Universal Epitopes for Human CD4<sup>+</sup>Cells on Tetanus and Diphtheria Toxins

Diethelm‐Okita, Brenda; Okita, David K.; Banaszak, Leonard J.; Conti‐Fine, Bianca M.

doi:10.1086/315324

Cited by 84 publications

(82 citation statements)

References 32 publications

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“…Analogous observations have been made in other human systems, including responses to the RhD protein [25][26][27] and for exogenous antigens such as tetanus and diphtheria toxoid-based vaccines, where commonly targeted regions of antigens have been termed universal epitopes. 28 Accessibility of particular regions of the antigen during processing has been suggested as a structural …”

Section: Discussionmentioning

confidence: 99%

Healthy Individuals Have Goodpasture Autoantigen-Reactive T Cells

Zou

Hannier

Cairns

et al. 2008

Journal of the American Society of Nephrology

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Autoreactive T cells in patients with Goodpasture's disease are specific for epitopes in the Goodpasture antigen (the NC1 domain of the ␣3 chain of type IV collagen) that are rapidly destroyed during antigen processing to a degree that diminishes their presentation to T cells. We hypothesized that patients' autoreactive T cells exist because antigen processing prevents presentation of the self-epitopes they recognize, circumventing specific tolerance mechanisms. We predicted that autoreactive T cells specific for these peptides should also exist in healthy individuals, albeit at low frequency and in an unprimed state. We obtained blood from healthy unrelated donors and, using a panel of 45 ␣3(IV)NC1 peptides, identified ␣3(IV)NC1-specific T cells in all donors. Thirty-six of 45 peptides elicited a proliferative T cell response from at least one subject, and 6 of the peptides evoked a response in Ͼ50% of the individuals. This consistency was not caused by selectivity of HLA class II molecules because the donors expressed a diversity of HLA antigens, but was largely a result of the substrate-specificity of the endosomal proteases Cathepsin D and E. There was a significant correlation between high susceptibility to Cathepsin D digestion and the capacity to stimulate primary T cell responses (P ϭ 0.00006). In summary, healthy individuals have low frequencies of unstimulated ␣3(IV)NC1-reactive T cells with similar specificities to the autoreactive T cells found in patients with Goodpasture disease. In both cases, existence of the ␣3(IV)NC1-reactive T cells can be accounted for by destructive processing.

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Section: Discussionmentioning

confidence: 99%

Healthy Individuals Have Goodpasture Autoantigen-Reactive T Cells

Zou

Hannier

Cairns

et al. 2008

Journal of the American Society of Nephrology

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“…To consider the use of these Abs in Ab-mediated Ag delivery, we embedded a universal Th epitope, 632DR (32,33), from TT Ag into the full IgG clone of E10 that cross-reacts with both DC-SIGN and L-SIGN receptors. Peptide 632DR (aa 632-651) was genetically engineered into clone E10 by directed insertion at the junction between hinge and C H 2 domain with flanking 20S proteasomal cleavage sites (Fig.…”

Section: Ab-targeted Delivery Of a Peptide Ag Induces A Sustained Hummentioning

confidence: 99%

Internalizing Antibodies to the C-Type Lectins, L-SIGN and DC-SIGN, Inhibit Viral Glycoprotein Binding and Deliver Antigen to Human Dendritic Cells for the Induction of T Cell Responses

Dakappagari¹,

Maruyama²,

Renshaw³

et al. 2006

The Journal of Immunology

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The C-type lectin L-SIGN is expressed on liver and lymph node endothelial cells, where it serves as a receptor for a variety of carbohydrate ligands, including ICAM-3, Ebola, and HIV. To consider targeting liver/lymph node-specific ICAM-3-grabbing nonintegrin (L-SIGN) for therapeutic purposes in autoimmunity and infectious disease, we isolated and characterized Fabs that bind strongly to L-SIGN, but to a lesser degree or not at all to dendritic cell-specific ICAM-grabbing nonintegrin (DC-SIGN). Six Fabs with distinct relative affinities and epitope specificities were characterized. The Fabs and those selected for conversion to IgG were tested for their ability to block ligand (HIV gp120, Ebola gp, and ICAM-3) binding. Receptor internalization upon Fab binding was evaluated on primary human liver sinusoidal endothelial cells by flow cytometry and confirmed by confocal microscopy. Although all six Fabs internalized, three Fabs that showed the most complete blocking of HIVgp120 and ICAM-3 binding to L-SIGN also internalized most efficiently. Differences among the Fab panel in the ability to efficiently block Ebola gp compared with HIVgp120 suggested distinct binding sites. As a first step to consider the potential of these Abs for Ab-mediated Ag delivery, we evaluated specific peptide delivery to human dendritic cells. A durable human T cell response was induced when a tetanus toxide epitope embedded into a L-SIGN/DC-SIGN-cross-reactive Ab was targeted to dendritic cells. We believe that the isolated Abs may be useful for selective delivery of Ags to DC-SIGN- or L-SIGN-bearing APCs for the modulation of immune responses and for blocking viral infections.

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“…Alternatively, the T-cells may crossreact with unrelated peptides (presented by various Class II molecules) and enhance the immune response against universal epitopes (Cresswell, 1994;Madden, 1995;Watts, 1997). These epitopes have been localized to fragment C, both the N-terminal region (H CN ) and particularly the C-terminal region (H CC ) of this fragment (Diethelm-Okita et al, 2000). These epitopes have been widely used to enhance vaccine immunogenicity and efficacy in a variety of immunotherapeutic systems, particularly in the field of cancer (Anderson et al, 1996;King et al, 1998;Robinson et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Comparative human and mouse antibody responses against tetanus toxin at clonal level

Yousefi

Younesi

Bayat

et al. 2015

Journal of Immunotoxicology

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Tetanus is a highly fatal disease caused by tetanus neurotoxin (TeNT) and remains a major threat to human and animal health, despite preventive strategies. TeNT is composed of heavy and light chain linked by a disulfide bond. The antibody response to TeNT is polyclonal and directed to multiple epitopes within both the light and heavy chains, leading to toxin neutralization. This study was undertaken to localize and compare neutralizing epitopes recognized by human and mouse TeNT-specific antibodies at a clonal level. In the present study, 22 murine hybridoma clones and 50 human lymphoblastoid cell lines secreting monoclonal antibodies (mAb) were generated against TeNT. The specificity of these mAb was determined using different recombinant fragments of tetanus toxin. Moreover, this study investigated the in vitro toxin neutralizing activity of these mAb by a ganglioside GT1b assay. The results showed that tetanus toxoid immunization in humans and BALB/c mice induced a vigorous humoral immune response against different fragments of TeNT, particularly the carboxyl-terminal fragment of the heavy chain (known as fragment C). The fragment C-specific human and mouse mAb could largely neutralize TeNT. However, while all fragment C-specific human mAb reacted with the carboxyl-terminal part of this fragment (H CC ), the majority of the mouse mAb failed to recognize this region. These results suggested that fragment C is the major target for the TeNT neutralizing antibodies, although different epitopes seem to be targeted by human and mouse antibodies.

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Universal Epitopes for Human CD4⁺Cells on Tetanus and Diphtheria Toxins

Cited by 84 publications

References 32 publications

Healthy Individuals Have Goodpasture Autoantigen-Reactive T Cells

Healthy Individuals Have Goodpasture Autoantigen-Reactive T Cells

Internalizing Antibodies to the C-Type Lectins, L-SIGN and DC-SIGN, Inhibit Viral Glycoprotein Binding and Deliver Antigen to Human Dendritic Cells for the Induction of T Cell Responses

Comparative human and mouse antibody responses against tetanus toxin at clonal level

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Universal Epitopes for Human CD4+Cells on Tetanus and Diphtheria Toxins

Cited by 84 publications

References 32 publications

Healthy Individuals Have Goodpasture Autoantigen-Reactive T Cells

Healthy Individuals Have Goodpasture Autoantigen-Reactive T Cells

Internalizing Antibodies to the C-Type Lectins, L-SIGN and DC-SIGN, Inhibit Viral Glycoprotein Binding and Deliver Antigen to Human Dendritic Cells for the Induction of T Cell Responses

Comparative human and mouse antibody responses against tetanus toxin at clonal level

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Universal Epitopes for Human CD4⁺Cells on Tetanus and Diphtheria Toxins