bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin-15 increases vaccine efficacy through a mechanism linked to dendritic cell maturation and enhanced antibody titers (47.16)
Authors: Saikh Kamal Uddin , Kissner Teri L. , Nystrom Steven , Ruthel Gordon , Ulrich Robert G. 
Published: January 2023

Abstract
Interleukin-15 (IL-15) is generally considered to be a growth factor for NK cells and for sustaining T-cell memory. However, previous data from our laboratory demonstrated that IL-15 is an important factor for development of human dendritic cells. In this study, we investigated the effect of IL-15 on antibody responses to STEBVax, a recombinant staphylococcal enterotoxin B (SEB) vaccine, in a pre-clinical model of toxic-shock syndrome induced by SEB. We first observed IL-15 treated mouse spleen cells in culture gained a dendritic cell-like morphology compared to untreated controls. Further, administration of IL-15 to mice resulted in an increased number of CD11c+dendritic cells recovered from spleens. A significant, IL-15 dose-dependent increase in antigen-specific antibody was observed after co-administration with vaccine. This effect required including an aluminum-based adjuvant (Alhydrogel). The co-administration of STEBVax with IL-15 and Alhydrogel also resulted in a significant increase in protection of mice from lethal toxic shock above levels obtained without IL-15. Thus, the antibody response enhanced by IL-15 appears to be mediated by mature dendritic cells. This suggests a potential use of IL-15 as an adjuvant for antibody-dependent responses to vaccines
Diverse Subsets of Regulatory T (Treg) Cells Mediates Suppression of Arthritis by An Oral Bacterial-Based Diarrheal Vaccine (47.22)
Authors: Kochetkova Irina , Trunkle Theresa , Callis Gayle , Pascual David W. 
Published: January 2023

Abstract
A Salmonella vaccine expressing enterotoxigenic E. coli colonization factor antigen I (CFA/I) behaves as an anti-inflammatory oral vaccine and shown to protect against EAE and collagen-induced arthritis (CIA) in an Ag-independent fashion. Immunization with Salmonella-CFA/I caused Th2 deviation, as well as the development of Treg cells, both contributing to protection. To inquire into the specific contribution of each to protection, cell-sorted CD4+CD25+ and CD4+CD25− T cells as well as total CD4+ T cells derived from DBA/1 mice orally immunized with Salmonella-CFA/I, were adoptively transferred into DBA/1 mice already induced with CIA. Treg cells produced elevated levels of IL-4, IL-10, and TGF-β, as well as IFN-γ and IL-17, as did the CD4+CD25− T cells, but in lesser amounts. CIA was followed, and mice receiving Treg cells or CD4+CD25− T cells showed reduced incidence and very weak clinical disease; however, mice receiving total CD4+ T cells showed suppressed CIA for 2 wks, after which clinical disease was identical with disease obtained with either CD4+ T cell subset. Upon termination, LN CD4+ T cells were restimulated with collagen II (CII). No IL-4 or TGF-β were detected, but IL-10 and IFN-γ were elevated for each adoptive transfer group, more so than from untreated mice. Notably, IL-17 was markedly suppressed by the total CD4+ T cells, but elevated in the others. Thus, these studies show that the collective action of input TGF-β+, IL-4+, and IL-10+ regulatory cells modify the development of CII-specific regulatory and Teff cells, most notably, the suppression of IL-17 development.
Supported by AI-41123.
Endosomal targeting of a Mycobacterium tuberculosis protein elicits potent Th1 host responses. (47.27)
Authors: Sieling Peter A. , Niazi Kayvan R. , Dy Maria C. , Swarbrick Gwendolyn , Lewinsohn David M. , Modlin Robert L. 
Published: January 2023

Abstract
Antigen specific IFN-γ producing CD4 T cells are critical for the control of infection by intracellular bacteria, including Mycobacterium tuberculosis, the causative agent of tuberculosis. Whereas traditional approaches to eliciting CD4 T cell responses utilize protein antigen, DNA vaccines are more readily prepared and at less expense. DNA vaccines have been used to elicit tumor-reactive T cell responses, but little information on DNA vaccines in microbial infection is available. In contrast to protein, a ready source for antigen processing, DNA must be transcribed and translated into protein for processing to take place. Moreover, to allow processing for CD4 T cell presentation, antigen must enter the endosomal pathway. We targeted a M. tuberculosis ESAT-6 DNA vaccine into the endosomal system using sequences from lysosome-associated membrane protein (LAMP). Human dendritic cells (DCs) transfected with ESAT-LAMP presented antigen to ESAT-6-specific CD4 T cell clones, inducing 3.8 times greater IFN-γ production in comparison to T cells exposed to DCs transfected with ESAT-6 containing no targeting sequences (ESAT-STOP). More strikingly, mice immunized with ESAT-LAMP DNA exhibited stronger (17.6-fold, p&lt;0.05) recall responses than ESAT-STOP or animals receiving vector DNA. These data indicate that DNA vaccination enhances T cell responses to microbial antigens and suggest that such an approach might stimulate protective host responses against microbial infection, including tuberculosis.
Intranasal Vaccination with an Iron-Superoxide Dismutase (FeSOD) Deficient Mutant of Francisella tularensis LVS Protects Mice against Lethal Challenge with F. tularensis SchuS4 (47.29)
Authors: Bakshi Chandra Shekhar , Metzger Dennis W 
Published: January 2023

Abstract
Francisella tularensis, the causative agent of tularemia is a potential bioweapon because of ease of its dissemination, multiple routes of infection, high infectivity and lethality. We have previously reported a mutant of F. tularensis LVS deficient in iron superoxide dismutase (sodBFt) and have demonstrated that this mutant is hypersensitive to oxidative stress and attenuated for virulence in mice. Herein, we evaluated further the efficacy of this mutant as a vaccine candidate against respiratory tularemia. We observed that immunization with sodBFt mutant offered 100% protection against 10–100LD100 doses of the highly virulent F. tularensis SchuS4 strain in BALB/c mice and a consistent 40% protection in C57BL/6 mice with a significantly extended median time to death as compared to naïve or LVS vaccinated mice. The sodBFt vaccinated mice exhibited significantly lowered bacterial burden, less severe histopathological lesions in the liver and spleen and a regulated production of proinflammatory cytokines following SchuS4 challenge as compared to the LVS vaccinated mice. We observed increased levels of heat shock protein GroEL, peroxidase/catalase (KatG) and bacteroferritin (Bfr) in the cell lysates and culture filtrate of sodBFt mutant as compared to F. tularensis LVS. Studies on the role of these proteins in the generation of a strong protective immunity in the sodBFt vaccinated mice are currently underway. To conclude, our results demonstrate that sodBFt mutant is a better vaccine candidate than F. tularensis LVS and this study is a major step forward towards the development of a live attenuated vaccine for the prevention of respiratory tularemia.
Towards site-directed covalent vaccination: HIV neutralization by antibodies to an electrophilic gp120 V3 peptide (47.38)
Authors: Nishiyama Yasuhiro , Mitsuda Yukie , Planque Stephanie , Hara Mariko , Taguchi Hiroaki , Salas Maria , Hanson Carl V , Paul Sudhir 
Published: January 2023

Abstract
We observed recently that antibodies (Abs) to an analog of full-length HIV gp120 analog containing electrophilic phosphonate groups located at Lys (E-gp120) form stable immune complexes characterized by very slow dissociation and resistance to denaturants. We hypothesize that the unusual stability is due to the partial covalent character of the complexes, mediated by enhanced Ab nucleophilic reactivity developing in response to electrophilic immunization. Here we tested the feasibility of inducing an epitope-specific nucleophilic Ab response on-demand using as immunogen the electrophilic analog of the principal neutralizing determinant of HIV gp120 (E-PND). Murine IgG Abs raised to E-PND and non-electrophilic PND displayed binding to intact HIV particles. Complexes of HIV with anti-E-PND IgG dissociated ~25-times slower than the complexes with anti-PND IgG. Anti-E-PND IgG neutralized HIV more potently than anti-PND IgG, determined using a T cell line assay (difference in IC50, ~50-fold). The slower dissociation kinetics can be expected to maintain long-lasting blockade of gp120 recognition by host receptors, resulting in superior HIV neutralization. These results suggest the utility of electrophilic immunization to enhance the protective efficacy of site-specific humoral immunity against peptide antigens.
Anti-proliferative effect of interleukin-27 on melanoma cells (48.23)
Authors: Yoshimoto Takayuki , Morishima Noriko , Mizuguchi Junichiro 
Published: January 2023

Abstract
Interleukin (IL)-27 is a member of the IL-6/IL-12 family and activates both signal transducer and activator of transcription (STAT)1 and STAT3 through its receptor, which consists of WSX-1 and gp130. We previously demonstrated that IL-27 has potent antitumor activities, which are mediated through CD8+ T cells, natural killer (NK) cells or its anti-angiogenic activity. Here, we demonstrate that IL-27 also possesses a direct anti-proliferative activity on melanoma cells. Although WSX-1 expression was hardly detected in parental mouse melanoma B16F10 cells, IL-27 activated STAT1 and STAT3 and up-regulated major histocompatibility complex (MHC) class I in B16F10 transfectants expressing wild-type WSX-1. In contrast, IL-27 failed to activate STAT1 and up-regulate MHC class I in those expressing mutant WSX-1, in which the putative STAT1-binding Tyr-609 of the cytoplasmic region was replaced by Phe. IL-27 greatly inhibited the cell growth of transfectants expressing wild-type WSX-1 but not the mutant, and induced apoptosis and G1 arrest. Several human melanoma cells were also reveled to express both IL-27 receptor subunits, and activation of STAT1 and STAT3 and growth inhibition by IL-27 were observed. These results suggest that IL-27 has an anti-proliferative activity on mouse and human melanoma cells through WSX-1/STAT1.
Cell-based Mechanism of Action of a TCR/IL-2 Fusion Protein against Established Tumors (48.36)
Authors: Wen Jinghai , Zhu Xiaoyun , Liu Bai , You Lijing , Lee Hyung , Han Kaiping , Sheehan John , Chavaillaz Pierre-Andre , Rhode Peter , Wong Hing 
Published: January 2023

Abstract
We have previously reported that a single-chain T cell receptor/IL-2 fusion protein, recognizing aa264–272 peptide of human p53, exhibits potent antitumor activities in mouse xenograft models. In this study, we compare the biological activities of 264scTCR/IL-2 with that of Mart-1scTCR/IL-2, a TCR/IL-2 fusion lacking p53 recognition. Although 264scTCR/IL-2 and Mart-1scTCR/IL-2 exhibit equivalent activities for NK cells activation, 264scTCR/IL-2 shows significantly better antitumor activity than Mart-1scTCR/IL-2 against p53+/HLA-A2+ human tumors in mouse xenograft models. We also observed a dose-dependent increase in activated NK cells infiltration into tumors following 264scTCR/IL-2 treatment and significantly more cell infiltration in tumors of 264scTCR/IL-2 treated mice than in those treated with Mart1scTCR/IL-2. The data are consistent with our hypothesis that 264scTCR/IL-2 activates immune cells, such as NK cells, to express high-affinity IL-2 receptors. Following stable interactions between the IL-2 domain and these receptors, the scTCR domain of the fusion molecule guides the immune cells to tumors displaying target peptide/HLA complexes where they mediate antitumor effects.
NIH-2R44CA097550
Inhibition of metastatic B16-F10 melanoma tumor growth by murine dialyzable spleen extracts (DSE) (48.39)
Authors: PEREZ-TAPIA SONIA MAYRA , MARTINEZ/RUIZ GUSTAVO , SALINAS NOEMI , ESTRADA-GARCIA IRIS CITLALLI , ESTRADA-PARRA SERGIO ANTONIO , VELASCO-VELAZQUEZ MARCO ANTONIO 
Published: January 2023

Abstract
Surgery, radiotherapy and chemotherapy are the most widely used and well-established modalities for treating malignant diseases. However, all modalities have major drawbacks. An alternative approach is to expand and activate tumour-specific immune cells in vivo. Dialyzable spleen extracts (DSE) are obtained from freeze-thawed murine spleen cell suspensions and subsequent dialysis (&lt;12 KDa), they have immunomodulatory activity and have shown to cure experimental murine tuberculosis. In this work a BALB/c DSE was used to examine in mice its effectiveness as a prophylactic anti-metastatic therapy, using the mouse B16-F10 melanoma model. 1 Unit DSE (equiv. 1x105 spleen cells) or 0.1 U, were orally given daily for 7 days to 6 and 4 mice respectively. A third group of mice (N=6) was treated with placebo. On day 8, all mice were bleed and each animal inoculated with 1x106 B16-F10 cells. On day 28 all animals were sacrificed, lungs were dissected and macroscopic metastatic nodules counted. An statistically decrease in metastatic nodules (P¡Ü0.01) was observed in both groups that received DSE when compared with the control group. These results indicate that DSE is a promising approach for inhibiting metastatic tumor growth. Further work will focus on the mechanism which elicit this antimetastatic activity.
This work was supported in part by SIP/IPN. 1Are fellows of COFAA, EDI and SNI.
CDC2-related kinase and metabolic regulation in B cell malignancies (49.19)
Authors: Saltis Mark , Davidson Wendy 
Published: January 2023

Abstract
Microarray and qPCR analyses revealed that pre-transformed murine B cells and a variety of human and murine B cell lymphomas constitutively express high levels of Pftk1, a CDC2-related kinase. Expression of Pftk1 also was induced in normal b cells following activation. These findings suggest that Pftk1 is associated with B cell activation and that dysregulation of expression may be an early event in B cell transformation. While the function of Pftk1 in B cells is unknown, published studies on adipocytes suggest that it may have a regulatory role in glycolysis. Concurrent with the increased expression of Pftk1 in B cell tumors, there is a 2–6 fold increase in the levels of transcripts for genes encoding the glycolytic pathway enzymes, including Hk2, Pgam1, Ldh1, and Pkm2. Currently, we are using a variety of molecular approaches to further investigate the relationship between enhanced Pftk1 expression and increased glycolysis in malignant B cells and to determine whether Pftk1 functions as an oncogene.
This work was supported by Arthritis Foundation Chapter Research Grant and NIH grant CA82872-02 awarded to W.F.D.
Vitamin C induces apoptosis in human colon cancer cells through endoplasmic reticulum stress and mitochondrial pathway (49.25)
Authors: Kim Jee Eun , Kang Jae Seung , Jung Da Jung , Hahm Eunsil , Lee Seung Koo , Bae Se Yeon , Hwang Young Il , Shin Dong Hoon , Lee Wang Jae 
Published: January 2023

Abstract
It has been reported that vitamin C plays an effective role in the treatment and prevention of cancer, but its specific mechanism is still not fully understood. In particular, the effect of vitamin C on the treatment and prevention of colorectal cancer, which has been increasingly a common disease in South Korea due to westernized diet of many Koreans, is still largely unknown. Therefore, we have examined the effects of vitamin C on the induction of apoptosis on HCT-8, human colon cancer cell line. We have first confirmed that the optimal concentrations of vitamin C for the induction of apoptosis on human colon cancer cell line, HCT-8 is 2 mM of vitamin C. Here we demonstrated that vitamin C induced ER stress through redox imbalance as antioxidant and, increased cytosol calcium level. Then, we investigated the changes of ER-stress induced molecules. As a result, the phosphorylation of pro-apoptotic protein, Bad decreased and Bad, which was subsequently released from 14-3-3, was translocated to the mitochondria. In addition, we also found that the vitamin C increased expression of pro-apoptotic protein, Bax and tumor suppressor gene product, p53, which usually resulted in apoptosis, in a time dependent manner. Moreover, we have witnessed that vitamin C treatment disrupts mitochondrial membrane potential in HCT-8, human colon cancer cell line. Taken together, vitamin C induced redox imbalance, resulting in apoptosis in human colon cancer cells by both endoplasmic reticulum stress and Bad/p53/Bax-mediated activation of mitochondrial pathway.
TRP-2 TCR Transgenic Mice as a Model to Study CD8+ T cell Responses to Melanoma Antigens (50.15)
Authors: Singh Vinod , Ji Qingyong , Hurwitz Arthur A. 
Published: January 2023

Abstract
To study the effects of T cell avidity on tumor immunity and autoimmunity, we have generated mice that bear T cell receptor (TcR) transgenes specific for a peptide from tyrosinase-related protein 2 (TRP-2), a melanosomal enzyme expressed by both normal melanocytes and melanoma cells. We have begun characterizing a founder mouse line derived from an intermediate avidity T cell line, designated clone 37. Interestingly, the clone 37 TcR transgenic (Tg) mice did not develop autoimmune depigmentation despite the presence of TRP-2-reactive T cells in the lymph nodes and systemic expression of TRP-2. These Tg T cells displayed a naïve phenotype (CD44low, CD62hi, CD69neg, and CD25neg) and proliferated upon stimulation in vitro with cognate antigen. No difference in T cell responsiveness or frequency was observed in the development of Clone 37 T cells following bone marrow reconstitution of wild type C57Bl/6 or TRP-2−/− mice. Adoptive transfer of clone 37 TCR Tg cells into C57BL/6 showed that these T cells do not encounter the endogenous TRP-2 antigen as well as a subcutaneous B16/BL6 melanoma tumor (i.e., they are “ignorant”). However, vaccination with TRP-2 peptide-pulsed dendritic cells induced proliferation of these adoptively transferred CD8+ T cells and subsequent migration into subcutaneous B16/BL6 tumors, but did not inhibit progressive tumor growth. Similarly, B16/BL6 tumors grew progressively in clone 37 TCR Tg mice despite the large number of tumor-associated antigen-specific CD8+ T cells. These findings demonstrate the ability of tumors to evade an anti-tumor immune response despite the presence of tumor-specific T cells. Our on-going studies will characterize two additional mouse lines bearing TcR transgenes from high and low avidity T cell clones and study the impact of different T cell avidities on tumor immunity and autoimmunity.
Role of Type I and Type II NKT cells in the host’s innate antitumor immune response to a B-cell lymphoma (50.26)
Authors: Gourapura Renukaradhya Jayamurthy , Khan Masood A , Vieira Marcus , Brutkiewicz Randy R 
Published: January 2023

Abstract
Natural killer T (NKT) cells are a T cell subpopulation known to possess immunoregulatory functions and recognize CD1d molecules. The majority of NKT cells express an invariant TCR [alpha] chain rearrangement and are called Type I NKT cells; all other NKT cells are Type II. In the current study, we have analyzed the roles for NKT cell subsets in the host’s innate antitumor response against the murine NS0 B-cell lymphoma model in vivo. As the NS0 cell line lacks detectable cell surface CD1d expression, murine CD1d1 cDNA or empty vector was transfected into NS0 cells to generate CD1d+ and control cell lines. In tumor-bearing mice, we found that Type I NKT cells conferred protection in a CD1d-dependent manner, whereas Type II NKT cells exhibited inhibitory activity. Pro- and anti-inflammatory cytokines secreted by splenocytes from tumor-bearing mice were predictive of tumor progression. Myeloid suppressor cells (CD11b+Gr1+) were present in larger numbers at the tumor site and in the spleen of tumor-bearing Type I NKT-deficient mice, suggesting a possible inhibition of antitumor immunosurveillance mediated by these cells. Therefore, there are distinct roles for NKT cell subsets in response to a B-cell lymphoma in vivo, pointing to potential novel targets to be exploited in the immunotherapy of blood cancers.
This study was supported by NIH grants RO1 CA89029 and AI46455 to RRB.[alpha]
Regulatory T cells (Tregs) contribute to suppression of anti-malarial immunity by concurrent nematode infection (51.1)
Authors: Stevenson Mary M. , Su Zhong , Segura Mariela 
Published: January 2023

Abstract
Here, we investigated the mechanisms involved in modulation of anti-malarial immunity by concurrent nematode infection. Both WT C57BL/6 (B6) and STAT-6 deficient (KO) mice co-infected with the gastrointestinal nematode Heligmosomoides polygyrus (Hp) 2 wk prior to blood-stage Plasmodium chabaudi AS (Pc) infection had significantly higher parasitemias and significantly lower serum IFN-γ levels compared to their respective controls infected with Pc alone. Hp-infected STAT-6 KO compared to WT mice produced significantly lower levels of Th2 cytokines (IL-4, IL-13) but Tregs (CD4+CD25+Foxp3− and CD4+CD25−Foxp3+) were significantly and similarly increased within 2 wk after Hp infection in both strains. Transfer of CD4+CD25+ Tregs from uninfected and Hp-infected B6 mice significantly increased malaria parasitemia in recipient mice while depletion of CD25+ cells suppressed parasitemia in Pc-infected mice but not in co-infected mice. FACS analysis revealed that anti-CD25 mAb (PC61) treatment reduced both CD4+CD25+ Tregs and CD4+Foxp3+ Tregs in Pc-infected but not in co-infected mice. Co-infection with Hp significantly enhanced Pc-induced TGF-β1 and IL-10 production. In vivo neutralization of TGF-β1 and blocking IL-10R with mAbs significantly reduced parasitemia in both Pc-infected and co-infected B6 mice; anti-IL-10R mAb treatment resulted in severe mortality. These results suggest that Tregs, and possibly immunoregulatory but not Th2 cytokines, contribute to suppression of anti-malarial immunity in nematode and malaria co-infected mice.
FcγRIII mediates IgG-induced IL-10 and is required for chronic Leishmania lesions (51.2)
Authors: Buxbaum Laurence U. , Thomas Bolaji N. 
Published: January 2023

Abstract
Chronic disease caused by the protozoan parasite Leishmania mexicana, requires IL-10 and the common γ chain (FcRγ) shared by the activating IgG receptors FcγRI, III, and IV and by FcαR and FcεR. FcRγ can also take the place of CD3ζ in some T cells. Which pathway is responsible for IL-10 production and suppression of a protective immune response is unknown. We recently showed that FcγRIII KO mice, like IL-10 and FcRγ KO mice, resolve L. mexicana lesions with a stronger Th1 response and much lower parasite burdens (by 4–5 logs) than WT mice. We now show that FcγRIII KO macrophages have a severe IL-10 defect, when induced by IgG-opsonized parasites, and that this defect is comparable to FcRγ KO macrophages. Thus FcγRIII appears to contribute most of the IgG-induced IL-10, supporting the in vivo findings. We also found that anti-Leishmania IgG responses (IgG1 and IgG2a) were not altered in FcγRIII KO mice compared to WT mice, consistent with the model that parasite-bound IgG alters T cell development and thus may determine the strength of the Th1 response rather than the reverse. Furthermore, depletion of CD25+ T cells did not change the chronic nature of L. mexicana lesions, nor was T cell IL-10 production from FcγRIII KO mice lower than from B6 mice. When taken together these findings support a model in which macrophage FcγRIII, rather than Treg cells, provides the IL-10 that suppresses a protective immune response to L. mexicana.