Topical/Mucosal Delivery of Sub-Unit Vaccines That Stimulate the Ocular Mucosal Immune System

Nesburn, Anthony B.; Bettahi, Ilham; Zhang, Xiuli; Zhu, Xiaoming; Chamberlain, Winston; Afifi, Rasha E.; Wechsler, Steven L.; BenMohamed, Lbachir

doi:10.1016/s1542-0124(12)70164-7

Cited by 38 publications

(106 citation statements)

References 73 publications

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“…Both MHC II molecules were significantly upregulated on NK cells, and HLA-DR expression was upregulated to the greatest extent on the CD56 bright CD16 2 NK cell subset (data not shown). Expression of MHC II molecules on human NK cells as mRNA and protein was reported (67,68) but not previously shown to be upregulated by lipopeptide or a viral pathogen, although similar lipopeptides induce maturation and upregulate MHC II on DCs (71).…”

Section: Discussionmentioning

confidence: 92%

Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

Kim

Osborne

Zeng

et al. 2012

The Journal of Immunology

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NK cells infiltrate human herpetic lesions, but their role has been underexplored. HSV can stimulate innate immune responses via surface TLR2, which is expressed on monocyte-derived dendritic cells (DCs) and NK cells. In this study, UV-inactivated HSV1/2 and immunodominant HSV2 glycoprotein D peptides conjugated to the TLR2 agonist dipalmitoyl-S-glyceryl cysteine stimulated CD4 T lymphocyte IFN-γ responses within PBMCs or in coculture with monocyte-derived DCs. NK cells contributed markedly to the PBMC responses. Furthermore, NK cells alone were activated directly by both Ags, also upregulating HLA-DR and HLA-DQ and then they activated autologous CD4 T lymphocytes. Using Transwells, Ag-stimulated NK cells and CD4 T lymphocytes were shown to interact through both cell-to-cell contact and cytokines, differing in relative importance in different donors. A distinct immunological synapse between Ag-stimulated NK cells and CD4 T lymphocytes was observed, indicating the significance of their cell-to-cell contact. A large proportion (57%) of NK cells was also in contact with CD4 T lymphocytes in the dermal infiltrate of human recurrent herpetic lesions. Thus, NK cells stimulated by TLR2-activating HSV Ags can present Ag alone or augment the role of DCs in vitro and perhaps in herpetic lesions or draining lymph nodes. In addition to DCs, NK cells should be considered as targets for adjuvants during HSV vaccine development.

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Section: Discussionmentioning

confidence: 92%

Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

Kim

Osborne

Zeng

et al. 2012

The Journal of Immunology

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“…Recurrent ocular herpes disease (primarily HSV-1) causes herpetic stromal keratitis, an immunoinflammatory and immunopathological lesion of the cornea that can lead to blindness (1,2,7,8). More than 80% of adults shed reactivated HSV in their tears many times per year, and Ͼ450,000 people in the U.S. have a history of recurrent ocular herpes disease (1,9).…”

mentioning

confidence: 99%

“…More than 80% of adults shed reactivated HSV in their tears many times per year, and Ͼ450,000 people in the U.S. have a history of recurrent ocular herpes disease (1,9). Recurrent genital herpes disease (primarily HSV-2), termed herpes genitalis, also has an immunoinflammatory and immunopathological course that leads to the development of genital lesions, ulcerations, and scarring (7,8). Genital herpes affects up to 33% of adults in the United States and the European Union (1,7,10).…”

mentioning

confidence: 99%

“…Despite the availability of many interventional strategies such as sexual behavior education, barrier methods, and costly guanine nucleoside antiviral drug therapies (e.g., Acyclovir and derivatives), controlling the spread of ocular and genital herpesvirus remains a challenge as clinical manifestation rates have continued to rise over the last decade (8,9,13). An effective immunoprophylactic and/or immunotherapeutic vaccine would be the most costeffective approach that could be helpful not only in developed nations but also in underdeveloped regions such as some sub-Saharan African areas, where 70% of high-risk, HIV-negative individuals and 85% of HIV-infected individuals are seropositive for herpes (12,14,15).…”

mentioning

confidence: 99%

“…Among some 11 herpes glycoproteins (2,7,8), the glycoprotein D (gD) 4 has been successful in eliciting T cell-mediated immunity in mouse, rabbit, and guinea pig herpes models when delivered emulsified in experimental Freud's or derivative adjuvants (8,16). However, in the two most recent phase II/III clinical trials, the delivery of gD with the clinical adjuvants MF59 and alum-monophosphoryl lipid A only induced moderate and transient protection or only protected previously uninfected women while failing to protect men or HSV-1-seropositive women (4,10,17,18).…”

mentioning

confidence: 99%

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HLA-A*0201-Restricted CD8+ Cytotoxic T Lymphocyte Epitopes Identified from Herpes Simplex Virus Glycoprotein D

Chentoufi

Zhang

Lamberth³

et al. 2008

The Journal of Immunology

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140

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Evidence obtained from both animal models and humans suggests that T cells specific for HSV-1 and HSV-2 glycoprotein D (gD) contribute to protective immunity against herpes infection. However, knowledge of gD-specific human T cell responses is limited to CD4+ T cell epitopes, with no CD8+ T cell epitopes identified to date. In this study, we screened the HSV-1 gD amino acid sequence for HLA-A*0201-restricted epitopes using several predictive computational algorithms and identified 10 high probability CD8+ T cell epitopes. Synthetic peptides corresponding to four of these epitopes, each nine to 10 amino acids in length, exhibited high-affinity binding in vitro to purified human HLA-A*0201 molecules. Three of these four peptide epitopes, gD53–61, gD70–78, and gD278–286, significantly stabilized HLA-A*0201 molecules on T2 cell lines and are highly conserved among and between HSV-1 and HSV-2 strains. Consistent with this, in 33 sequentially studied HLA-A*0201-positive, HSV-1-seropositive, and/or HSV-2-seropositive healthy individuals, the most frequent and robust CD8+ T cell responses, assessed by IFN-γ ELISPOT, CD107a/b cytotoxic degranulation, and tetramer assays, were directed mainly against gD53–61, gD70–78, and gD278–286 epitopes. In addition, CD8+ T cell lines generated by gD53–61, gD70–78, and gD278–286 peptides recognized infected target cells expressing native gD. Lastly, CD8+ T cell responses specific to gD53–61, gD70–78, and gD278–286 epitopes were induced in HLA-A*0201 transgenic mice following ocular or genital infection with either HSV-1 or HSV-2. The functional gD CD8+ T cell epitopes described herein are potentially important components of clinical immunotherapeutic and immunoprophylactic herpes vaccines.

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Antitumor activity of a self-adjuvanting glyco-lipopeptide vaccine bearing B cell, CD4+ and CD8+ T cell epitopes

Bettahi

Dasgupta

Renaudet

et al. 2008

Cancer Immunol Immunother

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Molecularly defined synthetic vaccines capable of inducing both antibodies and cellular anti-tumor immune responses, in a manner compatible with human delivery, are limited. Few molecules achieve this target without utilizing external immuno-adjuvants. In this study, we explored a self-adjuvanting glyco-lipopeptide (GLP) as a platform for cancer vaccines using as a model MO5, an OVA-expressing mouse B16 melanoma. A prototype B and T cell epitope-based GLP molecule was constructed by synthesizing a chimeric peptide made of a CD8(+) T cell epitope, from ovalbumin (OVA(257-264)) and an universal CD4(+) T helper (Th) epitope (PADRE). The resulting CTL-Th peptide backbones was coupled to a carbohydrate B cell epitope based on a regioselectively addressable functionalized templates (RAFT), made of four alpha-GalNAc molecules at C-terminal. The N terminus of the resulting glycopeptides (GP) was then linked to a palmitic acid moiety (PAM), obviating the need for potentially toxic external immuno-adjuvants. The final prototype OVA-GLP molecule, delivered in adjuvant-free PBS, in mice induced: (1) robust RAFT-specific IgG/IgM that recognized tumor cell lines; (2) local and systemic OVA(257-264)-specific IFN-gamma producing CD8(+) T cells; (3) PADRE-specific CD4(+) T cells; (4) OVA-GLP vaccination elicited a reduction of tumor size in mice inoculated with syngeneic murine MO5 carcinoma cells and a protection from lethal carcinoma cell challenge; (5) finally, OVA-GLP immunization significantly inhibited the growth of pre-established MO5 tumors. Our results suggest self-adjuvanting glyco-lipopeptide molecules as a platform for B Cell, CD4(+), and CD8(+) T cell epitopes-based immunotherapeutic cancer vaccines.

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Topical/Mucosal Delivery of Sub-Unit Vaccines That Stimulate the Ocular Mucosal Immune System

Cited by 38 publications

References 73 publications

Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

HLA-A*0201-Restricted CD8+ Cytotoxic T Lymphocyte Epitopes Identified from Herpes Simplex Virus Glycoprotein D

Antitumor activity of a self-adjuvanting glyco-lipopeptide vaccine bearing B cell, CD4+ and CD8+ T cell epitopes

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