bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oxidation-specific epitopes are an important target of innate immunity (P4261)
Authors: Gonen Ayelet , Oliveira Romulo , Diehl Cody , Cole Jason , Copps Jeffrey , Nizet Victor , Ghosh Partho , Witztum Joseph 
Published: January 2023

Abstract
Oxidation of LDL is important in atherosclerosis and generates oxidation-specific epitopes, which are proinflammatory and immunogenic. We showed that oxidation specific epitopes are recognized by innate immunity, including Natural Ab’s, scavenger receptors and innate proteins. In addition, many of these epitopes are also found on apoptotic cells and are share molecular mimicry with pathogens. For example, the NAb E06, scavenger receptor CD36 and CRP, all bind to PC on oxidized LDL, but also bind to the PC on apoptotic cells and on S. pneumonia. To determine if other oxidation specific epitopes share molecular mimicry with pathogens, we screened a pathogen library with oxidation specific epitopes NAbs. We found that the NAb E014, specific for malondialdehyde also bound to Streptococcus group A, demonstrating molecular mimicry between the two. I showed that E014 specifically binds to the M protein of Streptococcus group A. Using synthetic peptide arrays I narrowed the binding site on M protein to a 24AA section. I am currently studying the immunological consequences of molecular mimicry between peptides from M protein and the ubiquitous malondialdehyde. These data support the hypothesis that oxidation-specific epitopes are an important target of innate immunity and both oxidative events and pathogens have contributed to the natural selection of shared and potent innate immune responses to oxidative specific epitopes.
The effects of HIV-1 Tat protein on mycobacterial infection (P4219)
Authors: Li James , Pong John , Lau Allan 
Published: January 2023

Abstract
Human immunodeficiency virus infection remains a worldwide threat. With the emergence of HIV-1 induced immunodeficiency in the host, mycobacterial infection becomes a common opportunistic infection as its prevalence is dramatic increased. HIV-1 Tat is an important viral regulatory protein in promoting HIV replication and modulating the cytokine production, as demonstrated by our previous publications. In light of that, we would like to investigate whether HIV-1 Tat could affect mycobacteria induced immune responses. We first examined whether HIV-1 Tat could mediate mycobacteria induced cytokine production. The results demonstrated that HIV-1 Tat suppressed mycobacteria-induced TNF-α in human primary macrophage. Next, we examined whether HIV-1 Tat also suppress the intracellular survival of mycobacteria. Under the pretreatment of HIV-1 Tat in human primary macrophages, intracellular growth of mycobacteria was enhanced significantly. Since TNF-α is proposed to regulate mycobacterial survival, we would like to verify this hypothesis in order to provide the evidence to support our findings that HIV-1 Tat downregulated mycobacteria induced TNF-α is participated in suppressing the mycobacterial survival. The results showed that when we neutralized the mycobacteria produced TNF-α by antibodies, the survival of mycobacteria is increased. In summary, HIV-1 Tat may play a role in favouring mycobacterial opportunistic infection during AIDS progression.
Peptidoglycan acts as a Gram-positive endotoxin (P4035)
Authors: Coggeshall K. , Raisley Brent , Silasi-Mansat Robert , Sun Dawei , Keshari Ravi , Popescu Narcis , Kurosawa Shinichiro , Lupu Florea 
Published: January 2023

Abstract
We proposed that peptidoglycan (PGN) contributes to the systemic inflammation and sepsis accompanying Gram-positive infections. However responses are dependent on pre-existing IgG recognizing peptidoglycan and capable of engaging Fcgamma receptors. Mice lack these antibodies and hence respond weakly to in vivo PGN challenges. Non-human primates possess anti-PGN IgG and have been a useful and informative model for sepsis, We challenged 4 baboons with varying doses (7-48 mg/Kg) of PGN and noted: vascular leakage, increased circulating proinflammatory cytokines, increased activation of neutrophils and platelets, expression of tissue factor on monocytes, massive consumption of clotting factors and complement proteins, and microthrombosis-induced kidney failure. The severity of the outcome correlated with the pre-existing titer of anti-PGN antibodies such that animals with a higher titer had a poorer outcome. The pathological features induced by the sterile PGN infusion greatly resemble the pathological features induced by infusion of live bacteria from which the PGN was generated. The data support our hypothesis that PGN and anti-PGN antibodies are a major contributor to Gram-positive sepsis.
β-Glucuronidase is a key regulator of murine Lyme arthritis severity and rheumatoid arthritis (P4013)
Authors: Bramwell Kenneth , Ma Ying , Weis John , Teuscher Cory , Zachary James , Weis Janis 
Published: January 2023

Abstract
Lyme Disease is the most prevalent arthropod borne illness in the U.S. Up to 60% of patients develop inflammatory arthritis following infection. Host genetics play a key role, as inbred mouse strains exhibit consistent differences in Lyme arthritis severity. Our lab previously described maximal linkage (LOD 10.2) of disease severity to the Bbaa2 locus on mouse Chromosome 5. Recently, we developed advanced congenic mice carrying sub-intervals of Bbaa2 from susceptible C3H on an otherwise uniform resistant B6 genetic background. This led to the positional cloning of a novel disease regulator, the lysosomal enzyme β-Glucuronidase (Gusb). C3H mice are Gusb hypomorphs, exhibiting a 90% enzymatic deficiency. Two sub-strains of CBA mice carrying the hypomorphic or wild type Gusb alleles develop severe Lyme arthritis or are protected, respectively. A Gusbnull mouse strain on the B6 background develops severe Lyme arthritis, while heterozygotes are protected. Transgenic overexpression of Gusb in C3H mice to correct the defect led to reduced arthritis severity, indicating a single gene effect. Preliminary data show that Gusb congenic mice also develop more severe disease in the KBxN model of Rheumatoid arthritis, suggesting a conserved role. Deficiencies in Gusb and other lysosomal enzymes lead to lysosomal storage diseases. We found that treatment with Hydroxychloroquine, which accumulates in lysosomes, dramatically reduces Lyme arthritis severity in Gusb congenic mice.
Anti-tumor responses driven by alloreactivity (P2058)
Authors: Fast Loren , Reagan John , Nevola Martha , Quesenberry Peter 
Published: January 2023

Abstract
Previous work by our group found that infusion of G-CSF mobilized haploidentical donor white blood cells at a dose of 1 - 2 x 108 CD3+ cells/kg into refractory cancer patients who had received 100 cGy total body irradiation resulted in responses in a majority (14/27, 9 major) of patients with hematological malignancies despite elimination of the donor cells. The effector mechanism(s) responsible for these anti-cancer responses were not determined although it was noted that there was a cytokine storm that appeared within a day following the infusion of cells. One possible mechanism is that the alloreactive response overrides inhibitory mechanisms already in place in the cancer bearing patient allowing cancer reactive effector cells that are already present to become activated and lyse cancer cells. To test if this is the case, T cells were isolated from peripheral blood mononuclear cells obtained from newly diagnosed leukemic patients, mixed with fully allogeneic stimulator cells (from 1 or 2 different donors) and then tested for their ability to proliferate in response to the allogeneic stimulator cells on day five and for their ability to lyse autologous leukemia cells after stimulation for seven days. Anti-leukemic effector cells could be generated in eight out of the sixteen patients enrolled to date. The characteristics of the effector cells and the explanations for the lack of responses in some patients are the subject of current ongoing studies.
IL35 neutralization enhances tumor specific immunity in mouse models of cancer (P2024)
Authors: Turnis Meghan , Gravano David , Delgoffe Greg , Steinkamp Heidi , Vignali Dario 
Published: January 2023

Abstract
Regulatory T cells (Treg) are critical to maintenance of self-tolerance and prevention of autoimmunity; however, they also function to limit anti-cancer responses.Therefore, clarifying the mechanisms of Treg-mediated suppression in the context of cancer will aid in the rational design of new therapies.Our lab has identified a novel suppressive role for the IL35 heterodimer in Treg. IL35 is a member of the IL12 family composed of IL12a and Ebi3 subunits and is preferentially expressed by Treg. Treg and other suppressive factors in the tumor microenvironment inhibit antigen-specific cytotoxic lymphocyte responses; depletion or inhibition of Treg has been shown to decrease tumor burden and enhance patient outcome in both animal models and the clinic. We hypothesize that IL35 contributes critically to the tumor microenvironment and that its elimination will enhance tumor specific immunity. Using neutralizing antibodies specific for IL35-Ebi3, we have shown that systemic neutralization of IL35 significantly slows tumor growth compared with IgG control and enhances survival in the B16 melanoma model. Molecular analysis of tumor-infiltrating lymphocytes (TILs) has shown increased numbers, more activated CD8+ cells (CD44+CD62L-), and a greater proportion of proliferative cells by BrdU/Ki-67 staining in IL35-neutralized animals. We are currently extending studies to include metastatic and genetic models to better understand the mechanism of IL35 activity in the tumor microenvironment.
A novel CXCR7-targeted scFv-FC chimeric antibody kills CXCR7+ glioblastoma and leukemia cancer cells by antibody dependent cellular cytotoxicity (P2060)
Authors: Carlson Jeffrey , Jang Andrew , Burke Thomas , Lewen Susanna , Huang Kexin , Tu Hua , Zabel Brian 
Published: January 2023

Abstract
CXCR7 is an atypical chemokine receptor that plays a critical role in guiding progenitor cell migration during embryo- and organo-genesis. Following fetal development and birth, however, CXCR7 protein is difficult to detect on cells or tissues except in the context of cancer. CXCR7 is upregulated by a number of primary tumor types, including human B cell lymphoblasts and glioblastomas, and is selectively expressed on vascular endothelial cells associated with solid tumors. We engineered a chimeric single chain Fv-human FC (IgG1) antibody (X7scFv-huFC) that selectively targets and kills CXCR7+ human B cell leukemia and glioblastoma cell lines by antibody dependent cellular cytotoxicity (ADCC). Safety and pharmacokinetic studies of X7scFv-huFC in rodents will be presented, and our progress in efficacy studies, including xenograft models of human leukemia and glioblastoma in SCID mice, will be discussed.
Global targeting of MDSC escape mechanisms cures advanced 4T1 breast tumors (P2062)
Authors: Zorro Manrique Soraya , Spencer Christopher , Dominguez Ana , Bradley Judy , Mirza Noweeda , Ko Jennifer , Viso Carole , Gades Naomi , Finke James , Pease Larry , Gendler Sandra , Cohen Peter 
Published: January 2023

Abstract
4T1 is a metastatic breast cancer model with fulminant accumulation of MDSCs. Survival and function of MDSCs is often reported as STAT3-dependent, and STAT3 inhibitors such as sunitinib dramatically deplete 4T1 splenic MDSCs. Paradoxically, sunitinib fails to eradicate 4T1 intratumoral MDSCs or prevent tumor progression. We hypothesized that STAT3 activation is a consistent feature of splenic but not intratumoral MDSCs. PhosphoSTAT analyses of 4T1-bearers confirmed that splenic MDSCs of all Gr1 intensities were solely pSTAT3pos. In remarkable contrast, intratumoral Gr1high MDSCs largely lacked any pSTAT activation, and intratumoral Gr1dim MDSC precursors displayed varied expression of pSTAT5 and pSTAT1 in addition to pSTAT3. We therefore sought global means to target MDSCs. We determined that 4T1 and other tumor models could be cured by repetitive administration of cyclophosphamide alternating with TLR agonists such as CpG ODN1826. While cure required participation of host CD4+ and CD8+ T cells, global targeting of MDSCs was also observed: (1) as with sunitinib, pSTAT3pos splenic MDSCs were eradicated; (2) pSTAT expression by intratumoral MDSCs was fully abolished; (3) the remaining intratumoral MDSCs, all pSTATneg, outsurvived all other cells, and were likely induced to serve as the final mediators of tumor rejection. In conclusion, strategies which globally target MDSCs and promote the endogenous anti-tumor T cell response can cure advanced metastatic tumors.
Plasmacytoid and CD8α DC are both necessary to generate antitumor immunity following Ad5-TRAIL/CpG immunotherapy (P2078)
Authors: James Britnie , Kucaba Tamara , Griffith Thomas 
Published: January 2023

Abstract
It is now appreciated that there are distinct subsets of dendritic cells (DC) with specialized functions. Plasmacytoid DC (pDC) and CD8α DC can contribute to the priming, activation, and function of antitumor CD8 T cells; however, their specific roles and necessity in stimulating antitumor immunity is not clearly understood. Thus, we examined the distinct role pDC and CD8α DC play in an orthotopic model of metastatic renal cell carcinoma (RCC) treated with a recombinant adenovirus encoding TRAIL (Ad-TRAIL) combined with CpG ODN. Wild-type (WT) mice bearing RCC tumors and treated with Ad-TRAIL/CpG ODN cleared primary and metastatic tumors, and these mice survived long-term. In contrast, mice specifically depleted of either pDC (using an α-PDCA1 mAb) or CD8α DC (Batf -/- mice) had uncontrolled tumor growth and high mortality regardless of treatment. Both pDC-depleted and Batf3-/- mice exhibited significantly decreased infiltration of effector CD8 T cells in the primary tumor site, as compared to WT mice after therapy, possibly related to the reduced expression of pro-inflammatory cytokines in pDC-depleted mice and reduced uptake of apoptotic tumor cells in Batf3-/- mice. These data collectively suggest that both pDC and CD8αDC carry out independent, but complementary roles that are necessary to initiate an efficacious antitumor immune after Ad5-TRAIL/CpG ODN therapy.
Contribution of CCDC134, a potential cytokine, inducing CD8+ T cell-dependent antitumor effect in cancer immunotherapy (P2086)
Authors: Xiao Lin , Shao Wenwei , Gong Xiaoting , Huang Jing , Qiu Xiaoyan 
Published: January 2023

Abstract
CCDC134 (coiled-coil domain containing 134) was firstly identified to be a novel classical secretory protein by our lab. Although we previously identified CCDC134 as a novel MAPK-regulator which down-regulated the Raf-1/MEK/ERK and JNK/ SAPK pathways in some cancer cell lines. However, the critical function of CCDC134 still remains unclear. In view of CCDC134 characteristic, which was widely expressed in lymphocytes, especially up-regulated expression in activated CD4+, CD8+ T lymphocytes and maturated DC, we proposed the hypothesis if CCDC134 was involved in immune response as a potential cytokine. Here, we first found that CCDC134 greatly promoted activation, proliferation and cytotoxicity of CD8+ T cells via augmenting the expression of activation molecules (CD25, CD69) and effector molecules, such as IFN-γ, TNF-α, granzyme B and perforin in vitro. Moreover, by a series of experimental evidences, we have found that CCDC134 displayed strong anti-tumor activity in a CD8+ T cells, but not CD4+ T cells, and IFN-γ-dependent manner in vivo. In addition, CCDC134 markedly promoted phosphorylation of STAT5, but not STAT1, STAT3 in CD8+ T cells and CD8+ T cells proliferation augmented by CCDC134 was dependent on STAT5. Our data collectively suggested that CCDC134, perhaps was served as a so far unidentified cytokine-like protein, which showed strong anti-tumor effects via augmenting CD8+ T cells-mediated tumor immunity.
Measuring potency of bispecific effector/target-linking antibodies for inducing cytotoxicity of tumor cells using an impedance-based assay platform (P2094)
Authors: Young Judy , Montgomery Harley , Sun Laura , Junttila Teemu , Mai Elaine 
Published: January 2023

Abstract
Cancer patients mount weak tumor-specific T-cell responses due to immune escape mechanisms of tumors. Although cytotoxic T-cells are potent killers, activation requires antigen processing, specific recognition, and co-stimulation. Bispecific antibody-derived proteins that bind both CD3 and tumor antigens can bypass these requirements by directly linking cytotoxic T cells to tumor cells and have been shown clinically to enhance T cell-mediated tumor cell killing. Our goal was to assess the relative potency of anti-CD3/anti-tumor antigen full-length IgG1 bispecific antibodies. Assays based on electrical impedance are well suited for tumor cell killing assays because the adherent target cells generate an impedance signal, while the non-adherent effector cells do not. Human tumor cells were plated with CD8+ T cells and bispecific antibodies, and cytotoxicity was recorded in real time at intervals during culture. Tumor cell killing was found to be dependent on the bispecific antibody concentration, with EC50 values of 27-40 pM. In addition, killing was dependent on the number of CD8 T cells added, with an optimal effector:target cell ratio of 4:1. Compared to a well established but labor-intensive FACS-based assay performed in parallel, the results of the impedance assay agreed closely. Moreover, impedance-based cell killing assays have the advantages of real-time, label-free readings as well as simple assay development and performance.
CD4+ T cell-mediated protection against tumors: no bystander killing (P2114)
Authors: Schjesvold Fredrik , Tveita Anders , Sundnes Olav , Haraldsen Guttorm , Bogen Bjarne 
Published: January 2023

Abstract
Background: MHC class II-restricted CD4+ T cells reactive against the Id peptide of MHC class II-negative MOPC315 murine myeloma cells can protect mice against injected tumors. This protection occurs via indirect recognition of secreted tumor-specific antigen, presented on MHC class II-molecules of tumor-infiltrating CD11b+ cells. Activated Id-specific Th1 cells produce IFNγ that activate macrophages which become cytotoxic to tumor cells. We wanted to assay the ability of such CD4+/M1 macrophage mediated protection to prevent the outgrowth of antigen-loss tumor variants. Methods: Id-specific TCR-transgenic SCID mice were challenged with a mixed population of Id-secreting and non-secreting MOPC315 cells, differentially labeled with fluorescent proteins. Tumor growth was monitored by in vivo imaging. Tumor-infiltrating macrophages were assayed for their ability to inhibit tumor growth. Results: In the presence of a large excess of antigen-secreting tumor cells, outgrowth of antigen loss-variants occurred with no evidence of bystander killing. A predominance of alternatively activated macrophages was seen in areas dominated by antigen loss-variants, whereas classic activation was the dominant phenotype in areas populated by regressing Id-secreting tumor cells. In vitro, growth of antigen loss-variants was completely inhibited by the provision of the tumor-specific antigen. This data suggests strict spatial requirements of antigen for effective macrophage-mediated protection.
Lenalidomide increases peripheral T regulatory phenotype cells in patients with HIV associated Kaposi Sarcoma (P2030)
Authors: Han Semi , Bui Jack , Reid Erin , Arora Sumit 
Published: January 2023

Abstract
Kaposi Sarcoma, an angioproliferative vascular tumor, is the most common malignancy in patients with HIV and presents a treatment conundrum because of its variable natural history. Lenalidomide is a drug that has immune-modulatory, anti-neoplastic, and anti-angiogenic properties. It is used in the treatment of myelodysplastic disease and multiple myeloma, but its in vivo effects on peripheral blood immune activity is not fully explored. In this preliminary report from a phase I/II trial of lenalidomide in the treatment of HIV associated Kaposi Sarcoma, we found that lenalidomide increased the number and percentage of T regulatory phenotype cells in the peripheral blood. In patients with measurable regression of Kaposi Sarcoma lesion size as well as number of lesions, there was also an observable accumulation in FOXP3 expressing cells in the Kaposi Sarcoma lesion. These findings enable us to speculate on three novel concepts: 1) lenalidomide increases the frequency of circulating T regulatory phenotype cells, 2) lenalidomide’s anti-angiogenic mechanism may be due to T regulatory cell induction, and 3) in contrast to their role in promoting tumor growth by inhibiting tumor immunosurveillance, T regulatory cells may inhibit angioproliferative tumors therefore act as an effective therapeutic agent for tumors such as Kaposi Sarcoma.
OSU-2S: a novel non-immunosuppressive FTY720 derivative mediates potent cytotoxic activity through PKC dependent phosphorylation of tumor suppressor SHP1 and down modulation of Tcl1 oncogene in chronic lymphocytic leukemia (P2120)
Authors: Mani Rajeswaran , Frissora Frank , Mao Yicheng , Chiang Chi-ling , Mo Xiaokui , Jarjoura David , Baskar Sivasubramanian , Rader Christoph , Lee Robert , Lee L.James , Chen Ching-Shih , Byrd John , Muthusamy Natarajan 
Published: January 2023

Abstract
We have recently demonstrated cytotoxic activity of FTY720, a sphingosine analogue, against several B cell malignancies including chronic lymphocytic leukemia (CLL).To overcome the limitations associated with immunosuppressive properties of FTY720, we have developed OSU-2S, a synthetic FTY720 derivative with cytotoxic potency and negated immunosuppressive property. Treatment of primary CLL cells with OSU-2S resulted in potent cytotoxicity associated with PKC mediated phosphorylation of Serine591 (S591) of SHP1 and its nuclear translocation consistent with a potential role for S591 phosphorylation. Concentrations of bisindolylmaleimide that inhibited PKC and thus SHP1S591 phosphorylation abrogated OSU-2S mediated cytotoxicity in CLL cells. Gene expression profiling (GEP) revealed OSU-2S mediated down regulation of TCL1A. Consistent with this OSU-2S induced down regulation of TCL1A at mRNA and protein levels in primary CLL cells. The therapeutic efficacy of OSU-2S was demonstrated in Eµ-Tcl1 transgenic CLL mouse model and SCID-Raji xenograft models with significant reduction in leukemic B cells. Further, administration of OSU-2S immunoliposome targeting receptor tyrosine kinase-like orphan receptor (ROR1) expressed in lymphoid malignancies including CLL in Eμ-human ROR1 transgenic mice resulted in selective depletion of ROR1 positive B cells. In summary, we have identified OSU-2S as a modulator of tumor suppressor and oncogene targets in CLL resulting in potent cytotoxicity.