed the transcription factor RORγt and the key cytokines IL-17 and IL-22. Co-transfer of wild-type and Tbet-deficient CD4 T cells revealed that the transcription factor Tbet represses the Th17 program in vivo in a cell-intrinsic manner. Together, these findings demonstrate the importance of the transcription factor Tbet in both promoting the useful Th1 response and suppressing the inappropriate Th17 response during viral infection.
Mast cells are present during the early stages of Chikungunya virus infection
Authors: Haese Nicole , Kreklywich Craig , Legasse Alfred , Heise Mark , Axthelm Michael , Messoudi Ilhelm , Streblow Daniel N 
Published: January 2023

Abstract
Chikungunya virus (CHIKV) is a positive-sense RNA, arthropod-borne Alphavirus. In recent years the largest recorded outbreak of CHIKV occurred in the Islands of the Indian Ocean and India. CHIKV has continued to spread causing millions of cases across more than 40 countries. Acute symptoms of infection include the abrupt onset of fever, rash, fatigue, headache, backache, and arthralgia, with arthralgia lasting up to several years in some individuals. Ongoing studies analyzing cohorts of CHIKV infected humans have led to a well-developed understanding of the clinical manifestations of CHIKV disease. What is unknown is the role different components of the immune response play in controlling CHIKV dissemination and disease development. In our current study we utilized a non-human primate (NHP) model of CHIKV infection to characterize the early stage of CHIKV infection. Adult male and female rhesus macaques (RM) were infected subcutaneously with CHIKV-LR. Analysis of vRNA loads in joint tissues of infected RM revealed that the highest viral loads were detectable at 2 dpi with at least a log decrease in vRNA levels by 7 dpi. T cells, B cells, PMNs, macrophages, and mast cells were visible in the joints of CHIKV infected RMs at 2 and 7 dpi. To our knowledge this is the first time mast cells have been identified in the tissue of CHIKV infected NHPs. Levels of key proinflammatory cytokines/chemokines were also increased from 3–7 dpi. The gene expression profile in joint tissues reveled an increase in the expression of genes involved in recruitment, activation, and maintenance of mast cells. These findings suggest that infiltration of immune cells including the newly identified mast cells from 2 to 7 dpi assist in controlling CHIKV infection.
CD81: a novel lymphoma therapeutic target
Authors: Catalan Felipe Vences , Kuo Chiung-chi , Rajapaksa Ranjani , Duault Caroline , Levy Ronald , Levy Shoshana 
Published: January 2023

Abstract
Tetraspanin CD81 was initially described as a target of a monoclonal antibody (mAb) able to inhibit proliferation of lymphomas and activated lymphocytes, which suggests that CD81 plays a role in their survival. Indeed, studies in CD81 knockout mice have demonstrated its role in innate and adaptive immune responses, by regulating lymphocyte activation, proliferation and antibody production. Furthermore, CD81 deficiency leads to reduced anti-tumor immune suppression by MDSCs and Tregs, resulting in decreased tumor growth and metastasis. Moreover, treatment with anti-mouse CD81 mAbs reduces metastasis in tumor-bearing wild type mice.
Here we demonstrate that an anti-human CD81 mAb effectively reduces growth of lymphoma cell lines in vivo and improves survival. To further enhance the in vivo efficacy of our mouse IgG1 anti-CD81 mAb, we class switched the hybridoma to produce IgG2a and we also engineered a chimeric human IgG1 anti-CD81 mAb. Indeed, both isotypes when compared to Rituximab, show superior efficacy in eliminating tumor cells in vivo. And in vitro studies demonstrate superior direct killing, antibody-dependent cell cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Finally, despite the expression of CD81 on normal lymphocytes which creates a challenge for antibody-based therapies, we demonstrate that B cell lymphoma cell lines were selectively sensitive to anti-CD81 therapy. Taken together, we proposed CD81 as a potential target for treating lymphoma.
Enhancement of Anti-Tumor Activities of Daratumumab Using ALT-803, an IL-15 Superagonist, in an Experimental Model and Against Primary Human Lymphoma Cells
Authors: Wong Hing C , Shrestha Niraj , Liu Bai , Alter Sarah , Jeng Emily K , Fehniger Todd A , Rhode Peter R 
Published: January 2023

Abstract
Daratumumab has recently been approved by FDA for treatment of patients with relapsed or refractory multiple myeloma. Daratumumab has been shown to reduce the tumor burden by targeting CD38 expressing tumor cells. In this study, we examined the in vitro as well as in vivo ability of ALT-803, a novel IL-15 superagonist-complex, to enhance the tumor targeting antibody dependent cellular cytotoxicity (ADCC) of daratumumab in combination therapy. Using freshly isolated PBMCs, we demonstrated that ALT-803 significantly enhanced the ADCC activity of Daratumumab against Daudi, human B lymphoma, cells. We also observed that purified human NK cells, which were activated by ALT-803, enhanced daratumumab-mediated ADCC activity against primary human B-lymphoma cells. We also assessed the in vivo effects of ALT-803 on daratumumab-mediated antitumor activity against Daudi cells in the SCID xenograft model. We observed that both ALT-803 and daratumumab alone were capable of reducing Daudi tumor burden in tumor-bearing mice. However, the combination of ALT-803 with daratumumab increased antitumor activity which significantly reduced Daudi cells in the bone marrow. These observations indicate that the addition of ALT-803 to daratumumab treatment enhances the antitumor efficacy of Daratumumab compared to daratumumab alone. In addition, we have evidence that ALT-803 also augment the Antibody Dependent Cytotoxicity of Phagocytosis of Daratumumab against tumor cells. In a current clinical study, our correlative studies also show that ALT-803 augment the ADCC activity of Daratumumab against Daudi cells. This also demonstrates that ALT-803 possesses synergistic antitumor activities with tumor-specific antibodies in vivo.
A novel, dual-specific antibody conjugate targeting CD134 and CD137 costimulates T cells and elicits antitumor immunity
Authors: Ryan Joseph , Mittal Payal , Svedova Julia , Menoret Antoine , Wasser Jeffrey S. , Adler Adam J. , Vella Anthony T. 
Published: January 2023

Abstract
Checkpoint inhibiting antibodies targeting CTLA-4 and PD-1, along with costimulatory agonists, exhibit impressive anticancer efficacy and evidence of durable tumor regression in patients. Despite this success however, many patients fail to respond, likely due to multiple immunosuppressive tactics employed by cancer cells. Combination therapies designed to counteract these immunosuppressive features show promise, but strategies relying on multiple agents suffer from logistical and regulatory challenges, as well as increased risks of adverse events. We developed a novel immunotherapeutic agent by fusing two TNFR family costimulatory agonists (anti-CD134/CD137) into a single biologic encompassing the therapeutic benefits of both agents while avoiding many of the drawbacks associated with traditional combination therapies. Our preliminary data show that this dual-specific, tetravalent antibody conjugate induces potent and differential in vitro potentiation of cytokine secretion from CD3-stimulated splenocytes, compared to that observed with single agonists alone or in combination. We hypothesize that this a consequence of unique signaling and hybrid costimulatory events. Secondly, this conjugate, referred to as OrthomAb, potently delayed tumor growth and reduced tumor burden in the aggressive B16 melanoma model. In vivo antitumor efficacy exceeded that of either individual unconjugated agonist. Importantly, this work establishes a framework for fusion of immunomodulatory biologics into a single drug with the benefit of combination immunotherapy to treat cancer.
CC-122 is more potent but transcriptionally mirrors Lenalidomide in Chronic Lymphocytic Leukemia
Authors: Do Priscilla , Cheney Carolyn , Yu Lianbo , Mo Xiaokui , Awan Farrukh , Muthusamy Natarajan , Byrd John C , Blachly James S 
Published: January 2023

Abstract
Lenalidomide (Len) is an immune modulatory drug for the treatment of hematological malignancies which contrasts with a large repertoire of immunosuppressive treatments. Len is FDA approved for Multiple Myeloma (MM), yet its development in Chronic Lymphocytic Leukemia (CLL) has been hampered by a potentially fatal, dose-limiting toxicity known as tumor flare. Tumor flare consists of enlarged, painful lymph nodes (LN) and cytokine release and is managed by lower dosage/prophylactic measures. Len and next-generation reagent CC-122, target cereblon, leading to degradation of transcription factors IKZF1/IKZF3. We compared CC-122 to Len using primary CLL B and T cells and CLL-derived cell line, OSU-CLL. We present a key difference between CC-122 and Len treated activated CLL T cells.
CC-122 0.1–10uM or 1uM Len are not directly cytotoxic to primary CLL B cells (avg. fold change 0.94–1.49 normalized to vehicle, N=8). CC-122 was more potent than Len by degradation of IKZF1/IKZF3, and immune activation measured by CD86 induction (7.2% more CD86+ induction, p=0.0026, N=12). RNA-seq analysis of the OSU-CLL cell line showed that at physiologically relevant doses, CC-122 (0.1uM) and Len (1uM) have no significant differences. Microarray analysis of 0.1uM CC-122 v. 1uM Len on αCD3 activated CLL T cells showed only two significantly different genes: CXCL13 and HLADQ-A1, p&lt;0.0001. CXCL13, a B cell chemoattractant in CLL, was ≥ 3 fold increased with 1uM Len v. 0.1–1uM CC-122 (N=3). Overexpression of the CXCL13 receptor, CXCR5, in CLL but not MM may contribute to migration of CLL cells to the LN and potentially tumor flare. Retaining the anti-tumor activity of Len while mitigating tumor flare is of clinical interest and critical to the development of CC-122.
CD19/CD3 bispecific antibodies induce potent response against chronic lymphocytic leukemia cells ex vivo
Authors: Robinson Hannah Ruth , Qi Junpeng , Baskar Sivasubramanian , Rader Christoph , Wiestner Adrian 
Published: January 2023

Abstract
While treatment of chronic lymphocytic leukemia (CLL) has been advanced by introduction of targeted therapies such as tyrosine kinase inhibitors, there remains a need for adjunct therapies capable of inducing response in the setting of relapse on or resistance to first-line agents. Blinatumomab is a bispecific antibody (bsAb) against CD19/CD3, designed to target endogenous T cells against B cells via the formation of cytolytic synapses. It is approved for treatment of relapsed/refractory B-cell acute lymphoblastic leukemia, and has shown promise for use in non-Hodgkin’s lymphoma. Designed in the relatively small 54.1 kDa BiTE format, blinatumomab has a half-life of 2.1 hours and requires continuous intravenous infusion for clinical efficacy. In contrast, our novel anti-CD19/CD3 bsAb, designed in the 100 kDa single chain Fv-Fc format (CD19/CD3-scFv-Fc), has an approximately 100-fold longer half-life and could therefore be suitable for weekly dosing. We found that both blinatumomab and CD19/CD3-scFv-Fc induce potent killing of CLL cells ex vivo compared to cells treated with control HER2/CD3-scFv-Fc bsAb or medium alone. This response was associated with robust expansion of autologous CD4+ and CD8+ T cells, as shown by absolute cell counts and CFSE-detected population doubling. Notably, while HER2/CD3-scFv-Fc induced T cell expansion, no CLL directed cytotoxicity was observed. Our results identify CD19/CD3-scFv-Fc as a possible novel immune-based treatment for CLL.
Systemic Stimulatory Cancer Immunotherapy Induces Corticosterone-mediated Thymic Involution
Authors: Minnar Christine Mall , Sckisel Gail D. , Beerthuijzen Johanna M.T. , Aguilar Ethan G. , Mirsoian Annie , Crittenden Marka , Blazar Bruce R. , Monjazeb Arta M. , Murphy William J. 
Published: January 2023

Abstract
Cancer immunotherapies (IT) are quickly becoming frontline therapies for a variety of cancers and are often immunostimulatory in nature. We have previously demonstrated that systemic administration of strong immunostimulatory regimens in mice resulted in memory T cell activation but also concurrent immune paralysis of naïve T cell responses. The thymus is critical for generation of naïve T cells. While it is known that thymic involution occurs with age along with a decrease in the naïve T cell pool, there have been few studies investigating the effects of IT on the thymus. Here we demonstrate that immunostimulatory regimens (αCD40/IL-2 or systemic LPS) lead to marked, but transient, thymic involution in young mice. As soon as 48 hours after therapy initiation, the thymic cellularity decreased by 60%. Importantly, we show that this thymic hypocellularity correlated with significant increases in systemic corticosterone immediately following the initiation of therapy. Prior adrenalectomy prevented thymic involution emphasizing the role of glucocorticoids post IT. Interestingly, stress induced thymic involution was followed by a ‘rebound effect’ with significant increase in thymic cellularity compared to control mice occurring two weeks after IT cessation. Importantly, similar effects on corticosteroid levels in cancer patients receiving high dose IL2 therapy was observed and this was correlated with later decreases in T cell receptor excision circles (TRECs) as indicators of recent thymic emigrants. These results suggest that thymic involution following strong immunostimulatory regimens acts as a negative feedback loop for developing T cells which may be more pronounced in aged recipients where such a pool is already limited.
Synergistic Anti-tumor Activity of Local SS1P with Systemic CTLA-4 Blockade Causes Complete Regression of Both Injected and Un-injected Tumors in Mice
Authors: Leshem Jasmin , O’Brien James , Reiter Yoram , Pastan Ira 
Published: January 2023

Abstract
SS1P consists of an anti-mesothelin Fv attached to Pseudomonas exotoxin A and kills tumor cells by inhibiting protein synthesis. Because of its unique mechanism of cell killing, SS1P does not inhibit the immune system like other anti-cancer drugs. Here we determined if SS1P can cooperate with anti-CTLA-4 to induce anti-tumor immunity and cause complete tumor regressions.
A BALB/c breast cancer cell line was transfected with human mesothelin (66C14-M) and implanted in two different locations. SS1P was injected directly into one tumor and anti-CTLA-4 given IP.
In mice treated with anti-CTLA-4 and SS1P, tumor regressions occurred in 11 out of 12 SS1P injected tumors (91%) and in 7 out of 12 un-injected tumors (53%). No tumor regressions occured with drugs given separately. Pathological evaluation showed a large sterile central abscess in injected tumors surrounded by a collar of inflammation containing a mixture of lymphocytes and other mononuclear cells. Analysis of responding tumors showed a time dependent increase in CD8+ cells located mainly in the inflammation collar. RNA analysis of responding tumors showed that 385/768 immune related gene transcripts were elevated by twofold or more including CD8a, PDL2 and IL1 alpha (13, 21 and 27-fold).
Altogether, combining local SS1P with anti-CTLA-4 promotes massive inflammation that cures multi-centered cancer disease providing a strong rational to explore this combination therapy in patients.
TCR-like antibody duocarmycin conjugates promote cytotoxicity of tumor cells expressing low peptide/HLA targets
Authors: Herrera Christian E , Lowe Devin B , Bivens Camille K , Mobley Alexis S , McCormick Amanda , Wichner Timea , Sabnani Manoj K , Wood Laurence M , Weidanz Jon A 
Published: January 2023

Abstract
Immunotherapeutic strategies such as unmodified antibodies have significantly advanced treatment options for individuals with cancer. Yet, to further improve the efficacy of this approach, engineered platforms such as antibody drug conjugates (ADCs) are under development. Current FDA-approved ADC designs incorporate tubulin inhibitors that abate cancer growth and mediate clinical protection for patients. However, successful ADC treatment typically requires high tumor antigen (TA) surface expression to bind/internalize ADC material, destabilize cytoskeletal networks, and suppress tumorigenesis. Unfortunately, few known TAs are localized on cancer cells at elevated densities, potentially minimizing the therapeutic index and widespread application of current ADC regimens. Our group sought to overcome this ADC limitation of TA expression by crosslinking the DNA alkylating compound duocarmycin with T cell receptor (TCR)-like antibodies, which specifically bind TA peptide/human leukocyte antigen (HLA) complexes analogous to a TCR. In select assays, a panel of TCR-like ADCs were capable of distinguishing human breast and colon cancer lines and promoting potent cell cytotoxicity even under common scenarios of low TA peptide/HLA densities. Additionally, TCR-like antibody TA peptide/HLA binding appeared to play an important role in ADC-mediated cytotoxicity, supporting the notion that spatial TA ligand interactions influence ADC function. Overall, our data highlight the proof-of-principle that TCR-like ADCs induce cancer cell death under physiologically-relevant TA expression profiles and support their translational development, particularly alongside agents that disrupt DNA replication.