Intranasal Administration of Retinal Antigens Induces Transient T cell Activation and Apoptosis within Drainage Lymph Nodes but not Spleen

Laliotou, Barbara; Duncan, Linda; Dick, Andrew D.

doi:10.1006/jaut.1998.0269

Cited by 13 publications

(10 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite previously demonstrating, after tolerance induction and immunisation, Th2 responses (IL-2 and IL-10 producing) from infiltrating T cells within retina,19 there remains little evidence to support a bias toward Th2 responses as a direct result of tolerance mechanisms within the lymph node 40. Here we have shown increased STAT4 signalling, concomitant with antigen specific proliferation, signifying Th1 reactivity and is in keeping with our previous data of a transient IFN-γ burst within SCLN17 and supports an initial T cell activating event. Together with the observation by Burkhart et al 18 that IFN-γ and IL-4 cytokine production followed different kinetics in cervical lymph nodes and spleen, our data support the possibility of separate roles for SCLN and spleen in the induction of nasal tolerance.…”

Section: Discussionsupporting

confidence: 90%

“…Application of soluble antigens via mucosal surfaces leads to a transient activation of T cells in the drainage lymph nodes and Peyer's patches of the gut and apoptosis17( reviewed by Lowrey et al 2 and Wardrop and Whitacre3). Such activation induced cell deletion is not complete and the resulting T cell populations are unresponsive to further stimulation34 but may still produce IL-10 18…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Single dose intranasal administration of retinal autoantigen generates a rapid accumulation and cell activation in draining lymph node and spleen: implications for tolerance therapy

Dick

Sharma²,

Liversidge³

2001

British Journal of Ophthalmology

View full text Add to dashboard Cite

Background/aims-A single intranasal delivery of retinal autoantigen suppresses eVectively experimental autoimmune uveoretinitis (EAU). To further unravel underlying mechanisms the authors wished to determine, firstly, the kinetics of antigen delivery and, secondly, the early cellular responses involved in the initial stages of nasal mucosal tolerance induction. Methods-Flow cytometry, cell proliferation assays, and microscopy were used to track antigen following a single, intranasal dose of Alexa-488 labelled retinal antigen. Results-A rapid accumulation of antigen within both superficial cervical lymph nodes (SCLN) and spleen was observed after 30 minutes. Significant proliferative responses to IRBP were elicited by 48 hours indicating that systemic priming of naive T cells to retinal antigen had occurred. Cell activation was further confirmed by immunoprecipitation studies, which demonstrated phosphorylation of STAT4 but not STAT6 in both lymph nodes and spleen. However, at 24 hours, STAT4 heterodimerisation with STAT 3 was only observed in spleen. Conclusions-The results provide novel evidence that following a single intranasal application rapid transfer of antigen occurs. Resulting T cell proliferation develops consequent to diVerential cell signalling in SCLN and spleen. Further understanding of these underlying cellular mechanisms, in particular as is inferred by the results the contribution of local versus systemic tolerance induction, may assist in strategies to clinically apply mucosal tolerance therapy successfully. (Br J Ophthalmol 2001;85:1001-1006 Models of tolerance induction via the mucosa have been shown to be eVective for the prevention of several autoimmune diseases. The eVectiveness of the treatment is dependent on parameters such as the antigen used, its dose and route of delivery, and various mechanisms have been identified, including T cell anergy, generation of regulatory Th3 (TGF producing) cells or CD8+ T cells and T cells.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Single dose intranasal administration of retinal autoantigen generates a rapid accumulation and cell activation in draining lymph node and spleen: implications for tolerance therapy

Dick

Sharma²,

Liversidge³

2001

British Journal of Ophthalmology

View full text Add to dashboard Cite

show abstract

“…Our previous investigation in the rat EAU model with a long term regimen has demonstrated a reduced percentage of IFN-γ+ macrophages and CD4+ T cells with an increased percentage of IL-4+ or IL-10+ CD4+ T cells 29. Moreover, previous work has also shown transient T cell activation in the draining lymph nodes following the intranasal administration of retinal antigens, and that suppression of systemic Th1 responses is mediated by spleen regulatory cells during low dose tolerance therapy 26. Interestingly, a single high dose of antigen administered intranasally led to the induction of Th2 responses in the IDDM mouse model, and the adoptive co-transfer of splenic T cells from GAD64 peptide treated mice protects recipient NOD-scid/scid mice from IDDM 46.…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2001

Self Cite

View full text Add to dashboard Cite

Experimental autoimmune uveitis (EAU) is a T cell mediated disease that specifically targets the neural retina. Although EAU can be induced by a variety of retinal antigens in many diVerent animal strains, 1 EAU in the mouse more closely resembles the pathology of a spectrum of human posterior segment intraocular inflammatory (PSII) conditions including sympathetic ophthalmia, sarcoidosis, and birdshot retinochoroidopathy. 2-4As a result of the close clinicopathological correlation of EAU in mice to human PSII, the model has been extensively used for the investigation of underlying immunological mechanisms and furthermore for the development of novel therapeutic approaches.

show abstract

“…These cells are typically antigen specific, are CD4 + , secrete the immune suppressive cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β (7,8), and have been termed T H 3 cells or regulatory T cells (T regs ) (9). In other settings in which antigen-induced tolerance was achieved via a mucosal route (intranasal), there is evidence of activation-induced cell death of responder T cells (10), a possibility that should be explored in future studies of oral antigen administration. Preliminary evidence has recently shown that these processes could be counterproductive, at least theoretically, if T regs are also deleted or sequestered (M. von Herrath, personal communication) and that the balance of induction/deletion is strongly influenced by the dose (frequency), with more frequent dosing being more harmful (11–13).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Outcome of Individuals Treated With Oral Insulin

et al. 2011

View full text Add to dashboard Cite

OBJECTIVETo evaluate the long-term intervention effects of oral insulin on the development of type 1 diabetes and to assess the rate of progression to type 1 diabetes before and after oral insulin treatment was stopped in the Diabetes Prevention Trial–Type 1 (DPT-1).RESEARCH DESIGN AND METHODSThe follow-up included subjects who participated in the early intervention of oral insulin (1994–2003) to prevent or delay type 1 diabetes. A telephone survey was conducted in 2009 to determine whether diabetes had been diagnosed and, if not, an oral glucose tolerance test (OGTT), hemoglobin A1c (HbA1c), and autoantibody levels were obtained on all subjects who agreed to participate.RESULTSOf 372 subjects randomized, 97 developed type 1 diabetes before follow-up; 75% of the remaining 275 subjects were contacted. In the interim, 77 subjects had been diagnosed with type 1 diabetes and 54 of the remainder have had an OGTT; 10 of these were diagnosed with type 1 diabetes, subsequently. Among individuals meeting the original criteria for insulin autoantibodies (IAAs) (≥80 nU/mL), the overall benefit of oral insulin remained significant (P = 0.05). However, the hazard rate in this group increased (from 6.4% [95% CI 4.5–9.1] to 10.0% [7.1–14.1]) after cessation of therapy, which approximated the rate of individuals treated with placebo (10.2% [7.1–14.6]).CONCLUSIONSOverall, the oral insulin treatment effect in individuals with confirmed IAA ≥80 nU/mL appeared to be maintained with additional follow-up; however, once therapy stopped, the rate of developing diabetes in the oral insulin group increased to a rate similar to that in the placebo group.

show abstract

Intranasal Administration of Retinal Antigens Induces Transient T cell Activation and Apoptosis within Drainage Lymph Nodes but not Spleen

Cited by 13 publications

References 52 publications

Single dose intranasal administration of retinal autoantigen generates a rapid accumulation and cell activation in draining lymph node and spleen: implications for tolerance therapy

Single dose intranasal administration of retinal autoantigen generates a rapid accumulation and cell activation in draining lymph node and spleen: implications for tolerance therapy

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

Long-Term Outcome of Individuals Treated With Oral Insulin

Contact Info

Product

Resources

About