Article

Type II collagen oral tolerance; mechanism and role in collagen-induced arthritis and rheumatoid arthritis

The Catholic University of Korea Rheumatism Research Center, Catholic Institutes of Medical Science 505 Banpo-dong, Seocho-gu Seoul 137-701 South Korea
Modern Rheumatology (impact factor: 1.58). 04/2012; 19(6):581-589. DOI:10.1007/s10165-009-0210-0 pp.581-589

ABSTRACT Oral tolerance means a diminished immune response to previously fed antigens. Repeated oral administrations of type II collagen
(CII) induce oral tolerance and inhibit the development of collagen-induced arthritis (CIA). Dendritic cells (DCs) in the
gut-associated lymphoid tissue (GALT) take up the CII and then present it to T cells to generate regulatory T cells (Tregs),
which induce systemic immune tolerance to CII. Inhibitory cytokines, such as transforming growth factor (TGF)-β and interleukin
(IL)-10, and several immune regulatory molecules, including indoleamine 2,3-dioxygenase (IDO) and retinoic acid, play an important
role in Treg generation. Each DC subset may play different roles, and CD11c+CD11b+DCs and IDO+DCs are important in the generation
of antigen-inducible Tregs in CII oral tolerance. Upon stimulation with the antigen involved in its generation, Treg is activated
and regulates the immune response through inhibitory cytokine production, cell-to-cell contact-dependent mechanisms, DC modification,
and bystander suppression. The DCs and Tregs are deeply involved in oral tolerance through reciprocal interactions. Several
clinical trials have been conducted in RA patients to examine the efficacy of CII oral tolerance. An understanding the mechanism
of oral tolerance to CII would give clinicians new insights into the development of natural immune tolerance and new therapeutic
approaches for the treatment of autoimmune diseases.

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    Article: Functional transforming growth factor-β receptor type II expression by CD4+ T cells in Peyer's patches is essential for oral tolerance induction.
    Rebekah S Gilbert, Ryoki Kobayashi, Shinichi Sekine, Kohtaro Fujihashi
    [show abstract] [hide abstract]
    ABSTRACT: Our previous studies have shown that Peyer's patches (PPs) play a key role in the induction of oral tolerance. Therefore, we hypothesized that PPs are an important site for Transforming Growth Factor (TGF)-β signaling and sought to prove that this tissue is of importance in oral tolerance induction. We found that expression of TGF-β type II receptor (TGFβRII) by CD4(+) T cells increases and persists in the PPs of normal C57BL/6 mice after either high- or low-dose feeding of OVA when compared to mesenteric lymph nodes (MLNs) and spleen. Approximately one-third of these TGFβRII(+) CD4(+) T cells express the transcription factor Foxp3. Interestingly, the number of TGFβRII(+) CD4(+) T cells in PPs decreased when OVA-fed mice were orally challenged with OVA plus native cholera toxin (CT). In contrast, numbers of TGFβRII(+) CD4(+) T cells were increased in the intestinal lamina propria (iLP) of these challenged mice. Further, these PP CD4(+) TGFβRII(+) T cells upregulated Foxp3 within 2 hours after OVA plus CT challenge. Mice fed PBS and challenged with OVA plus CT did not reveal any changes in TGFβRII expression by CD4(+) T cells. In order to test the functional property of TGFβRII in the induction of oral tolerance, CD4dnTGFβRII transgenic mice, in which TGFβRII signaling is abrogated from all CD4(+) T cells, were employed. Importantly, these mice could not develop oral tolerance to OVA. Our studies show a critical, dose-independent, role for TGFβRII expression and function by CD4(+) T cells in the gut-associated lymphoid tissues, further underlining the vital role of PPs in oral tolerance.
    PLoS ONE 01/2011; 6(11):e27501. · 4.09 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

autoimmune diseases
 
cell-to-cell contact-dependent mechanisms
 
CII oral tolerance
 
clinicians new insights
 
DC modification
 
different roles
 
diminished immune response
 
gut-associated lymphoid tissue
 
immune regulatory molecules
 
indoleamine 2,3-dioxygenase
 
induce systemic immune tolerance
 
inhibitory cytokine production
 
Inhibitory cytokines
 
natural immune tolerance
 
Oral tolerance
 
RA patients
 
regulatory T cells
 
Repeated oral administrations
 
retinoic acid
 
transforming growth factor