Adjuvant-free IgG responses induced with antigen coupled to antibodies against class II MHC

Carayanniotis, George; Barber, Brian H.

doi:10.1038/327059a0

Cited by 117 publications

(80 citation statements)

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“…5 and 6). At different times after immunization, the effectiveness of priming was assessed in two ways (1). Transgenic cells in the inguinal LN (after s.c. injection) or spleen (after i.v.…”

Section: Differential Stimulation Of Cd4 ϩ and Cd8 ϩ T Cells By Targementioning

confidence: 99%

“…One of these is vaccination, the efficiency of which can be enhanced by optimizing Ag delivery to DCs. This can be done by using Abs specific for DC-expressed molecules as in vivo Ag carriers; using such an approach, a lowered requirement for Ag dose in stimulating immune responses in mice has been observed after targeting a variety of molecules, including MHC class II, CD11c, CD205, CD80/86, F4/80-like receptor (FIRE), CIRE, and the undefined Ag recognized by the mAb 33D1 (1)(2)(3)(4)(5)(6)(7)(8)(9). In addition, in vitro studies have shown that Abs specific for the mannose receptor or DC-SIGN can effectively deliver Ag to human DCs, indicating that this strategy will also be applicable to human vaccination (10,11).…”

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confidence: 99%

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Preferential Induction of CD4+ T Cell Responses through In Vivo Targeting of Antigen to Dendritic Cell-Associated C-Type Lectin-1

Carter

Thompson

Reid

et al. 2006

The Journal of Immunology

163

154

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Targeting of Ags and therapeutics to dendritic cells (DCs) has immense potential for immunotherapy and vaccination. Because DCs are heterogeneous, optimal targeting strategies will require knowledge about functional specialization among DC subpopulations and identification of molecules for targeting appropriate DCs. We characterized the expression of a fungal recognition receptor, DC-associated C-type lectin-1 (Dectin-1), on mouse DC subpopulations and investigated the ability of an anti-Dectin-1 Ab to deliver Ag for the stimulation of immune responses. Dectin-1 was shown to be expressed on CD8α−CD4−CD11b+ DCs found in spleen and lymph nodes and dermal DCs present in skin and s.c. lymph nodes. Injection of Ag-anti-Dectin-1 conjugates induced CD4+ and CD8+ T cell and Ab responses at low doses where free Ag failed to elicit a response. Notably, qualitatively different immune responses were generated by targeting Ag to Dectin-1 vs CD205, a molecule expressed on CD8α+CD4−CD11b− DCs, dermal DCs, and Langerhans cells. Unlike anti-Dectin-1, anti-CD205 conjugates failed to elicit an Ab response. Moreover, when conjugates were injected i.v., anti-Dectin-1 stimulated a much stronger CD4+ T cell response and a much weaker CD8+ T cell response than anti-CD205. The results reveal Dectin-1 as a potential targeting molecule for immunization and have implications for the specialization of DC subpopulations.

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Section: Differential Stimulation Of Cd4 ϩ and Cd8 ϩ T Cells By Targementioning

confidence: 99%

mentioning

confidence: 99%

Preferential Induction of CD4+ T Cell Responses through In Vivo Targeting of Antigen to Dendritic Cell-Associated C-Type Lectin-1

Carter

Thompson

Reid

et al. 2006

The Journal of Immunology

163

154

View full text Add to dashboard Cite

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“…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).…”

mentioning

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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“…Thus, sustained Ag presentation, as is the case in the repeated administration of protein therapeutics, may lead to effective T cell activation and differentiation (35). Furthermore, the targeting of specific receptors on APCs even in the absence of proinflammatory signals may generate efficient Ab responses (36).…”

Section: Professional Apcs Are the First Immune-sensitive Depots For mentioning

confidence: 99%

Auditing Protein Therapeutics Management by Professional APCs: Toward Prevention of Immune Responses against Therapeutic Proteins

Dasgupta

Bayry²,

André³

et al. 2008

The Journal of Immunology

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Alloimmunization is a crippling concern in the management of patients undergoing administration of protein therapeutics as evidenced in replacement therapy and other treatment procedures. Several issues in the genesis and modulation of such deleterious immune responses have been studied. While authors have focused on the downstream events of the specific immune response and suggested modification of protein therapeutics to eliminate epitopes that interact with B cell receptors, T cell receptors, or MHCII molecules, the mechanisms underlying Ag interaction with APCs, a step upstream of immune effectors, have been grossly neglected. We wish to emphasize that the recent knowledge in understanding the capacities of an APC to handle an Ag and the importance of the surrounding microenvironment in this process are crucial for designing novel protein therapeutics with reduced immunogenicity.

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Adjuvant-free IgG responses induced with antigen coupled to antibodies against class II MHC

Cited by 117 publications

References 0 publications

Preferential Induction of CD4+ T Cell Responses through In Vivo Targeting of Antigen to Dendritic Cell-Associated C-Type Lectin-1

Preferential Induction of CD4+ T Cell Responses through In Vivo Targeting of Antigen to Dendritic Cell-Associated C-Type Lectin-1

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

Auditing Protein Therapeutics Management by Professional APCs: Toward Prevention of Immune Responses against Therapeutic Proteins

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