Effect of<i>in vivo</i>administration of anti-CTLA-4 monoclonal antibody and IL-12 on the induction of low-dose oral tolerance

Barone, K.Siobhan; Herms, B.; Karlosky, L.; Murray, Susan; Qualls, Joseph E.

doi:10.1046/j.0009-9104.2002.01961.x

Cited by 8 publications

(7 citation statements)

References 49 publications

(55 reference statements)

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“…This is consistent with mouse studies of low-dose oral tolerance 28 and in anergy induction using systemic CTLA-4 monoclonal and IL-12 injections. 29 Our data show that CTLA-4 regulates cellular proliferation, whereas IL-12 promotes CTL effector differentiation.…”

Section: Discussionsupporting

confidence: 88%

CTLA-4 Ablation and Interleukin-12–Driven Differentiation Synergistically Augment Cardiac Pathogenicity of Cytotoxic T Lymphocytes

Love

Grabie

Duramad

et al. 2007

Circulation Research

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Abstract-CD8ϩ cytotoxic T lymphocytes contribute to viral and autoimmune myocarditis and cardiac allograft rejection. The role of cytotoxic T-lymphocyte-associated antigen (CTLA)-4 as a negative regulator of CD4 ϩ T cells is well defined, yet CTLA-4 regulation of CD8 ϩ T cells is less clear. We studied CTLA-4 regulation of cytotoxic T lymphocytes in a transgenic model of CD8 ϩ T-cell-mediated myocarditis. We generated CTLA-4 Ϫ/Ϫ Rag 2 Ϫ/Ϫ OT-1 mice, the CD8 ϩ T cells of which express an ovalbumin (OVA) peptide-specific, class I major histocompatibility complex-restricted T-cell receptor. CTLA-4Ϫ/ϪTc12 OT-1 effectors, differentiated with interleukin-12 present, are hyperproliferative in vitro, compared with CTLA-4 ϩ/ϩTc12 OT-1 controls. Transfer of low doses of CTLA-4 Ϫ/ϪTc12 OT-1 cells to cMy-mOVA mice, which express OVA on cardiac myocytes, causes severe myocarditis, with 99% mortality, compared with no mortality after transfer of low doses of CTLA-4 ϩ/ϩTc12 OT-1 cells. High doses of CTLA-4 ϩ/ϩTc12 cells cause lethal myocarditis in cMy-mOVA mice, but high doses of CTLA-4 ϩ/ϩTc0 CTL, generated without interleukin-12, are hypoproliferative within the cardiac-draining lymph node and do not significantly infiltrate the heart. In contrast, CTLA-4 Ϫ/ϪTc0 cytotoxic T lymphocytes do proliferate in the cardiac-draining lymph node and diffusely infiltrate the heart. Nonetheless, high doses of CTLA-4 Ϫ/ϪTc0 cells cause only limited tissue damage, and the disease is not lethal. These data show that CTLA-4 regulates myocarditic CD8 ϩ T cell responses and that CTLA-4 deficiency partly overcomes a differentiation block that exists when naïve CD8 ϩ T cells are stimulated without interleukin-12. Therefore, targeting CTLA-4 solely or in conjunction with interleukin-12 could influence effector CD8 ϩ T cell responses in therapeutically beneficial ways. ϩ T-cell activation and differentiation by members of the B7 and CD28 regulatory molecules remain incompletely understood. Cytotoxic T-lymphocyte antigen (CTLA)-4 is a CD28 family member that is expressed on the surface of lymphocytes after T-cell receptor (TCR) stimulation. 1 CTLA-4 and CD28 share specificity for the B7 molecules CD80 (B7-1) and CD86 (B7-2). It is well documented that CD80 and CD86 binding to CTLA-4 on CD4 ϩ T cells results in downregulation of cell-cycle progression and interleukin (IL)-2 production. 2,3 In contrast, there are conflicting studies regarding the effects of CTLA-4 ligation on CD8 ϩ T-cell regulation. 4,5 Several reports indicated that CTLA-4 blockade does not alter cytotoxic T lymphocyte (CTL) responses to lymphocytic choriomeningitis virus, mouse mammary tumor virus, or Leishmania major infection in mice. 4,6,7 Yet experiments with CTLA-4 -deficient class I major histocompatibility complex-restricted TCR transgenic mice indicate that CTLs are hyperresponsive to antigen on restimulation, suggesting a negative regulatory role in CTL activation. 4,5,8 Furthermore, blockade of CTLA-4 with neutralizing antibody augments CTL-mediated responses against tu...

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Section: Discussionsupporting

confidence: 88%

CTLA-4 Ablation and Interleukin-12–Driven Differentiation Synergistically Augment Cardiac Pathogenicity of Cytotoxic T Lymphocytes

Love

Grabie

Duramad

et al. 2007

Circulation Research

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“…Several studies have demonstrated a role for CTLA-4 function in the development of oral tolerance, but effects on cytokine secretion varied on the dose of the antigen fed while the DTH response was not monitored. 69,70 Administration of anti-CTLA-4 antibodies during 50 mg ovalbumin (OVA) feeding completely abrogated the suppression of cytokine production by Th1 and Th2 cells. 70 By contrast, the administration of anti-CTLA-4 antibodies during 1 mg OVA feeding only abrogated suppression of Th2 type immune responses but not Th1.…”

Section: Introductionmentioning

confidence: 99%

“…70 By contrast, the administration of anti-CTLA-4 antibodies during 1 mg OVA feeding only abrogated suppression of Th2 type immune responses but not Th1. 69 Co-administration of IL-12 along with anti-CTLA-4 antibodies was required to abrogate the suppression of Th1 cytokine secretion during tolerance induction 1 mg OVA feed. 69 These results indicate that the CTLA-4 pathway is important for establishing oral tolerance, but suggests that its role is most important in high dose oral tolerance.…”

Section: Introductionmentioning

confidence: 99%

“…69 Co-administration of IL-12 along with anti-CTLA-4 antibodies was required to abrogate the suppression of Th1 cytokine secretion during tolerance induction 1 mg OVA feed. 69 These results indicate that the CTLA-4 pathway is important for establishing oral tolerance, but suggests that its role is most important in high dose oral tolerance. Whether this relates to different mechanisms mediating oral tolerance to low and high antigen doses, i.e., low doses favoring the induction of pTregs and higher doses the induction of anergy or clonal deletion remains to be established.…”

Section: Introductionmentioning

confidence: 99%

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Tipping the balance: inhibitory checkpoints in intestinal homeostasis

et al. 2019

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The small intestinal and colonic lamina propria are populated with forkhead box P3 (FOXP3) + CD4 + regulatory T cells (Tregs) and interleukin-10-producing T cells that orchestrate intestinal tolerance to harmless microbial and food antigens. Expression of coinhibitory receptors such as CTLA-4 and PD-1 serve as checkpoints to these cells controlling their T-cell receptor (TCR)-mediated and CD28-mediated activation and modulating the phenotype of neighboring antigen presenting cells. Recent discoveries on the diversity of co-inhibitory receptors and their selective cellular expression has shed new light on their tissue-dependent function. In this review, we provide an overview of the co-inhibitory pathways and checkpoints of Treg and effector T cells and their mechanisms of action in intestinal homeostasis. Better understanding of these inhibitory checkpoints is desired as their blockade harbors clinical potential for the treatment of cancer and their stimulation may offer new opportunities to treat chronic intestinal inflammation such as inflammatory bowel disease.

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“…Tsuji et al [17] have reported that the oral administration of lipopolysaccharide inhibited the induction of oral tolerance to a simultaneously ingested oral antigen, while λ-carrageenan did not, even if both of them had the same function for modulating the immune response toward dominant Th1. Furthermore, several reports have indicated that the administration of IL-12 negatively modulated the induction of oral [18,19,20] and other tolerances [21]. However, the effect of orally administered IL-12 on oral tolerance has not been clarified.…”

Section: Introductionmentioning

confidence: 99%

Oral Administration of IL-12 Abrogates the Induction but Not the Maintenance of Oral Tolerance

Yoshida¹,

Uno²,

Hirano³

et al. 2006

Int Arch Allergy Immunol

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Background: IL-12 is a Th1-inducing cytokine and known to be induced by some food factors. This function of such foods is expected to be applied for antiallergic materials. However, the influence of IL-12 on the immune responses has not been fully investigated. Oral tolerance is an immunologically unresponsive state induced by orally administered food antigens. Although a failure in the induction of oral tolerance would result in food allergy, the mechanisms for the induction and abrogation of oral tolerance have not been clarified. IL-12 induced by food factors may also affect the induction of oral tolerance. In this study we examined the effect of the oral administration of IL-12 on the induction and maintenance of oral tolerance. Methods: BALB/c mice were fed β-lactoglobulin with or without IL-12. After immunizing them with the antigen, the serum antibody titer of these mice was measured to evaluate the induction of oral tolerance. Results: The induction of oral tolerance was prevented in the mice that had been simultaneously fed the antigen and IL-12. On the other hand IL-12 did not abrogate the already established oral tolerance when it was administered after feeding the antigen. We also found that oral tolerance could be induced normally in mice that had failed to induce such tolerance by simultaneous feeding of IL-12 and the antigen. Conclusions: The results indicate that IL-12 induced in the intestine by some food factors is involved in the regulation of oral tolerance.

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Effect ofin vivoadministration of anti-CTLA-4 monoclonal antibody and IL-12 on the induction of low-dose oral tolerance

Cited by 8 publications

References 49 publications

CTLA-4 Ablation and Interleukin-12–Driven Differentiation Synergistically Augment Cardiac Pathogenicity of Cytotoxic T Lymphocytes

CTLA-4 Ablation and Interleukin-12–Driven Differentiation Synergistically Augment Cardiac Pathogenicity of Cytotoxic T Lymphocytes

Tipping the balance: inhibitory checkpoints in intestinal homeostasis

Oral Administration of IL-12 Abrogates the Induction but Not the Maintenance of Oral Tolerance

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