A genetically engineered non-toxic vaccine adjuvant that combines B cell targeting with immunomodulation by cholera toxin A1 subunit

Ågren, Lena; Ekman, L.; Löwenadler, Björn; Lycke, Nils

doi:10.1016/s0165-2478(97)88001-7

Cited by 74 publications

(100 citation statements)

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“…In parallel, we investigated if CT as adjuvant can be replaced by the nontoxic CT derivative CTA1-D2D1 that was generated analogously to the previously published CTA1-DD. 45 The basic difference between CTA1-DD and CTA1-D2D1 consists in the spacing of the 2 D domains. In CTA1-DD, there is a 2-amino acid insertion (PE) which is lacking in both the individual Ig binding domains of CTA1-D2D1 and the native protein A of S. aureus.…”

Section: Resultsmentioning

confidence: 99%

“…This fusion peptide (OVA 257-280 , SIINFEKLTEWTSSNVMEERKIKV) mimics the naturally occurring adjacent sequence order of the CTL and Th epitope (H-2K b MHC class I epitope, 257 SIINFEKL 264 ; I-A b MHC class II epitope, 265 TEWTSSNVMEERKIKV 280 38 ). The E7 multiepitope peptide (E7 [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] , QAEPDRAHYNIVTFCCKCD) comprises 3 different epitopes in an overlapping form: the H-2D b MHC class I epitope 49 RAHYNIVTF 57 , the I-A and I-E MHC class II epitope 48 DRA-HYNIVTF 57 and the linear panspecific B-cell epitope 44 QAEPD 48 . 39 Alternatively, mice were immunized with an E7 single epitope peptide (E7 [49][50][51][52][53][54][55][56][57] ) encompassing only the E7 CTL sequence ( 49 RAHYNIVTF 57 ).…”

Section: Peptides Proteins and Adjuvantsmentioning

confidence: 99%

“…The vaccine (35 ll) was applied onto the bare skin and left for 30 min before removing with tap water. Mice were transcutaneously immunized either with peptides (OVA 257-280 and E7 [49][50][51][52][53][54][55][56][57] , 100 lg/mouse; E7 [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] , 200 lg/mouse) or with proteins (OVA and E7, 100 lg/mouse) dissolved in PBS/DMSO with or without CT (in PBS, 50 lg/mouse) and CpG (in HPLC-purified water, 100 lg/mouse) as adjuvants. For s.c. immunization, peptides were dissolved in PBS, mixed 1:1 with TM according to the manufacturer's recommendation and applied into the tail base.…”

Section: Immunizationsmentioning

confidence: 99%

“…Mice were immunized transcutaneously 3 times in biweekly intervals either with 200 lg E7 [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] peptide and CT/CpG or with CT/CpG alone or were left untreated. Nine days after the last boost, mice were challenged s.c. into the right flank with 5 3 10 5 C3 cells in 100 ll PBS under isoflurane anesthesia.…”

Section: Tumor Protectionmentioning

confidence: 99%

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Transcutaneous immunization in mice: Induction of T-helper and cytotoxic T lymphocyte responses and protection against human papillomavirus-induced tumors

2006

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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 applied ovalbumin protein or an ovalbuminderived fusion peptide containing a CTL and Th epitope together with a combination of cholera toxin (CT) and CpG oligodeoxynucleotide (CpG) onto cold wax-depilated and hydrated bare skin. TCI with the ovalbumin fusion peptide induced more robust CTL and Th responses than that with ovalbumin protein. The fusion peptide in combination with the nontoxic CT derivative CTA1-D2D1 and CpG induced an antigen-specific CTL response, albeit less efficiently than in combination with complete CT. Further, we compared the potency of HPV-16 E7 oncoprotein-derived peptides containing single (CTL) or multiple (CTL 1 Th 1 B cell) epitopes to induce effective CTL responses. Strong E7-specific CTL responses were detected only after TCI with the E7 multiepitope peptide. This peptide was also shown to protect mice against tumor growth after challenge with HPV-16 E7-positive tumor cells. TCI with E7 protein and CT/CpG led to formation of an E7-specific humoral immune response. ' 2005 Wiley-Liss, Inc.Key words: transcutaneous immunization; human papillomavirus type 16 E7 (HPV-16 E7); CTA1-D2D1; cytotoxic T lymphocyte; T helper cell; ovalbumin; tumor protection TCI is a novel strategy in modern vaccinology. By this application, blood-borne transmission of diseases through the reuse of needles, which is a common practice in remote parts of the world, can be circumvented and better compliance of vaccinees obtained. Apart from its benefits toward vaccine safety, TCI targets LCs, a dense population of highly accessible APCs within the skin. 1 An important feature of vaccination against viral infections and virus-based tumors is the induction of CTLs. 2-4 Upon activation by APCs, predominantly DCs, CTLs are able to selectively kill antigen-expressing cells. 5 For clearance of certain viral infections, the aid of Th cells for CTL activation is necessary. 6 The bias to one of the 2 Th subsets (Th1 > Th2) is a prerequisite for specific CTL induction. 7 Generation of specific CTLs against proteinaceous or peptidebased vaccines in combination with adjuvants after TS of the skin is possible. 8-10 TS leads to removal of the outermost horny layer of the skin, resulting in enhanced permeability and maturation and activation of LCs via inflammatory cytokines secreted from keratinocytes. 11,12 The barrier function of the SC can also be bypassed by hydration of the skin, which leads to swelling of the keratinocytes and pooling of fluid into intercellular spaces. This kind of pretreatment of the skin leads to ...

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Section: Resultsmentioning

confidence: 99%

Section: Peptides Proteins and Adjuvantsmentioning

confidence: 99%

Section: Immunizationsmentioning

confidence: 99%

Section: Tumor Protectionmentioning

confidence: 99%

See 2 more Smart Citations

Transcutaneous immunization in mice: Induction of T-helper and cytotoxic T lymphocyte responses and protection against human papillomavirus-induced tumors

2006

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“…CT, the other adjuvant used, is a potent mucosal as well as a systemic adjuvant, with effects on T cells, B cells and antigen-presenting cells. CT has been found to strongly enhance antigen presentation by induction of interleukin-1 production by macrophages [13]; it also promotes the upregulation of the expression of the costimulatory molecules CD80 and CD86 on naïve B cells, which is important for T-and B-cell collaboration [32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Breaking the Non‐Responsiveness of C57BL/6 Mice to the Malarial Antigen EB200 – The Role of Carrier and Adjuvant Molecules

et al. 2003

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Poor immunogenicity and major histocompatibility complex (MHC) restriction of immune responses to certain recombinant proteins or synthetic peptides impose problems in developing effective vaccines. EB200 is one of the vaccine candidate antigens from Plasmodium falciparum, which induces MHC-restricted immune responses in mice of different haplotypes. A way of overcoming this problem is to conjugate the antigen to an immunogenic protein carrier and to use optimal adjuvant substances. We have investigated the carrier effect of glutathione-S-transferase (GST) in CBA and C57BL/6 mice which are high and low responder to EB200, respectively. Our results reveal that the MHC restriction in C57BL/6 mice was broken by the use of GST as a carrier. Studies on the B-cell repertoires in both strains of mice immunized with GST-EB200 by preparing hybridoma cell lines indicate that the B-cell repertoires were similar in both CBA and C57BL/6 mice. However, the antibody affinity and the magnitude of the response were still lower in the low-responder C57BL/6 mice compared with that in CBA even when cholera toxin (CT) was used as adjuvant. To improve the response, the efficacy of various adjuvant substances like alum and Hsp 70 from Trypanosoma cruzi and the combination of various adjuvants was analysed. CT and Hsp 70 together act synergistically and markedly improve the immunogenicity of EB200 by increasing antibody affinity and the magnitude of the responses in C57BL/6 mice, which may be explained by the complementary effect of adjuvants. These results are of importance in the design of efficient vaccines.

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Cholera toxin induces maturation of human dendritic cells and licences them for Th2 priming

Sallusto²,

et al. 2000

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Cholera toxin (CT) is a potent mucosal adjuvant that amplifies B and T cell responses to mucosally co‐administered antigens, stimulating predominant Th2‐type responses. However, little is known about the mechanism of adjuvanticity of CT and on the influence this toxin may have on Th2 cell development during the priming of an immune response. We analyzed the effect of CT on dendritic cells (DC), which are responsible for the priming of immune responses at the systemic as well as at the mucosal level. We found that CT induces phenotypic and functional maturation of blood monocyte‐derived DC. Indeed, CT‐treated DC up‐regulate expression of HLA‐DR molecules, B7.1 and B7.2 co‐stimulatory molecules, and are able to prime naive CD4+CD45RA+ T cells in vitro, driving their polarization towards the Th2 phenotype. Furthermore, CT‐matured DC express functional chemokine receptors CCR7 and CXCR4 which may render them responsive to migratory stimuli towards secondary lymphoid organs. Interestingly, the maturation program induced by CT is unique since CT does not induce but rather inhibits cytokine (IL‐12p70 and TNF‐α) and chemokine (RANTES, MIP‐1α and MIP‐1β) secretion by lipopolysaccharide‐ or CD40 ligand‐activated DC. Our results help to elucidate the mechanism of action of CT as an adjuvant and highlight a new stimulus of bacterial origin that promotes maturation of DC.

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A genetically engineered non-toxic vaccine adjuvant that combines B cell targeting with immunomodulation by cholera toxin A1 subunit

Cited by 74 publications

References 0 publications

Transcutaneous immunization in mice: Induction of T-helper and cytotoxic T lymphocyte responses and protection against human papillomavirus-induced tumors

Transcutaneous immunization in mice: Induction of T-helper and cytotoxic T lymphocyte responses and protection against human papillomavirus-induced tumors

Breaking the Non‐Responsiveness of C57BL/6 Mice to the Malarial Antigen EB200 – The Role of Carrier and Adjuvant Molecules

Cholera toxin induces maturation of human dendritic cells and licences them for Th2 priming

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