Immunoglobulin as a vehicle for foreign antigenic peptides immunogenic to T cells

Lunde, Elin; Bogen, Bjarne; Sandlie, Inger

doi:10.1016/s0161-5890(97)00143-0

Cited by 29 publications

(40 citation statements)

References 49 publications

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“…In one strategy, T cell epitopes have been added to the C terminus of the Fc-region [23,24]. In another strategy, T cell epitopes have been introduced as loops between g -strands in constant domains of the H chain [25,26]. The latter strategy has the advantage that it maintains Ig structure and in vivo stability (K. W. Schjetne, unpublished).…”

Section: Discussionmentioning

confidence: 99%

Antibody‐mediated delivery of antigen to chemokine receptors on antigen‐presenting cells results in enhanced CD4⁺ T cell responses

et al. 2003

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Here, we have investigated if targeting of T cell epitopes to chemokine receptors results in improved CD4 + T cell responses. Mouse monoclonal antibodies (mAb) with ‹ L chains were targeted to various chemokine receptors expressed on human monocytes or immature dendritic cells (DC), and proliferation of cloned human, DR4-restricted CD4 + T cells specific for mouse C ‹ 40-48 was measured. When using monocytes as antigen-presenting cells, mAb specific for CCR1, CCR2, CCR5, and CXCR4 were 100-10,000-fold more efficient at inducing T cell proliferation when compared to isotype-matched control mAb on a per molecule basis. Targeting of immature DC was less effective and was only seen with anti-CCR1 and anti-CXCR4 mAb. Anti-chemokine receptors mAb required to be processed by the conventional endosomal MHC class II presentation pathway. The mAb did not induce signaling through the chemokine receptors as they failed to induce mobilization of cytosolic Ca 2+ and actin polymerization. They also failed to induce APC maturation. The results strongly suggest that chemokine receptors channel antigen into the endocytic pathway for presentation on MHC class II molecules. Targeting T cell epitopes to chemokine receptors by recombinant antibody should be a useful vaccine strategy for the induction of strong CD4 + T cell responses.

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Section: Discussionmentioning

confidence: 99%

Antibody‐mediated delivery of antigen to chemokine receptors on antigen‐presenting cells results in enhanced CD4⁺ T cell responses

et al. 2003

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“…The different T cell epitopes were introduced into the C H 1 domain of a human IgG3 H chain by site-specific in vitro mutagenesis, as previously described (23,24). The epitopes were introduced into the loop of C H 1 that corresponds to the CDR3 loop of V domains.…”

Section: Construction Of Mhc Class Ii-specific Troybodiesmentioning

confidence: 99%

“…Each T cell epitope was added by replacing the 12 nt encoding the 4-aa-long loop with nucleotides encoding the epitope. Initially, four different 5 iodo-4 hydroxy-3 nitrophenacetyl (NIP)-specific Ab were made (Table I): L6-2 315 contain the 91-101 epitope from the 2 315 Ig L chain (23), whereas the L6-HA, L6-HEL, and L6-OVA Ab contain the 110-120 HA (25), the 46-61 HEL (26), and the 323-339 OVA (27) T cell epitopes, respectively (24). These nontargeting Ab with peptide are denoted peptide Ab.…”

Section: Construction Of Mhc Class Ii-specific Troybodiesmentioning

confidence: 99%

“…The resulting pLNOH2 and pLNO vectors were transfected into NS0 cells by electroporation, and transfectants were selected and cloned in medium containing 800 g/ml G418. Ab were affinity purified from cell supernatant by use of protein L (Affitech, Oslo, Norway)-or protein G-Sepharose columns, and Ab concentrations quantified by an ELISA specific for human IgG3 (23). The recombinant E ␣ -specific Ab are denoted: ␣E ␣ .L6-2 315 , ␣E ␣ .L6-HA, ␣E ␣ .L6-HEL, and ␣E ␣ .L6-OVA (Table I).…”

Section: Construction Of Mhc Class Ii-specific Troybodiesmentioning

confidence: 99%

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Efficient Delivery of T Cell Epitopes to APC by Use of MHC Class II-Specific Troybodies

Lunde

Western

Rasmussen

et al. 2002

The Journal of Immunology

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A major objective in vaccine development is the design of reagents that give strong, specific T cell responses. We have constructed a series of rAb with specificity for MHC class II (I-E). Each has one of four different class II-restricted T cell epitopes genetically introduced into the first C domain of the H chain. These four epitopes are: 91–101 λ2315, which is presented by I-Ed; 110–120 hemagglutinin (I-Ed); 323–339 OVA (I-Ad); and 46–61 hen egg lysozyme (I-Ak). We denote such APC-specific, epitope-containing Ab “Troybodies.” When mixed with APC, all four class II-specific Troybodies were ∼1,000 times more efficient at inducing specific T cell activation in vitro compared with nontargeting peptide Ab. Furthermore, they were 1,000–10,000 times more efficient than synthetic peptide or native protein. Conventional intracellular processing of the Troybodies was required to load the epitopes onto MHC class II. Different types of professional APC, such as purified B cells, dendritic cells, and macrophages, were equally efficient at processing and presenting the Troybodies. In vivo, class II-specific Troybodies were at least 100 times more efficient at targeting APC and activating TCR-transgenic T cells than were the nontargeting peptide Ab. Furthermore, they were 100–100,000 times more efficient than synthetic peptide or native protein. The study shows that class II-specific Troybodies can deliver a variety of T cell epitopes to professional APC for efficient presentation, in vitro as well as in vivo. Thus, Troybodies may be useful as tools in vaccine development.

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“…In the original molecule, this epitope encompasses the V region CDR3 loop. Such Ab-peptide chimeras stimulate specific CD4 ϩ T cells both in vitro and in vivo (22,23). Targeting of these Abs to B cells increases antigen presentation efficiency in vitro as well as in vivo (23).…”

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The principle of delivery of T cell epitopes to antigen-presenting cells applied to peptides from influenza virus, ovalbumin, and hen egg lysozyme: Implications for peptide vaccination

Rasmussen

Lunde

Michaelsen

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Targeting of antigens to antigen-presenting cells (APCs) increases CD4 ؉ T cell activation, and this observation can be exploited in the development of new vaccines. We have chosen an antigen-targeting approach in which we make recombinant antibodies (Abs) with T cell epitopes in their constant region and APC-specific variable regions. Three commonly used model epitopes, amino acids 110 -120 of hemagglutinin, 323-339 of ovalbumin, and 46 -61 of hen egg lysozyme, were introduced as loops in the C H1 domain of human IgG3. For all three epitopes, we show that the recombinant molecules are secreted from transfected cells. The epitopes are presented to specific T cells, and targeting to IgD on B cells in vitro enhances the presentation efficiency by 10 4 to 10 5 compared with the free peptide. After i.v. injection, the epitopes targeted to IgD are presented by splenic APCs to activate specific T cells, whereas little or no activation could be detected without targeting, even after the amount of antigen injected was increased 100-fold or more. Because a wide variety of T cell epitopes, in terms of both length and secondary structure, can be tolerated in loops in constant domains of Abs, the Ab constant region seems to have the intrinsic stability that is needed for this fusion molecule strategy. It might thus be possible to load the Ab with several different epitopes in loops in different domains and thereby make a targeted multisubunit vaccine.O ver recent years, considerable efforts have been directed toward the development of efficient vaccines aimed to stimulate T cells. Effector CD4 ϩ T cells are central in this regard because they regulate B cells and are essential for induction of CD8 ϩ CTL responses through both cytokine secretion (1) and dendritic cell sensitization (2). CD4 ϩ T cells mainly recognize peptides derived from the processing of extracellular antigens by antigen-presenting cells (APCs), presented in association with MHC class II molecules. Targeting of antigen to APCs by coupling to APC-specific Abs increases CD4 ϩ T cell activation, probably because of increased uptake of antigen (3, 4).Several new prospects for preparation of T cell vaccines have been suggested based on the identification and characterization of MHC-associated peptides. Synthetic peptides that correspond to these T cell epitopes may represent ideal subunits for safe vaccines. However, synthetic peptides are poor immunogens because of their small molecular size and very short serum half-life. To circumvent these disadvantages, a variety of recombinant proteins that carry short immunogenic epitopes have been described, and these so-called antigenized molecules represent a new generation of subunit vaccines (5-9). Genetically engineered Ab molecules can function as such delivery systems for T cell peptides (10, 11) and have the advantage of being self-proteins devoid of the side effects sometimes associated with microbial vaccines and, moreover, have a long half-life compared with synthetic peptides.Abs are processed by APCs, and s...

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Immunoglobulin as a vehicle for foreign antigenic peptides immunogenic to T cells

Cited by 29 publications

References 49 publications

Antibody‐mediated delivery of antigen to chemokine receptors on antigen‐presenting cells results in enhanced CD4⁺ T cell responses

Antibody‐mediated delivery of antigen to chemokine receptors on antigen‐presenting cells results in enhanced CD4⁺ T cell responses

Efficient Delivery of T Cell Epitopes to APC by Use of MHC Class II-Specific Troybodies

The principle of delivery of T cell epitopes to antigen-presenting cells applied to peptides from influenza virus, ovalbumin, and hen egg lysozyme: Implications for peptide vaccination

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Immunoglobulin as a vehicle for foreign antigenic peptides immunogenic to T cells

Cited by 29 publications

References 49 publications

Antibody‐mediated delivery of antigen to chemokine receptors on antigen‐presenting cells results in enhanced CD4+ T cell responses

Antibody‐mediated delivery of antigen to chemokine receptors on antigen‐presenting cells results in enhanced CD4+ T cell responses

Efficient Delivery of T Cell Epitopes to APC by Use of MHC Class II-Specific Troybodies

The principle of delivery of T cell epitopes to antigen-presenting cells applied to peptides from influenza virus, ovalbumin, and hen egg lysozyme: Implications for peptide vaccination

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Antibody‐mediated delivery of antigen to chemokine receptors on antigen‐presenting cells results in enhanced CD4⁺ T cell responses

Antibody‐mediated delivery of antigen to chemokine receptors on antigen‐presenting cells results in enhanced CD4⁺ T cell responses