CTLA-4 is required for the induction of high dose oral tolerance

Samoilova, Elena B.; Horton, Jennifer L.; Zhang, H; Khoury, Samia J.; Weiner, Howard L.; Chen, Y

doi:10.1093/intimm/10.4.491

Cited by 87 publications

(65 citation statements)

References 48 publications

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“…It has been suggested that CTLA-4 is required for oral tolerance induction. However, this remains controversial because it has been reported that CTLA-4 blockade can abolish oral tolerance induced by oral exposure to OVA (9,10,24), while others have reported that CTLA-4 blockade failed to overcome development of oral tolerance to OVA in a similar model (25). In the present model, mice orally exposed to peanut without adjuvant do not develop PPE-specific IgE and only very low IgG responses.…”

Section: Discussionmentioning

confidence: 54%

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CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization

Wijk¹,

Hoeks²,

Nierkens³

et al. 2005

The Journal of Immunology

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Although food allergy has emerged as a major health problem, the mechanisms that are decisive in the development of sensitization to dietary Ag remain largely unknown. CTLA-4 signaling negatively regulates immune activation, and may play a crucial role in preventing induction and/or progression of sensitization to food Ag. To elucidate the role of CTLA-4 signaling in responses to food allergens, a murine model of peanut allergy was used. During oral exposure to peanut protein extract (PPE) together with the mucosal adjuvant cholera toxin (CT), which induces peanut allergy, CTLA-4 ligation was prevented using a CTLA-4 mAb. Additionally, the effect of inhibition of the CTLA-4 pathway on oral exposure to PPE in the absence of CT, which leads to unresponsiveness to peanut Ag, was explored. During sensitization, anti-CTLA-4 treatment considerably enhanced IgE responses to PPE and the peanut allergens, Ara h 1, Ara h 3, and Ara h 6, resulting in elevated mast cell degranulation upon an oral challenge. Remarkably, antagonizing CTLA-4 during exposure to PPE in the absence of CT resulted in significant induction of Th2 cytokines and an elevation in total serum IgE levels, but failed to induce allergen-specific IgE responses and mast cell degranulation upon a PPE challenge. These results indicate that CTLA-4 signaling is not the crucial factor in preventing sensitization to food allergens, but plays a pivotal role in regulating the intensity of a food allergic sensitization response. Furthermore, these data indicate that a profoundly Th2-biased cytokine environment is insufficient to induce allergic responses against dietary Ag.

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Section: Discussionmentioning

confidence: 54%

“…Although very little is known about the role of the CD28-CTLA-4/B7 pathway in food allergy, anti-CTLA-4 treatment has been shown to abrogate systemic hyporesponsiveness to orally administered OVA in oral tolerance models (9,10). This suggests that CTLA-4 signaling might be decisive in oral tolerance development.…”

mentioning

confidence: 99%

CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization

Wijk¹,

Hoeks²,

Nierkens³

et al. 2005

The Journal of Immunology

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“…Although the nature of the second signal is still under intense investigation, B7-mediated costimulation has been considered to be the most likely candidate. However, recent reports from several laboratories including ours indicate that B7 may also be required for the induction of T cell tolerance, and that B7:CTLA4 interaction is essential for maintaining peripheral T cell tolerance (31)(32)(33)(34)(35). Thus, it appears that the costimulatory molecule B7 may be required for the development of both immunity and tolerance.…”

mentioning

confidence: 84%

An Intra-Peyer’s Patch Gene Transfer Model for Studying Mucosal Tolerance: Distinct Roles of B7 and IL-12 in Mucosal T Cell Tolerance

Chen¹,

Song²,

Eck

et al. 2000

The Journal of Immunology

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Development of mucosal immunity and tolerance requires coordinated expression of a number of genes within the mucosa-associated lymphoid tissue (MALT). To study the roles of these genes in the MALT, we have established a MALT-specific gene transfer model using replication-defective adenovirus as vector. In this model, the target gene of interest is directly delivered into the Peyer’s patch by intra-Peyer’s patch injection of the recombinant virus. Using this gene transfer model, we investigated the roles of B7-1 and IL-12 in the development of mucosal tolerance. We found that intra-Peyer’s patch injection of OVA induced Ag-specific T cell hyporesponsiveness, as manifested by decreased T cell proliferation and IL-2/IFN-γ production upon subsequent immune challenge. Intra-Peyer’s patch B7-1 gene transfer at the time of OVA administration partially reversed the inhibition of T cell proliferation and IL-2 secretion, but had no effect on IFN-γ production. By contrast, intra-Peyer’s patch IL-12 gene transfer completely restored T cell proliferation and IFN-γ secretion and partially reversed IL-2 inhibition. Using an adoptive TCR transgenic model, we further demonstrated that B7 and IL-12 played distinct roles during the inductive phase of mucosal tolerance. B7 selectively increased T cell proliferation and IL-2 secretion without affecting IFN-γ production, whereas IL-12 increased both IL-2 and IFN-γ production. These results indicate that B7 alone may not be sufficient to abrogate mucosal tolerance, and that cytokines such as IL-12 may also be required. Based on these findings, we propose a new model to explain the paradoxical roles of B7 in mucosal immunity and tolerance.

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“…Both CTL-associated antigen (CTLA)-4 and programmed death-1 (PD1) are markers that are associated with the suppressive capacity of naturally occurring Tr cells [28][29][30][31]. For PD1 no staining above background could be found on antigenspecific T cells (data not shown), whereas for CTLA-4 increased expression was only found on cells that had divided six or seven times at 72 h (Fig.…”

Section: Ctl-associated Antigen-4 Programmed Death-1 and > 4 I 7 Expmentioning

confidence: 99%

Functional CD25^– and CD25⁺ mucosal regulatory T cells are induced in gut‐draining lymphoid tissue within 48 h after oral antigen application

Broere

Unger

Garssen³

et al. 2003

Eur J Immunol

105

109

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Oral antigen application induces tolerance, leading to suppression of a subsequent systemic challenge with this antigen. The suppression is mediated by mucosal regulatory T (Tr) cells that may differentiate from naive peripheral T cells in the gut-draining lymphoid tissue. However, little is known about the initial steps of this differentiation process. In this study we show that 48 h after oral OVA treatment, antigen-specific T cells in mesenteric lymph nodes (MLN) and Peyer's Patches (PP) were activated and had divided up to four times. The first division was already seen in PP after 24 h. Analysis of surface marker expression and cytokine secretion of the dividing antigen-specific T cells revealed that they sequentially obtained an activation-and memory-like phenotype. These cells secreted IL-2 in most stages of division but only transiently IFN-+ whereas no IL-4 or IL-10 secretion was detected. Remarkably, 48 h after antigen application, isolated dividing cells were suppressive, as they transferred tolerance to naive mice. Even though CD25 was expressed heterogeneously, both CD25+ and CD25 -OVA-specific T cells from MLN could transfer tolerance. Together these findings show that differentiation of functional Tr cells occurs in the MLN and PP within 2 days after antigen ingestion and involves the generation of CD25 + and CD25 -antigenspecific T cells.

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CTLA-4 is required for the induction of high dose oral tolerance

Cited by 87 publications

References 48 publications

CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization

CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization

An Intra-Peyer’s Patch Gene Transfer Model for Studying Mucosal Tolerance: Distinct Roles of B7 and IL-12 in Mucosal T Cell Tolerance

Functional CD25^– and CD25⁺ mucosal regulatory T cells are induced in gut‐draining lymphoid tissue within 48 h after oral antigen application

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CTLA-4 is required for the induction of high dose oral tolerance

Cited by 87 publications

References 48 publications

CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization

CTLA-4 Signaling Regulates the Intensity of Hypersensitivity Responses to Food Antigens, but is Not Decisive in the Induction of Sensitization

An Intra-Peyer’s Patch Gene Transfer Model for Studying Mucosal Tolerance: Distinct Roles of B7 and IL-12 in Mucosal T Cell Tolerance

Functional CD25– and CD25+ mucosal regulatory T cells are induced in gut‐draining lymphoid tissue within 48 h after oral antigen application

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Functional CD25^– and CD25⁺ mucosal regulatory T cells are induced in gut‐draining lymphoid tissue within 48 h after oral antigen application