bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD30 / CD30L interactions promote class-switched antibody responses to T-dependent antigens (34.3)
Authors: Willis Cynthia R , Hu Yi-Ling , Leith Anh , Rottman James B 
Published: January 2023

Abstract
The cell-surface glycoproteins CD30 and CD30L are members of the TNFR and TNF superfamilies, respectively. CD30 is expressed on subpopulations of activated T and B cells. CD30L is expressed on activated T cells, macrophages, and dendritic cells, as well as germinal center B cells. CD30 / CD30L interactions provide activation-induced costimulatory signals that sustain T-cell responses, mediate B-cell activity, and generate long-lived memory T cells for chronic B-cell help. Although other activation-induced costimulatory molecules induce antibody isotype class switching, it is less clear what the function is of CD30 signaling on class switching and antibody production. Therefore, we tested the effect of in vivo blockade of the CD30 / CD30L pathway on antibody class switching in response to T-dependent antigens using two systems that require activated-T cells to stimulate B-cell responses. First, BALB/c mice immunized with a T-dependent antigen and treated with anti-CD30L antibodies produced less antigen-specific antibodies of IgG1 and IgE isotypes as compared to control-treated mice, whereas antigen-specific antibodies of the IgM isotype were similar in all groups. Likewise, NZB/W F1 lupus-prone mice treated with anti-CD30L antibodies produced less anti-dsDNA antibodies of the IgG1 and IgG2a isotypes as compared to control-treated mice, whereas anti-dsDNA antibodies of the IgM isotype were similar in all groups. In both systems, specific subpopulations of lymphocytes necessary for responses to T-dependent antigens were reduced by blockade of the CD30 / CD30L pathway. Our results demonstrate that CD30 / CD30L interactions positively regulate T-cell dependent B-cell responses necessary for class-switched antibody responses.
Migration and retention of CD8 T cells within the intestinal epithelium (39.19)
Authors: Casey Kerry Anne , Vezys Vaiva , Masopust David 
Published: January 2023

Abstract
Memory CD8 T cells persist in the small intestinal epithelium in a highly activated state. To test whether an antigen reservoir or other enduring byproduct of infection was required for the maintenance of this phenotype, we transferred TCR transgenic CD8 T cells of fixed specificity into Rag deficient hosts. Firstly, introduction to a lymphopenic environment was sufficient to induce dissemination of donor T cells to the intestinal mucosa. Once there, they adopted the quintessential properties of small intestine lymphocytes including expression of CD69 and Granzyme B, suggesting that the maintenance of an activated phenotype within intestinal epithelium was independent of residual byproducts of infection. Notably, memory CD8 T cells within small intestinal epithelium express CD103 integrin, a ligand for epithelium expressed E-cadherin. Using virus specific TCR transgenic cells deficient for CD103, we assessed the role of this molecule in migration and maintenance. While cells deficient for CD103 migrated to intestinal epithelium without defect shortly after infection, they exhibited a profoundly reduced capacity to persist in that compartment after clearance of the infection. Thus, the establishment of a resident memory CD8 T population with an activated phenotype within the intestinal epithelium occurs in the absence of residual infectious byproducts and is largely dependent upon expression of CD103.
Effect of B7.1 costimulation on T-cell based immunity against TAP-negative cancer can be facilitated by TAP1 expression (40.11)
Authors: Zhang Qian-Jin , Li Xiao-Lin , Liu Yong-Yu , Knight David , Odaka Yoshi , Mathis J. Michael , Shi Runhua , Glass Jonathan 
Published: January 2023

Abstract
Tumors deficient in TAP expression cannot efficiently induce T cell immunity, and are resistant to T cell lysis. Here we show that introduction of B7.1 molecule into TAP-negative (TAP-) and TAP1-transfected (TAP1+) CMT.64 tumor cells dramatically augments T cell immunity against TAP- tumors. Differences in the immune responses were observed between TAP- and TAP1+ CMT.64 cells depending on the dose of inoculation. While mice immunized with B7.1 expressing TAP1+ cells rejected TAP- tumors with high and low dose inoculations, only high dose inoculations with B7.1 expressing TAP- cells resulted in tumor rejection. The induced protective immunities were T cell dependent as indicated by depletion of CD8 or CD4 cells in immune competent mice. We also found that B7.1 and TAP1 coexpression decreased tumorigenicity. In addition, when CMT.64 cells infected with vaccinia viruses carrying B7.1 and/or TAP1 were used for immunization, we found that B7.1 and TAP1 coexpression, but not B7.1 expression alone, played a critical role in induction of protective immunity after a high dose inoculation, suggesting that viral antigens significantly affected TAP negative and B7.1 expressing cells for tumor antigen presentation and T cell priming. Our results indicate that B7.1-provoked antitumor immunity against TAP- cancer is facilitated by TAP1 expression and thus, both genes should be considered for cancer therapy in the future.
IL-18-elicited regulatory NK cells with immunoablative functions (40.22)
Authors: Ullrich Evelyn , Terme Magali , Aymeric Laetitia , Chaput Nathalie , Schultze Joachim , Mackensen Andreas , Zitvogel Laurence 
Published: January 2023

Abstract
Cancer-induced tolerance involves multiple immunosuppressive pathways, which subvert adaptive immune responses. Extensive phenotypic characterization of NK cells from tumor-bearing mice led us to the observation of a consistent expansion of c-kit(CD117)-expressing NK cells (Kit+NK) compromising the NK cell arm of tumor immunosurveillance.
Purified Kit+NK cells failed to produce IFNγ in response to IL-2 and could not promote DC maturation. Adoptive transfer of Kit+NK cells into tumor-bearing mice promoted tumor progression. Micro array comparison of CD3-NK1.1+Kit+ and CD3-NK1.1+Kit- cells revealed that genes involved in tolerance (B7-H1, CTLA4, Lag3, Hmox1) or bone marrow homeostasis (Cxcl2, CD81, CD63, Csf2) were markedly up-regulated in Kit+NK. B7-H1 appeared particularly intriguing as we found that Kit+NK killed Kit-NK cells in a B7-H1/PD-1-dependent manner.
Moreover, IL-18 produced by B16F10 tumors converts Kit- into Kit+NK cells endowed with immunoablative functions in lymph nodes. Upon tumor inoculation, Kit+NK, which upregulate B7-H1, accumulate in lymphoid organs in an IL-18R/MyD88-dependent manner and directly kill conventional NK cells, thereby promoting the progression of NK-controlled cancers.
In summary, these data suggest that IL-18 promotes the expansion of Kit+NK cells endowed with immunosuppressive functions that could act as negative regulator of general NK responses.
Attenuation effects of CD4+CD25+ regulatory T cells on cisplatin induced nephrotoxicity in mice (40.24)
Authors: Lee Hyojung , Keum Dongjune , Lee Youngseop , Hong Moo-Chang , Shin Min-Kyu , Kim Yangseok , Bae Hyunsu 
Published: January 2023

Abstract
Cisplatin is a chemotherapeutic agent, which is widely used for a variety of malignancies, such as ovarian, head and neck cancers. However, its nephrotoxicity limits the use of this drug. This research examines whether CD4+CD25+ Regulatory T cells (Treg) have protective effects on cisplatin induced acute renal failure in mice. For the experiment, 1x 106 CD4+CD25+ T cells, CD4+CD25- T cell, were reconstituted into each group of T cell-deficient (nu/nu) mice. After 10 days, all groups of mice received a single dose of cisplatin at 40mg/kg intraperitoneally. Treg adoptive transferred nu/nu mice had a marked attenuation in serum creatine, BUN, and survival. At 48h time point, the Treg group had a significantly reduced increase in TNF-a, IL-1b cytokines when compared with the control group and CD4+CD25- group. In addition, the renal tubular injury worsened less in Treg reconstituted mice. These results suggest that CD4+CD25+ regulatory T cell can attenuate cisplatin induced acute kidney injury.
Bi-functional fusion proteins: Induction of effective apoptosis of malignant cell lines by dual signaling (41.14)
Authors: Orbach Ariel , Rachmilewitz Jacob , Tykocinski Mark L , Dranitzki Elhalel Michal 
Published: January 2023

Abstract
One mechanism involved in evolution of death resistant malignant cells is upregulation of anti-apoptotic signals. CTLA-4FasL, that integrates the capacities to bind to B7 and to Fas receptor (CD95), induces effective apoptosis of activated T cells by activating the caspases in parallel to decreasing the expression of the anti-apoptoic protein cFLIP. Aims: Explore the ability of CTLA-4FasL and CD40FasL (binds to CD40L and CD95) to induce apoptosis of malignant B and T cell lines, and test whether they decrease cFLIP in conjunction with caspases activation. Results: CTLA-4FasL induced effective apoptosis of malignant T and B cell lines that express CD95 (tested by annexin/PI). Activation of caspase 3, 8 and 9 was verified by western blots. Only B7 expressing B cells responded to CTLA-4FasL presence with rapid abrogation of cFLIP expression. CD40FasL also induced apoptosis of T and B cell lines, and was most toxic to T cell line that expressed high levels of CD40L in addition to CD95. These CD40L expressing cells decrease cFLIP in response to CD40FasL. CTLA-4FasL and CD404FasL were more potent than either of their components, alone or in combination. Conclusion: Both fusion proteins activate Fas receptor, but maximal potency is seen when target malignant cells express a binding site for the second domain of the fusion proteins (B7 or CD40L). This potency is probably related to inhibition of anti-apoptotic signals.
Antitumor efficacy of palmitylated IL-2 in adoptive and active immunotherapies (41.30)
Authors: Chou Sharon , Xu Lipeng , Chen Aoshuang , Zheng Guoxing 
Published: January 2023

Abstract
Although soluble IL-2 has shown antitumor activity in preclinical studies, clinical use of IL-2 (usually applied systemically) has been limited by its severe toxicity. This necessitates efforts on minimizing toxicity of IL-2-based therapies. Previously, we showed that recombinant immunoregulatory proteins (such as costimulators), after being chemically palmitylated, can be incorporated into cell membranes via the lipid anchorage. Hence, we hypothesized that palmitylation of IL-2 may permit controlled targeting of IL-2, to either antitumor T cells or cells in the tumor microenvironment, thereby bypassing the need to apply IL-2 systemically. In this study, we demonstrated that palmitylated human IL-2 (pal-IL-2) can be incorporated into the surfaces of antitumor T cells, and the pal-IL-2-modified T cells show increases in proliferation and survival in vitro. Subsequently, we showed that pal-IL-2 modification of CD8+ TCR-transgenic OT-1 T cells enhances therapeutic efficacy of the T cells, upon adoptive transfer, against established E.G7-OVA tumors. Also, we showed that intratumoral injection of pal-IL-2 into B16F10 tumor-bearing mice inhibits the growth of tumors and prolongs the survival of treated animals, whereas injection of soluble IL-2 (as control) has minimal efficacy. Collectively, our study suggests that palmitylation of cytokines may provide a novel approach to target cytokines to antitumor T cells or the tumor microenvironment, to minimize the systemic toxicity and, thus, improve the therapeutic efficacy of the cytokines.
Loss of pre-existing tumor-specific T-cells and increase in regulatory T-cells after peptide-vaccination in combination with PADRE, CpG 7909, and Montanide ISA51 (41.42)
Authors: Kuball Jurgen , deBoer Karin , Wagner Eva , Wattad Mohammed , Antunes Edite , Lotz Carina , vanDorp Suzanne , Hol Samantha , Huber Christoph , Greenberg Philip D , Heit Wolfgang , Theobald Matthias 
Published: January 2023

Abstract
T-cells with specificity for antigens derived from Wilms-Tumor-gene (WT1), Proteinase3(Pr3), and mucin1(MUC1) have been demonstrated to lyse AML blasts and MM cells and strategies to enhance or induce such tumor-specific T-cells by vaccination are currently explored in multiple clinical trials. To test the safety and immunogenicity of a vaccine composed of WT1-, Pr3-, and MUC1-derived Class I-restricted peptides in combination with CpG 7909 and Montanide ISA51 adjuvants and the PADRE helper epitope, 9 patients with AML or MM were repetitively vaccinated. No clinical responses were observed. Comprehensive immunologic analyses revealed that 5 out of 9 patients harboured non-functional and 2 out of 9 functional MUC1- or WT1-specific CD8+ T-cells prior vaccination. However, neither the pre-existing nor naive de novo WT1-/Pr3-/MUC1-specific CD8+ cells were expanded in vivo by vaccination. Moreover, the pre-existing WT1-/MUC1-specific T-cells became no longer detected following vaccination, whereas the frequency and function of CMV-specific CD8+ T-cells was unchanged. A more than 2-fold increase in PADRE-specific CD4+ T-helper-cells was observed but these did not produce IL2, and CD4+ T-cells with a regulatory phenotype increased more than 2-fold. These results are in stark contrast to previous vaccination studies, and should be carefully taken into consideration in the context of multiple ongoing as well as future clinical vaccination trials.
Denileukin diftitox (DT) and interferon (IFN)-alpha boost numbers and maturation of a novel stimulatory CD11b+Gr-1+ cell in ovarian cancer (41.62)
Authors: Thibodeaux Suzanne R , Shin Tahiro , Daniel Benjamin , Lin Pei Yi , Livi Carolina , Wall Shawna , Brumlik Michael , Kious Mark , Jeansonne Duane , Ludwig Sara , Curiel Tyler 
Published: January 2023

Abstract
CD11b+Gr-1+ cells increase in spleen, ascites and mesenteric lymph nodes in BL6 mice challenged with intraperitoneal OVA-expressing ID8 ovarian carcinoma cells, and boost rather than suppress tumor (OVA)-specific immunity. We studied regulation of CD11b+Gr-1+ cells. ID8-challenged mice treated with DT to deplete regulatory T cells, or DT plus IFN-α had improved survival. Surprisingly, DT or IFN-α each increased percentage and numbers of CD11b+Gr-1+ cells in spleen and ascites. IFN-α, but not DT, increased CD11b+Gr-1+ cell CD86 and DR expression, suggesting maturation and differential DT versus IFN-α effects. Effects are not tumor-specific as DT or IFN-α each also increased CD11b+Gr-1+ cells in BL6 mice without tumor. ID8 tumor challenge in B7-H1-/- BL6 mice resulted in ~50% fewer CD11b+Gr-1+ cells compared to after ID8 challenge in wild type mice, suggesting that B7-H1 signals regulate CD11b+Gr-1+ cell generation. Intradermal EG7 tumor in BL6 mice boosts suppressive CD11b+Gr-1+ cells. Strikingly, DT or IFN-α each reduced CD11b+Gr-1+ cells in EG7-bearing mice ~60%. Increasing stimulatory CD11b+Gr-1+ cells or reducing inhibitory CD11b+Gr-1+ cells could represent novel mechanisms of treatment effects of Treg depletion or IFN-α.
Supported by the NCI, the Rippel Foundation, and Voelcker and Greehey Funds.
Modulation of immune response by varying ligand density on the surface of nanoparticles (42.22)
Authors: Bandyopadhyay Arunima , Bockenstedt Linda , fahmy Tarek 
Published: January 2023

Abstract
Targeting antigen presenting cells with biodegradable nanoparticles provides an excellent opportunity for the development of vaccines. Polymeric nanoparticles with entrapped antigens serve as an excellent platform for controlled release of antigens. Immune response can be optimized and enhanced by selectively targeting the antigen loaded nanoparticles to dendritic cells. Here we report our findings using the PLGA nanoparticulate system to target DCs by targeting their surface receptor DEC205. These nanoparticles encapsulate the model antigen ovalbumin and are surface modified with anti DEC205 at different ligand densities. Our studies demonstrate that targeting bone marrow derived DCs using different modifications of nanoparticles but targeting the same receptor lead to altered T cell responses. These studies have implications in designing a novel nanoparticle based vaccine delivery system.
Isolation of high affinity human scFv antibodies against mouse and human tumor endothelial marker 1 (TEM1) using yeast-display scFv library derived from an autoimmune patient. (42.4)
Authors: Zhao Aizhi , Li Chunsheng , Coukos George , Siegel Don L , Scholler Nathalie 
Published: January 2023

Abstract
TEM1 is predominantly expressed on neovasculature, thus ideally suited for targeted imaging and therapy for cancer. Yeast has emerged as an alternative technology for display and selection of recombinant antibody fragments (scFv). Because autoimmune disorders may produce self-reactive specificities, an autoimmune repertoire derived from a patient with thrombotic thrombocytopenic purpura (TTP) was screened to isolate anti-TEM1 scFv.
A yeast-display scFv library was constructed by homologous recombination of the TTP patient repertoire originally expressed on M13 bacteriophage. The library (10^9 members) was flow sorted with decreasing antigen concentration until a scFv pool detecting 2 nM of rhTEM1/GST was obtained. Secreted scFv were expressed and 470 scFv were screened by ELISA for binding to rhTEM1/GST. Nearly 50% of the scFv gave colorimetric signals higher than 3 standard deviations above background. No cross-reactivity with GST control protein was detected. Sequencing of 29 scFv identified 8 unique antibodies. Two of these clones exhibited Kd's in the 100 pM range and bound to both mouse and human TEM1. Such cross-reactive anti-mouse/human TEM will facilitate proof of concept for the development of novel anti-angiogenic targeted therapies.
Our data suggest that the use of large scFv libraries derived from autoimmune patient repertoires may provide a rich source of high affinity antibody reagents to therapeutically relevant molecules.
This work was supported by the Claneil Foundation
Mimogen restores the HBV specific cytotoxic T lymphocytes responses in chronic HBV carriers (42.9)
Authors: Wu Yuzhang 
Published: January 2023

Abstract
Despite effective prophylactic vaccines against hepatitis B virus existing for over 20 years, there is no effective therapy in the treatment of chronic hepatitis B (CHB). Viral persistence is thought to be related to poor HBV-specific T-cell responses. Whereas we recently showed that the frequency of HBV-specific T-cells could be detectable but not effective to clear virus which reflecting an early intermediate stage of differentiation. A phase II clinical trial was performed in CHB carriers to investigate whether the artificial antigen (mimogen) could restore T-cell responsiveness and change the stage of differentiation. 24 patients with chronic hepatitis B nonresponder to approved treatments for HBV infection were enrolled in the trial. . HBV-specific T cell responses were assessed by proliferation, tetramer staining, intracellula cytokine staining (ICCS) and cytometric bead array (CBA). The study provides evidence that mimogen is safe and immunologically effective. Despite increasing the frequency of HBV-specific CTLs, mimogen could restore the function and convert the premature state of HBV-specific CTLs. Thus mimogen may be a new immunotherapeutic for the cure of CHB.
Exercise reduces inflammatory responses to influenza virus infectoin in aged mice (43.12)
Authors: Yu Shan , Sim Young-Je , Singh Navrozedeep , Kohut Marian 
Published: January 2023

Abstract
In order to examine the extent to which exercise alters the inflammatory and clinical responses to respiratory infection in old mice, 19-month old male BALB/cJ mice were assigned to exercise (EX) and non-exercise (non-EX) groups. After 3 months of exercise or control treatment, mice were intranasally infected with influenza virus. Bronchoalveolar lavage (BAL) fluid was collected at 4 and 7 days post-infection (DPI) to assess viral titer and cytokines/chemokine profiles. Sera were collected for antibody measurement at 7 and 10 DPI. Lungs were collected for lesion scores at 10DPI. Weight loss and food intake were recorded daily. The results showed that the virus titer in EX mice at 4 DPI was significantly lower than non-EX mice. At 7DPI, 14% of the mice in EX had virus in lungs whereas 35% of non-EX had detectable virus. IL-12p70 & IL-1α in BAL were significantly lower in EX than in non-EX, with trends for reduced IP-10, MIP-1α and RANTES at 4 DPI. At 7 DPI, EX mice had less IL-12p70, IL-1β, and IFNγ in BAL as compared to non-EX mice, whereas IL-10 tended to be higher in EX mice. Anti-influenza IgG titer was significantly lower in EX compared to non-EX at 7 and 10 DPI. Lung lesion scores were significantly lower in EX compared to that in non-EX at 10 DPI. Non-EX lost more weight and ate less food than EX over time. In summary, exercise improved influenza viral clearance, improved clinical scores, and reduced lung inflammation in aged mice.
Investigating the immunomodulatory effects of Chinese herbs on mouse (43.16)
Authors: Li Ching , Chu I-Ching , Liao Hui-Fen 
Published: January 2023

Abstract
Chinese herbs Radix Isatidis and Viola yedoensis Makino have been implicated to possess antiviral activity. This study is to test whether these herbs are capable of modulating the immune function in Balb/cByJ mouse that supports such activity. We first confirmed that the extract from Viola yedoensis Makino, but not Radix Isatidis or a homeopathic medicinal drink Método Canova, could inhibit the replication of HSV-1 and enterovirus 71 in human neuroblastoma SK-N-SH cell line. Subsequently, the herbal extracts and Método Canova were subjected to the immunomodulatory tests with 120 6-8 weeks old mice. The animals were randomly divided into to 8 groups, of which 6 groups were fed with the half human-to-mouse-body-weight-adjusted doses of the herbal medicine and Método Canova for 9 weeks. At 8th week, these 6 groups and an unfed group of mice were injected peritoneally with one dose of the immune suppressant 5'-fluorouracil, and all 8 groups of animals were sacrificed a week later for immune function evaluations, which included the measurements of the WBC counts and the IgG levels, the numbers for B-, T-, and I-A/I-E-splenocytes, the proliferative rates for B- and T-splenocytes upon stimulation, and the serum cytokine and chemokine levels with protein arrays. Among the tests, we detected that serum BLC and MIP-2 levels were dramatically increased in mice fed with Radix Isatidis. This result indicates that taking the herb extract can improve the responsiveness of immune cells to inflammation, as these two chemokines possess the capability of inducing neutrophils, macrophages, and B-cells chemotaxis. However, no mouse in any group showed a clear improvement in cellular immunity that can suppress viral infections.