scholarly journals High dose and low dose Lactobacillus acidophilus exerted differential immune modulating effects on T cell immune responses induced by an oral human rotavirus vaccine in gnotobiotic pigs

Vaccine ◽  
2012 ◽  
Vol 30 (6) ◽  
pp. 1198-1207 ◽  
Author(s):  
Ke Wen ◽  
Guohua Li ◽  
Tammy Bui ◽  
Fangning Liu ◽  
Yanru Li ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Lactobacillus Acidophilus ◽  
Low Dose ◽  
High Dose ◽  
Rotavirus Vaccine ◽  
Human Rotavirus ◽  
T Cell Immune Responses ◽  
Gnotobiotic Pigs

scholarly journals B-Cell-Deficient and CD8 T-Cell-Depleted Gnotobiotic Pigs for the Study of Human Rotavirus Vaccine-Induced Protective Immune Responses

2016 ◽  
Vol 29 (2) ◽  
pp. 112-127 ◽  
Author(s):  
Ke Wen ◽  
Tammy Bui ◽  
Mariah Weiss ◽  
Guohua Li ◽  
Jacob Kocher ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
B Cell ◽  
Cd8 T Cell ◽  
Rotavirus Vaccine ◽  
Human Rotavirus ◽  
Gnotobiotic Pigs

The Absence of Vasoactive Intestinal Peptide Augments Allo-Reactivity and the Anti-Viral Response in Bone Marrow Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3267-3267
Author(s):  
Lauren T. Southerland ◽  
Jian-Ming Li ◽  
Sohrab Hossain ◽  
Cynthia Giver ◽  
Wayne Harris ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Low Dose ◽  
T Cell Response ◽  
High Dose ◽  
Mcmv Infection

Abstract Background: The severe morbidity and mortality associated with bone marrow transplantation (BMT) is caused by uninhibited immune responses to alloantigen and suppressed immune responses to pathogens. Vasoactive Intestinal Peptide (VIP) is an immunomodulatory neuropeptide produced by T-cells and nerve fibers in peripheral lymphoid organs that suppresses immune responses by induction of tolerogenic dendritic cells. In order to determine the immunoregulatory effects of VIP, we examined T-cell immune responses to allo- and viral-antigens in VIP knockout (KO) mice and mouse BMT recipients of hematopoietic cells from VIP KO donors. Methods: VIP KO mice and VIP WT littermates were infected with lethal or sub-lethal doses (5 × 104− 5 × 105 PFU) of murine cytomegalovirus (mCMV) and the T-cell response to viral antigen was measured by flow cytometry for mCMV peptide-MHC class 1-tetramer+ CD8+ T-cells. We transplanted 5 × 106 BM plus 1 × 106 splenocytes (SP) either from VIP KO or VIP WT donors in an C57BL/6 to F1(BL/6 × Balb/c) allo-BMT model and assessed survival, GvHD, donor T-cell expansion, chimerism, and response to mCMV vaccination and mCMV infection. Results: B-cell, αβ and γδ T-cell, CD8+ T-cell, CD11b+ myeloid cell, and dendritic cell numbers were equivalent between VIP KO and WT mice, while VIP KO mice had higher number of CD4+ and CD4+CD62L+CD25+ T-cells. Non-transplanted VIP KO mice survived mCMV infection better compared to VIP WT, with a brisker anti-viral T-cell response in the blood. In the allogeneic BMT setting, recipients of VIP KO BM plus VIP KO SP had more weight loss and lower (40%) 100 day post-transplant survival compared to the recipients of VIP KO BM plus WT SP (80% survival), recipients of WT BM plus KO SP (100% survival), and recipients of WT BM plus WT SP (80% survival). Recipients of VIP KO grafts had a significantly greater anti-mCMV response that peaked four days earlier than the tetramer response of mice transplanted with WT cells. This increased anti-viral response to vaccination correlated with a greater and more rapid T-cell response to secondary viral challenge. Conclusions: These experiments suggest that the absence of all VIP in the body, or the absence of VIP in a transplanted immune system, enhances anti-viral immunity and allo-immune responses. Modulation of the VIP pathway is a novel method to regulate post-transplant immunity. Figure 1: VIP knockout(KO) mice have an increased CMV tetramer response. VIP KO and VIP WT mice were infected (day 0) with either a sub-lethal low dose (5 × 10^4 PFU) or a lethal high dose (5 × 10^5 PFU) of CMV. Peripheral blood was stained for T cell markers and tetramer and analyzed by flow cytometry. On day 3, high dosed VIP KO mice had a higher number of tetramer positive CD8 T cells and better survival than WT mice (all high dose VIP WT died prior to day 10). VIP KO mice had a significant increase in tetramer positive CD8 T cells between days 3 and 10. *** p<0.01, difference between VIP KO and VIP WT littermate at designated dose level and day. Figure 1:. VIP knockout(KO) mice have an increased CMV tetramer response. VIP KO and VIP WT mice were infected (day 0) with either a sub-lethal low dose (5 × 10^4 PFU) or a lethal high dose (5 × 10^5 PFU) of CMV. Peripheral blood was stained for T cell markers and tetramer and analyzed by flow cytometry. On day 3, high dosed VIP KO mice had a higher number of tetramer positive CD8 T cells and better survival than WT mice (all high dose VIP WT died prior to day 10). VIP KO mice had a significant increase in tetramer positive CD8 T cells between days 3 and 10. *** p<0.01, difference between VIP KO and VIP WT littermate at designated dose level and day.

scholarly journals Sequential Immunization with Universal Live Attenuated Influenza Vaccine Candidates Protects Ferrets against a High-Dose Heterologous Virus Challenge

2018 ◽  
Author(s):  
Irina Isakova-Sivak ◽  
Victoria Matyushenko ◽  
Tatiana Kotomina ◽  
Irina Kiseleva ◽  
Elena Krutikova ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Cd8 T Cell ◽  
Influenza Viruses ◽  
Influenza Vaccines ◽  
Control Group ◽  
High Dose ◽  
T Cell Immune Responses

The development of universal influenza vaccines, i.e. vaccines that can provide broad protection against seasonal and potentially pandemic influenza viruses, has been a priority for more than 20 years. Several approaches have been proposed that redirect the adaptive immune responses from immunodominant hypervariable regions to low-immunogenic but highly conserved regions of viral proteins. Here we induced broadly reactive anti-hemagglutinin (HA) stalk antibody by sequential immunizations with live attenuated influenza vaccines (LAIVs) expressing chimeric HA (cHA). These vaccines contained the HA stalk domain from H1N1pdm09 virus but antigenically unrelated globular head domains from avian influenza viruses H5N1, H8N4 and H9N2. In addition, the source of the viral nucleoprotein (NP) of the LAIV strains was changed from A/Leningrad/17 master donor virus (MDV) to wild-type (WT) H1N1pdm09 virus, in order to induce CD8 T-cell immune responses more relevant to current infections. To avoid any difference in protective effect of the various anti-neuraminidase (NA) antibodies, all LAIVs were engineered to contain the NA gene of Len/17 MDV. Na&iuml;ve ferrets were immunized with three doses of (i) classical LAIVs containing non-chimeric HA and NP from MDV (LAIVs (NP-MDV)); (ii) cHA-based LAIVs containing NP from MDV (cHA LAIVs (NP-MDV)); and (iii) cHA-based LAIVs containing NP from H1N1pdm09 virus (cHA LAIVs (NP-WT)). A high-dose challenge with H1N1pdm09 virus induced significant pathology in the control, non-immunized ferrets, including high virus titers in respiratory tissues, clinical signs of disease and histopathological changes in nasal turbinates and lung tissues. All three vaccination regimens protected animals from clinical manifestations of disease: immunized ferrets did not lose weight or show clinical symptoms, and their fever was significantly lower than in the control group. Further analysis of virological and pathological data revealed the following hierarchy in the cross-protective efficacy of the vaccines: cHA LAIVs (NP-WT) &gt; cHA LAIVs (NP-MDV) &gt; LAIVs (NP-MDV). This ferret study showed that prototype universal LAIVs that combine the two approaches of inducing anti-HA stalk antibody and more relevant CD8 T-cell immune responses are highly promising candidates for further clinical development.

in Situ Vaccination for Patients with Previously Untreated Follicular Lymphoma: Analysis of Immune Responses

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3703-3703
Author(s):  
Debra K Czerwinski ◽  
Joshua Brody ◽  
Holbrook E Kohrt ◽  
Richard T. Hoppe ◽  
Ranjana H. Advani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Tumor Cells ◽  
Low Dose ◽  
Granzyme B ◽  
T Cell Response ◽  
Clinical Responses ◽  
T Cell Immune Responses

Abstract Abstract 3703 Introduction Local intratumoral injection of CpG ologonucleotides in conjunction with local low dose radiotherapy can induce regression of uninjected distant sites of disease in patients with follicular lymphoma (FL) (Brody et. al JCO). This maneuver activates the Toll-like receptor 9 (TLR9) within the tumor cells and in adjacent antigen presenting cells in the local tumor environment, such as dendritic cells and macrophages. A systemic anti-tumor T cell immune response is thereby induced. Our original phase I/II trial was conducted in patients who had been previously treated with standard therapies and had recurred with multiple sites of disease. We observed significant clinical responses as well as anti-tumor T cell immune responses as measured in vitro using peripheral blood T cells or T cells obtained from a pleural effusion adjacent to a responding tumor site. Methods We now extended the trial of in situ vaccination to newly diagnosed patients prior to any other therapy, a group that may have a more intact immune system. Patients were eligible if they had FL grades I-IIIa, stage III or IV and were not in need of immediate treatment. One involved lymph node was biopsied and viable suspensions of tumor cells were prepared and cryopreserved for use as stimulators in immune assays. A second site received low dose XRT (2Gy on each of two successive days) together with 10 weekly injections of 18mg of CpG ologonucleotide (PF-3512676, Pfizer) all into the same tumor site, beginning on the second day of XRT. Peripheral blood lymphocytes (PBL) were obtained prior to each injection and two weeks after the last injection. These were cryopreserved and used as responder cells for assays of T cell immune responses. We sought to determine the kinetics of anti-tumor T cell immune responses as well as which type of T cell response that was the most informative. Tumor cells were thawed and activated for 3 days with CpG and soluble CD40L. They were then incubated for 5 days with autologous PBL T cells. Fresh stimulator cells were then added for a final overnight culture. Responding T cells were stained for subtype (CD4, CD8, CD56, CD45RO), for their expression of activation markers (CD25, CD137 and CD278), for their expression of intracellular cytokines (IFN-g, TNF and IL-2), and for their expression of cytotoxic enzymes (perforin and granzyme B). The cells were then analyzed by multiparamer flow cytometry (BD LSRII). For measurement of perforin and granzymeB, the cells were gated on CD8+/CD3+/CD56- to exclude NK cells. Results In response to in situ vaccination, all patients made anti-tumor immune responses. Some generated only CD4 responses, some only CD8 responses and others made both CD4 and CD8 T cell responses. Representative data are shown in the figures below. We found that for CD4 responses the activation marker CD278 (ICOS) was particularly informative, and usually restricted to the CD45RO+ memory subset. For CD8 responses, the most robust readout was intracellular expression of the combination of Perforin and Granzyme B. CD8 Immune responses became positive as early as two weeks after the start of vaccination. CD4 responses became positive by four weeks of vaccination. As in our previous trial, we observed clinical responses, with regression of tumors at uninjected/untreated sites of disease. An evaluation of the magnitude and duration of these clinical responses and their relation to immune parameters awaits a more extended time of followup. Conclusions In situ vaccination efficiently induced immune responses in previously untreated patients with FL. These responses occurred within two weeks after initiation of vaccination. The immune responses was heterogeneous and included both CD4 and CD8 T cells. The most robust measures of T cell response will be correlated with clinical outcome. The identification of a limited panel of correlative immune response markers and an understanding of the response kinetics will allow a focused approach to immuno-monitoring in future clinical trials. Disclosures: Advani: Pharmacyclics: Research Funding.

scholarly journals Different Doses of Allergen Exposure on Dendritic Cells Determine Their Genetic/Epigenetic Regulation and T Cell Differentiation

2019 ◽  
Author(s):  
Jianjun Chen ◽  
Ying Wang ◽  
Zizhong Yu ◽  
Yue Zhou ◽  
Yun Zhu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Signaling Pathway ◽  
Low Dose ◽  
Mapk Signaling ◽  
Dose Effect ◽  
High Dose ◽  
Different Doses

Abstract Background: It has been reported that when DCs are exposed to high-dose antigens, they can induce Th0 cells into regulatory cells (Treg) and Th1 cells. When DCs are subjected to low-dose allergen, they can drive to Th2 cells. However, the mechanisms of such dose-effect relationship are poorly understood so far. Methods: Bone marrow immature DCs (imDCs) were generated from mice and stimulated with OVA of different concentrations (0, 10, 100, 1000, 10000 μg/ml, respectively). The mDCs were then seeded and cocultured with naïve T cells for 3 days, and then the markers of different T cell subgroups were flow cytometrically tested. RNA-seq detection and DNA methylation of DCs were performed. Results: When DCs were stimulated with low-dose (10ug/ml), 77 genes were up-regulated and 87 genes down-regulated. Most activated genes were related to ribosome synthesis and ion channel inhibition but not to the immune responses and Th2 activation. At the medium-dose (100μg/ml), 339 genes were up-regulated and 168 genes down-regulated. Most activated genes involved cytokine synthesis and regulation of immune responses. At high-dose (10000μg/ml), 2794 genes were up-regulated and 1156 genes down-regulated. Tumor necrosis factor signaling pathway, MAPK signaling pathway, antigen processing and presentation signaling pathway were mostly up-regulated. The related co-stimulators, co-inhibitory molecules, inhibitory cytokines, negative regulating enzymes were highly expressed. The monocarbate, coenzyme, fatty acid, glucolipid, starch, sucrose and other metabolism-related signaling pathways were down-regulated. Conclusion: The profiles of DNA methylation and RNA synthesis of DCs varied with different doses of OVA, which serves to induce T cells to differentiate in various directions.

Aryloxy Triester Phosphonamidates of Phosphoantigens Exhibit Favorable Stability and Potent Activation of Vγ9/Vδ2 T‐Cells

2018 ◽  
Author(s):  
Hachemi Kadri ◽  
Taher E. Taher ◽  
Qin Xu ◽  
Richard T. Bryan ◽  
Benjamin E. Willcox ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Serum Stability ◽  
T Cell Immune Responses ◽  
Further Development

We previously reported the application of the aryloxy triester phosphoramidate prodrug technology to the phosphoantigen (E)-4-hydroxybut-2-enyl phosphate (HMBP). Although these prodrugs exhibited potent activation of Vγ9/Vδ2 T‐cell immune responses, their stability was low due to the rapid cleavage of the -O-P- bond. To address this, we herein report the application of the same prodrug strategy to two HMBP phosphonates, which have stable -CH2-P- or -CF2-P- bonds. These HMBP phosphonate prodrugs, phosphonamidates, exhibited excellent serum stability and potent activation of Vgama9/Vdelta2 T‐cells making them attractive compounds for further development as potential immunotherapeutics.

Aryloxy Triester Phosphonamidates of Phosphoantigens Exhibit Favorable Stability and Potent Activation of Vγ9/Vδ2 T‐Cells

2018 ◽  
Author(s):  
Hachemi Kadri ◽  
Taher E. Taher ◽  
Qin Xu ◽  
Richard T. Bryan ◽  
Benjamin E. Willcox ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Serum Stability ◽  
T Cell Immune Responses ◽  
Further Development

We previously reported the application of the aryloxy triester phosphoramidate prodrug technology to the phosphoantigen (E)-4-hydroxybut-2-enyl phosphate (HMBP). Although these prodrugs exhibited potent activation of Vγ9/Vδ2 T‐cell immune responses, their stability was low due to the rapid cleavage of the -O-P- bond. To address this, we herein report the application of the same prodrug strategy to two HMBP phosphonates, which have stable -CH2-P- or -CF2-P- bonds. These HMBP phosphonate prodrugs, phosphonamidates, exhibited excellent serum stability and potent activation of Vgama9/Vdelta2 T‐cells making them attractive compounds for further development as potential immunotherapeutics.

scholarly journals B and T cell immune responses elicited by the Comirnaty® COVID-19 vaccine in nursing home residents

2021 ◽  
Author(s):  
Ignacio Torres ◽  
Eliseo Albert ◽  
Estela Giménez ◽  
María Jesús Alcaraz ◽  
Pilar Botija ◽  
...  
Keyword(s):  
Nursing Home ◽  
T Cell ◽  
Immune Responses ◽  
Nursing Home Residents ◽  
T Cell Immune Responses
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