Transcutaneous immunization in mice: Induction of T-helper and cytotoxic T lymphocyte responses and protection against human papillomavirus-induced tumors
Abstract:Previous reports have shown that transcutaneous immunization (TCI) with proteins or peptides in combination with adjuvants efficiently induces specific cellular and humoral immune responses. However, depending on the kind of skin pretreatment, induction of cellular immune responses was restricted to generation of either specific cytotoxic T lymphocytes (CTLs) or T-helper (Th) cells. In this study, we induced antigen-specific CTL responses together with the appropriate Th responses by TCI of C57BL/6 mice. We ap… Show more
“…Furthermore, the BCR can recognize epitopes within larger structures such as virus particles, and the spectrum of Ags recognized is not limited to peptide Ags but also includes carbohydrate, phospholipid, and nucleic acid Ags (3,4). Not surprisingly in this context, the presence of MHC-independent epitopes in addition to MHC-restricted epitopes could significantly enhance cellular immune responses in a recently described mouse model of human papillomavirus-induced tumors (25). With the intent to combine the advantages of both TCR and BCR, another group designed genetically engineered T cells with chimeric receptors.…”
Human B cells are currently not known to produce the proapoptotic protease granzyme B (GrB) in physiological settings. We have discovered that BCR stimulation with either viral Ags or activating Abs in the context of the acute phase cytokine IL-21 can induce the secretion of substantial amounts of GrB by human B cells. Importantly, GrB response to viral Ags was significantly stronger in B cells from subjects recently vaccinated against the corresponding viruses as compared with unvaccinated subjects. GrB-secreting B cells featured a homogeneous CD19+CD20+CD27−CD38−IgD− phenotype, improved survival, and enhanced expression of costimulatory, Ag-presenting and cell-adhesion molecules. B cell-derived GrB was enzymatically active and its induction required the activation of similar signaling pathways as those in CTLs. Our findings suggest that GrB-secreting B cells support the early antiviral immune response against viruses with endosomal entry pathways, thereby counteracting overwhelming viral replication at the beginning of an infection until virus-specific T cells from draining lymph nodes arrive at the site of infection. Our data may also explain the elevated serum GrB levels found in the early phase of various viral diseases.
“…Furthermore, the BCR can recognize epitopes within larger structures such as virus particles, and the spectrum of Ags recognized is not limited to peptide Ags but also includes carbohydrate, phospholipid, and nucleic acid Ags (3,4). Not surprisingly in this context, the presence of MHC-independent epitopes in addition to MHC-restricted epitopes could significantly enhance cellular immune responses in a recently described mouse model of human papillomavirus-induced tumors (25). With the intent to combine the advantages of both TCR and BCR, another group designed genetically engineered T cells with chimeric receptors.…”
Human B cells are currently not known to produce the proapoptotic protease granzyme B (GrB) in physiological settings. We have discovered that BCR stimulation with either viral Ags or activating Abs in the context of the acute phase cytokine IL-21 can induce the secretion of substantial amounts of GrB by human B cells. Importantly, GrB response to viral Ags was significantly stronger in B cells from subjects recently vaccinated against the corresponding viruses as compared with unvaccinated subjects. GrB-secreting B cells featured a homogeneous CD19+CD20+CD27−CD38−IgD− phenotype, improved survival, and enhanced expression of costimulatory, Ag-presenting and cell-adhesion molecules. B cell-derived GrB was enzymatically active and its induction required the activation of similar signaling pathways as those in CTLs. Our findings suggest that GrB-secreting B cells support the early antiviral immune response against viruses with endosomal entry pathways, thereby counteracting overwhelming viral replication at the beginning of an infection until virus-specific T cells from draining lymph nodes arrive at the site of infection. Our data may also explain the elevated serum GrB levels found in the early phase of various viral diseases.
“…The bacterial products CT and LT [31], which are able to serve remarkably as antigen and adjuvant, have been used predominantly to evoke humoral and/or cellular immunity. Other studies take advantage of the well-described model antigen Ovalbumin [9][10][11]. However, as discussed above, approaches involving such large molecules require an 'adequate' pre-treatment of the skin, in order to allow the passage through the skin barrier.…”
Section: Antigenic Componentmentioning
confidence: 98%
“…The majority of established TCI protocols use large immunogenic molecules like CT (86 kDa) or LT (84 kDa) as adjuvants and/or antigen [8] in combination with whole protein antigens like bovine serum albumin [8][9][10][11], diphteria toxoid (DT) [12], tetanus toxoid (TT) [12,13] among others. Therefore, they rely on an initial step of skin barrier disruption, generally either by tape-stripping [14,15], degreasing with acetone [9,10] or hydration [8,16].…”
“…Interestingly, TCI induces both systemic and mucosal immune responses (6,22,23,28,41,42,48). TCI has been shown to be safe and effective in animals and humans (9,21,23,42,47,58). In order to assess whether TCI would induce immune responses against C. difficile toxin A, we therefore transcutaneously immunized mice with a toxoid derivative of C. difficile toxin A (CDA), with or without the immunoadjuvant CT, and measured systemic and mucosal anti-CDA immune responses, including induction of toxin Aneutralizing antibodies in immunized mice.…”
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