Total dose and frequency of administration critically affect success of nasal mucosal tolerance induction

Jiang, Hui-Rong; Taylor, Nick; Duncan, Linda; Dick, Andrew D.; Forrester, John V.

doi:10.1136/bjo.85.6.739

Cited by 16 publications

(7 citation statements)

References 43 publications

(26 reference statements)

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“…3D). The requirement of booster tolerization for suppression of ischemic brain damage agrees with our previous stroke prevention study, which suggests that repeated low-dose tolerization is needed to produce an effective cohort of regulatory T cells in this model (23). The smaller lesion size in the PBS group at 6 h ( Fig.…”

Section: Discussionsupporting

confidence: 77%

Mucosal tolerance to E-selectin provides cell-mediated protection against ischemic brain injury

Chen

Ruetzler

Pandipati

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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We have demonstrated that induction of mucosal tolerance to E-selectin, a cytokine-inducible adhesion molecule restricted to activating blood vessels, prevents ischemic and hemorrhagic stroke in spontaneously hypertensive, genetically stroke-prone (SHR-SP) rats. We now examine whether mucosal tolerance to E-selectin has protective effects in ischemic brain damage after permanent middle cerebral artery occlusion (MCAO) in SHR-SP rats and whether these effects are related to generation of regulatory T cells. Rats were exposed to intranasal administration of E-selectin every other day for 10 days (single tolerization group) or on two tolerization schedules separated by 11 days (booster tolerization group). Control groups received PBS on corresponding schedules. MCAO was performed 48 h after the last dose of E-selectin or PBS. There were 45.8% and 37.9% (P < 0.05) decreases of infarction volume in the E-selectin booster group compared with the PBS group at 6 and 48 h, respectively. Single tolerization with E-selectin had only a slight trend toward a decrease in infarction volume (6.3%). CD8-positive cells were decreased in brains of E-selectin booster animals (46.6%, P < 0.01) compared with controls; splenocyte-culture supernatant levels of IL-10 were increased (59.3%, P < 0.05) in E-selectin booster animals. A decrease of infarction volume (34%, P < 0.05) was also observed in SHR-SP rats subjected to MCAO after adoptive transfer of splenocytes from E-selectin-tolerized compared with PBS-tolerized donors. The results indicate that, in addition to preventing stroke, mucosal tolerance to E-selectin is cytoprotective. Thus, immunomodulation targeted to activated blood vessel segments can both reduce stroke occurrence and attenuate brain damage if a stroke supervenes.

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Section: Discussionsupporting

confidence: 77%

Mucosal tolerance to E-selectin provides cell-mediated protection against ischemic brain injury

Chen

Ruetzler

Pandipati

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…Conjugation of insulin to CTB induced active mechanisms similar to that observed with the oral route. It appears that dose, frequency of intranasal antigen administration and timing of antigen delivery with regard to disease onset are critical determinants of tolerance induction and subsequent suppression of T cell‐mediated autoimmune disease [38]. In addition, previous studies using orally administered antigens outlined the risk of activation of immunity instead of tolerance induction [39], and the possibility to worsen an ongoing autoimmune disease [40].…”

Section: Discussionmentioning

confidence: 99%

Nasal administration of CTB-insulin induces active tolerance against autoimmune diabetes in non-obese diabetic (NOD) mice

Aspord

Thivolet

2002

Clinical and Experimental Immunology

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SUMMARYNasal administration of beta cell-derived auto-antigens has been reported to suppress the development of autoimmune diabetes. We investigated the tolerogenic effects of insulin conjugated to the B subunit of cholera toxin (CTB). Nasal administration of 1 m g of CTB-insulin significantly delayed the incidence of diabetes in comparison to CTB treated mice. However, administration of 4 or 8 m g of the conjugate had no protective effect. Protection induced by CTB-insulin was transferred to naive recipients by splenic CD4+ T cells. This result favours an active cellular mechanism of regulation, which was lost using higher (4-8 m g) or lower (0·1-0·5 m g) amounts of the conjugate. When co-administered with diabetogenic T cells, splenic T cells from CTB-insulin-treated mice reduced the lymphocytic infiltration of the islets. Reverse transcription-polymerase chain reaction analysis of recipients' pancreatic glands revealed an increase of TGF-b and IL-10 transcripts after donor mice tolerization, while levels of IFNg and IL-4 RNAs were unchanged. We observed a significant increase of T cell proliferation after unspecific stimulation in the spleen and pancreatic lymph nodes 24 h after CTB-insulin administration in comparison to control treatment. Higher amounts of IL-4 and IFN-g were noticed in pancreatic lymph nodes of tolerized mice upon in vitro stimulation. Antigen-specific unresponsiveness after immunization and upon subsequent in vitro exposure to homologous antigen was obtained in nasally treated animals. Our results underlined the importance of nasal mucosa as an inducing site of tolerance and provided evidence for similar mechanisms of action to what has been described for the oral route, which favoured a CTB-insulin specific effect.

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“…9 Mucosal tolerance is a phenomenon, whereby peripheral tolerance is maintained by administering the antigen of interest through the oral or nasal/respiratory routes. [10][11][12] The induction of tolerance by mucosal administration of autoantigens or immunodominant/immunogenic peptides has been reported in various experimental models of autoimmune diseases, including encephalomyelitis, 13,14 myasthenia gravis, 15,16 uveitis, 16,17 diabetes, [18][19][20] arthritis, [21][22][23] and autoimmune GN. 24,25 In several of these studies, nasal administration of the immunodominant peptide was more effective in inducing tolerance than oral peptide administration.…”

mentioning

confidence: 99%

Myeloperoxidase Peptide–Based Nasal Tolerance in Experimental ANCA–Associated GN

Gan

Tan

Ooi

et al. 2016

Journal of the American Society of Nephrology

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Less toxic treatment options for patients with myeloperoxidase (MPO)-ANCAassociated GN are needed. Using an established murine model of focal necrotizing GN mediated by autoimmunity to MPO (autoimmune anti-MPO GN), we assessed the capacity for nasal tolerance induced by nasal insufflation of the immunodominant nephritogenic MPO peptide established anti-MPO autoimmunity attenuated the subsequent development of GN, confirming that the immunosuppression induced by these T cells is antigen specific. Ex vivo studies showed that nasal tolerance to MPO is mediated by both conventional and induced T regulatory cells. The strong homology between the pathogenic human MPO B cell epitope recognized by ANCA in patients with acute vasculitis and the nephritogenic murine T cell MPO epitope emphasizes the clinical relevance of this study.

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Total dose and frequency of administration critically affect success of nasal mucosal tolerance induction

Cited by 16 publications

References 43 publications

Mucosal tolerance to E-selectin provides cell-mediated protection against ischemic brain injury

Mucosal tolerance to E-selectin provides cell-mediated protection against ischemic brain injury

Nasal administration of CTB-insulin induces active tolerance against autoimmune diabetes in non-obese diabetic (NOD) mice

Myeloperoxidase Peptide–Based Nasal Tolerance in Experimental ANCA–Associated GN

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