Cholera Toxin and Its B Subunit Promote Dendritic Cell Vaccination with Different Influences on Th1 and Th2 Development

ABSTRACT Cholera toxin (CT) is a strong mucosal adjuvant for codelivered antigens, whereas its nontoxic B subunit (CTB) is an efficient mucosal carrier molecule for the generation of immune responses to linked antigens. We investigated the effects of CT and CTB on the immunogenicity of in vitro-treated antigen-pulsed dendritic cells (DC) following intravenous injection into mice. Prior to infusion, DC were pulsed for 90 min with either free ovalbumin (OVA), OVA mixed with CT or CTB, or chemical conjugates of OVA with CT and CTB (OVA-CT and OVA-CTB). DC pulsed with OVA or with OVA and CTB gave rise to modest antibody and T-cell responses. Conjugation of OVA with CTB enhanced both the subsequent B-cell and T-cell responses to OVA and preferentially induced Th2 responses. CT was shown to be a strong adjuvant when it was coadministered to DC with OVA and was even stronger when it was coadministered with OVA-CTB and primed for a mixed Th1-Th2 response. The antibody and T-cell responses were further enhanced if OVA was coupled to CT, implying that CT can utilize a combined carrier and adjuvant function vis-a-vis linked antigens for DC vaccination. The immunopotentiating capacity of CT- and CTB-linked antigen was associated with both upregulated secretion of interleukin-1β by the pulsed DC and increased expression of CD80 and CD86 on the DC surface. These results imply that CT and CTB can be used to both markedly increase and partially direct the DC vaccine-induced immune response with respect to Th1 and Th2 responses, which has obvious implications for DC-based vaccine development.

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Cytotoxic T cell responses are enhanced by antigen design involving the presentation of MUC1 peptide on cholera toxin B subunit

Oncotarget ◽

10.18632/oncotarget.5307 ◽

2015 ◽

Vol 6 (33) ◽

pp. 34537-34548 ◽

Cited By ~ 6

Author(s):

Wuguang Lu ◽

Lingchong Qiu ◽

Zhanpeng Yan ◽

Zhibing Lin ◽

Meng Cao ◽

...

Keyword(s):

T Cell ◽

Cholera Toxin ◽

T Cell Responses ◽

Cytotoxic T Cell ◽

Cholera Toxin B Subunit ◽

Toxin B ◽

Cholera Toxin B ◽

B Subunit ◽

Cell Responses ◽

Cytotoxic T Cell Responses

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T Cell Responses after oral Immunisation of Humans with Cholera Toxin B Subunit

Clinical Science ◽

10.1042/cs084006pc ◽

1993 ◽

Vol 84 (s28) ◽

pp. 6P-7P

Author(s):

LRR Castello-Branco ◽

GE Griffin ◽

TA Poulton ◽

DJM Lewis

Keyword(s):

T Cell ◽

Cholera Toxin ◽

T Cell Responses ◽

Cholera Toxin B Subunit ◽

Toxin B ◽

Cholera Toxin B ◽

B Subunit ◽

Cell Responses ◽

Oral Immunisation

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Regulation of Cytokine Production in T-Cell Responses to Inhalant Allergen:GATA-3 Expression Distinguishesbetween Th1- and Th2-Polarized Immunity

International Archives of Allergy and Immunology ◽

10.1159/000053703 ◽

2001 ◽

Vol 124 (1-3) ◽

pp. 176-179 ◽

Cited By ~ 13

Author(s):

Claudia Macaubas ◽

Patrick G. Holt

Keyword(s):

T Cell ◽

Cytokine Production ◽

T Cell Responses ◽

Cell Responses ◽

Th1 And Th2

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TriMix and tumor antigen mRNA electroporated dendritic cell vaccination plus ipilimumab: link between T-cell activation and clinical responses in advanced melanoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000329 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000329 ◽

Cited By ~ 3

Author(s):

Brenda De Keersmaecker ◽

Sofie Claerhout ◽

Javier Carrasco ◽

Isabelle Bar ◽

Jurgen Corthals ◽

...

Keyword(s):

T Cell ◽

Dendritic Cell ◽

Clinical Response ◽

T Cell Activation ◽

Peripheral Blood ◽

T Cell Responses ◽

Cd8 T Cell ◽

Advanced Melanoma ◽

Dendritic Cell Vaccination ◽

Cell Responses

BackgroundWe previously reported that dendritic cell-based mRNA vaccination plus ipilimumab (TriMixDC-MEL IPI) results in an encouraging rate of tumor responses in patients with pretreated advanced melanoma. Here, we report the TriMixDC-MEL IPI-induced T-cell responses detected in the peripheral blood.MethodsMonocyte-derived dendritic cells electroporated with mRNA encoding CD70, CD40 ligand, and constitutively active TLR4 (TriMix) as well as the tumor-associated antigens tyrosinase, gp100, MAGE-A3, or MAGE-C2 were administered together with IPI for four cycles. For 18/39 patients, an additional vaccine was administered before the first IPI administration. We evaluated tumor-associated antigen specific T-cell responses in previously collected peripheral blood mononuclear cells, available from 15 patients.ResultsVaccine-induced enzyme-linked immunospot assay responses detected after in vitro T-cell stimulation were shown in 12/15 patients. Immune responses detected in patients with a complete or partial response were significantly stronger and broader, and exhibited a higher degree of multifunctionality compared with responses in patients with stable or progressive disease. CD8+ T-cell responses from patients with an ongoing clinical response, either elicited by TriMixDC-MEL IPI or on subsequent pembrolizumab treatment, exhibited the highest degree of multifunctionality.ConclusionsTriMixDC-MEL IPI treatment results in robust CD8+ T-cell responses in a meaningful portion of stage III or IV melanoma patients, and obviously in patients with a clinical response. The levels of polyfunctional and multiantigen T-cell responses measured in patients with a complete response, particularly in patients evidently cured after 5+ years of follow-up, may provide a benchmark for the level of immune stimulation needed to achieve a durable clinical remission.Trial registration numberNCT01302496.

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mRNA-based dendritic cell vaccination induces potent antiviral T-cell responses in HIV-1-infected patients

AIDS ◽

10.1097/qad.0b013e32834f33e8 ◽

2012 ◽

Vol 26 (4) ◽

pp. F1-F12 ◽

Cited By ~ 63

Author(s):

Ellen Van Gulck ◽

Erika Vlieghe ◽

Marc Vekemans ◽

Viggo F.I. Van Tendeloo ◽

Ann Van De Velde ◽

...

Keyword(s):

T Cell ◽

Dendritic Cell ◽

T Cell Responses ◽

Dendritic Cell Vaccination ◽

Cell Responses ◽

Hiv 1

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Lack of T-cell responses following autologous tumour lysate pulsed dendritic cell vaccination, in patients with relapsed osteosarcoma

Clinical & Translational Oncology ◽

10.1007/s12094-012-0795-1 ◽

2012 ◽

Vol 14 (4) ◽

pp. 271-279 ◽

Cited By ~ 35

Author(s):

Nourredine Himoudi ◽

Rebecca Wallace ◽

Kathryn L. Parsley ◽

Kimberly Gilmour ◽

Alpha-Umaru Barrie ◽

...

Keyword(s):

T Cell ◽

Dendritic Cell ◽

T Cell Responses ◽

Dendritic Cell Vaccination ◽

Cell Responses ◽

Autologous Tumour ◽

Tumour Lysate

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Sustained Specific and Cross-Reactive T Cell Responses to Zika and Dengue Virus NS3 in West Africa

Journal of Virology ◽

10.1128/jvi.01992-17 ◽

2018 ◽

Vol 92 (7) ◽

Cited By ~ 16

Author(s):

Bobby Brooke Herrera ◽

Wen-Yang Tsai ◽

Charlotte A. Chang ◽

Donald J. Hamel ◽

Wei-Kung Wang ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Dengue Virus ◽

Zika Virus ◽

Cell Response ◽

Vaccine Development ◽

T Cell Responses ◽

T Cell Response ◽

Zikv Infection ◽

Cell Responses

ABSTRACT Recent studies on the role of T cells in Zika virus (ZIKV) infection have shown that T cell responses to Asian ZIKV infection are important for protection, and that previous dengue virus (DENV) exposure amplifies the protective T cell response to Asian ZIKV. Human T cell responses to African ZIKV infection, however, remain unexplored. Here, we utilized the modified anthrax toxin delivery system to develop a flavivirus enzyme-linked immunosorbent spot (ELISPOT) assay. Using human ZIKV and DENV samples from Senegal, West Africa, our results demonstrate specific and cross-reactive T cell responses to nonstructural protein 3 (NS3). Specifically, we found that T cell responses to NS3 protease are ZIKV and DENV specific, but responses to NS3 helicase are cross-reactive. Sequential sample analyses revealed immune responses sustained many years after infection. These results have important implications for African ZIKV/DENV vaccine development, as well as for potential flavivirus diagnostics based on T cell responses. IMPORTANCE The recent Zika virus (ZIKV) epidemic in Latin America and the associated congenital microcephaly and Guillain-Barré syndrome have raised questions as to why we have not recognized these distinct clinical diseases in Africa. The human immunologic response to ZIKV and related flaviviruses in Africa represents a research gap that may shed light on the mechanisms contributing to protection. The goal of our study was to develop an inexpensive assay to detect and characterize the T cell response to African ZIKV and DENV. Our data show long-term specific and cross-reactive human immune responses against African ZIKV and DENV, suggesting the usefulness of a diagnostic based on the T cell response. Additionally, we show that prior flavivirus exposure influences the magnitude of the T cell response. The identification of immune responses to African ZIKV and DENV is of relevance to vaccine development.

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Abstract B094: Successful identification of neoantigen-specific T-cell responses in low mutation burden colorectal cancers for personalized cancer vaccine development

10.1158/2326-6074.cricimteatiaacr18-b094 ◽

2019 ◽

Author(s):

Jitske van den Bulk ◽

Dina Ruano ◽

Marieke E. Ijsselsteijn ◽

Marten Visser ◽

Ruud van der Breggen ◽

...

Keyword(s):

T Cell ◽

Cancer Vaccine ◽

Vaccine Development ◽

T Cell Responses ◽

Colorectal Cancers ◽

Cell Responses ◽

Mutation Burden ◽

Personalized Cancer

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Immunogenicity and Cross-Reactivity of Rhesus Adenoviral Vectors

Journal of Virology ◽

10.1128/jvi.00159-18 ◽

2018 ◽

Vol 92 (11) ◽

Cited By ~ 2

Author(s):

M. Justin Iampietro ◽

Rafael A. Larocca ◽

Nicholas M. Provine ◽

Peter Abbink ◽

Zi Han Kang ◽

...

Keyword(s):

T Cell ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

T Cell Responses ◽

Adenoviral Vectors ◽

Cross Reactivity ◽

Human Populations ◽

Humoral Immune ◽

Cell Responses ◽

The Impact

ABSTRACT Adenovirus (Ad) vectors are being investigated as vaccine candidates, but baseline antivector immunity exists in human populations to both human Ad (HuAd) and chimpanzee Ad (ChAd) vectors. In this study, we investigated the immunogenicity and cross-reactivity of a panel of recently described rhesus adenoviral (RhAd) vectors. RhAd vectors elicited T cells with low exhaustion markers and robust anamnestic potential. Moreover, RhAd vector immunogenicity was unaffected by high levels of preexisting anti-HuAd immunity. Both HuAd/RhAd and RhAd/RhAd prime-boost vaccine regimens were highly immunogenic, despite a degree of cross-reactive neutralizing antibodies (NAbs) between phylogenetically related RhAd vectors. We observed extensive vector-specific cross-reactive CD4 T cell responses and more limited CD8 T cell responses between RhAd and HuAd vectors, but the impact of vector-specific cellular responses was far less than that of vector-specific NAbs. These data suggest the potential utility of RhAd vectors and define novel heterologous prime-boost strategies for vaccine development. IMPORTANCE To date, most adenoviral vectors developed for vaccination have been HuAds from species B, C, D, and E, and human populations display moderate to high levels of preexisting immunity. There is a clinical need for new adenoviral vectors that are not hindered by preexisting immunity. Moreover, the development of RhAd vector vaccines expands our ability to vaccinate against multiple pathogens in a population that may have received other HuAd or ChAd vectors. We evaluated the immunogenicity and cross-reactivity of RhAd vectors, which belong to the poorly described adenovirus species G. These vectors induced robust cellular and humoral immune responses and were not hampered by preexisting anti-HuAd vector immunity. Such properties make RhAd vectors attractive as potential vaccine vectors.

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