Processing of lysozyme by macrophages: identification of the determinant recognized by two T-cell hybridomas.

Allen, Paul M.; Strydom, Daniël J.; Unanue, Emil R.

doi:10.1073/pnas.81.8.2489

Cited by 164 publications

(87 citation statements)

References 25 publications

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“…The immunogenic peptide from OVA, amino acids 323-339, has been shown to be immunodominant in H-2 d mice and is presented by I-A d (29,35). The immunodominant epitope from HEL, amino acids 46-61, encompasses the minimal epitope 52-61, which is presented by I-A k molecules (36,37).…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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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“…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%

“…To this end, Troybodies were constructed that have V regions specific for class II molecules, and various model T cell epitopes in the constant part. As model T cell epitopes, the following were used: aa residues 91-101 from the mouse 2 315 Ig L chain (33), 323-339 OVA (27), 110 -120 HA (25), and 46 -61 HEL (26). The 2 315 epitope is presented on I-E d class II molecules to CD4 ϩ T cells (6,33), as is the HA epitope (36).…”

Section: Construction Of Mhc Class Ii-specific Troybodies With T Cellmentioning

confidence: 99%

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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“…By examining the presentation of synthetic peptides in this manner, it has been possible to define the immunogenic epitopes within the peptide sequence of many antigens recognized by T cells. For example, the T-cell response to the antigen hen egg lysozyme (HEL) in CBA/J (H-2k) mice is mostly directed to the peptide sequence HEL(52-61), with a lesser response to other epitopes, including HEL(34-45) (Allen et aL., 1984(Allen et aL., , 1987aAdorini et al, 1988). The following general conclusions can be drawn from these studies.…”

Section: Mhc-1 Function and Cd8+ T Lymphocytesmentioning

confidence: 74%

Cellular mechanisms of antigen processing and the function of class I and II major histocompatibility complex molecules.

Harding

Unanue

1990

Cell Regul

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Processing of lysozyme by macrophages: identification of the determinant recognized by two T-cell hybridomas.

Cited by 164 publications

References 25 publications

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

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

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

Cellular mechanisms of antigen processing and the function of class I and II major histocompatibility complex molecules.

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