Direct Ex Vivo Analysis of Activated, Fas-sensitive Autoreactive T Cells in Human Autoimmune Disease

Bieganowska, Katarzyna; Ausubel, Lara J.; Modabber, Yalda; Slovik, Elissa; Messersmith, Wells A.; Hafler, David A.

doi:10.1084/jem.185.9.1585

Cited by 95 publications

(70 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1C). It has been shown that the frequency of antigen-specific Th cells in peripheral blood is low, even after immunization [19][20][21]. We therefore confirmed a KLH-specific increase in CD154…”

Section: Cd4supporting

confidence: 75%

See 1 more Smart Citation

Modulation of systemic antigen‐specific immune responses by oral antigen in humans

et al. 2010

View full text Add to dashboard Cite

Oral antigen uptake can induce systemic immune responses ranging from tolerance to immunity. However, the underlying mechanisms are poorly understood, especially in humans. Here, keyhole limpet hemocyanin (KLH), a neoantigen which has been used in earlier studies of oral tolerance, was fed in a repeated low-dose and a single high-dose protocol to healthy volunteers. KLH-specific CD4 1 T-cell proliferation and cytokine production, as well as KLH-specific serum Ab and the effects of oral KLH on a subsequent parenterally induced systemic immune response, were analyzed. Repeated low-dose oral KLH alone induced antigen-specific CD4 1 T cells positive predominantly for the gut-homing receptor integrin b7 and the cytokines IL-2 and TNF-a; some CD4 1 T cells also produced IL-4.Oral feeding of KLH accelerated a subsequent parenterally induced systemic CD4 1 T-cell response. The cytokine pattern of KLH-specific CD4 1 T cells shifted toward more IL-4-and IL-10-and less IFN-c-, IL-2-and TNF-a-producing cells. The parenterally induced systemic KLH-specific B-cell response was accelerated and amplified by oral KLH. The impact of single high-dose oral KLH on antigen-specific immune responses was less pronounced compared with repeated low-dose oral KLH. These findings suggest that oral antigen can effectively modulate subsequently induced systemic antigen-specific immune responses. Immunomodulation by oral antigen may offer new therapeutic strategies for Th type1-mediated inflammatory diseases and for the development of vaccination strategies. [1,[4][5][6][7]. Systemic tolerance in these models may result from a variety of effects including clonal anergy, clonal deletion and active regulation [2]. Understanding the mechanisms leading to such diverse outcomes after mucosal antigen uptake is not only important for mucosal vaccination [3,7], but may also offer new options for immunomodulation or the treatment of autoimmune diseases [8][9][10]. Unfortunately, responses to oral antigen differ significantly between species [8,11], and human studies are rare.Similar to mouse models, systemic immune responses can be induced in humans by oral uptake of pathogens which invade the mucosa, e.g. Salmonella typhi Ty21a [12,13], or of toxins which can bind to mucosal epithelial cells and compromise the mucosal barrier, e.g. cholera toxin [14,15].The induction of human oral tolerance has been described [16][17][18] after feeding keyhole limpet hemocyanin (KLH), a neoantigen which is safe to use in humans. Compared with rodent studies, the antigen doses used were much lower and effects observed were not as uniform: reduced delayed-type hypersensitivity (DTH) [17,18] and antigen-specific proliferation of PBMC [16][17][18] have been reported after feeding KLH, although KLH-specific B-cell responses were unaffected [16] or even amplified [17,18].Functional Th-cell subsets are believed to determine the type of immune responses, but have not been examined after oral antigen challenge in humans. The frequencies of human antigenspecific Th cells or e...

show abstract

Section: Cd4supporting

confidence: 75%

“…The frequencies of human antigenspecific Th cells or even T-regulatory cells responding to a specific antigen are usually low, ranging from 1:1000 to 1:1 000 000 [19]. We used antigen-reactive CD154 expression which allows the detection of antigen-specific CD4…”

Section: Introductionmentioning

confidence: 99%

Modulation of systemic antigen‐specific immune responses by oral antigen in humans

et al. 2010

View full text Add to dashboard Cite

show abstract

“…It is now evident that the interaction of Fas with FasL regulates a large number of pathophysiologic processes of apoptosis, including autoimmune diseases (11,12). Previous studies have also confirmed the observation that apoptotic cells in various cell types are implicated as the source of autoantigen when stimulated with different proapoptotic stimuli (13).…”

supporting

confidence: 49%

Effective treatment with oral administration of rebamipide in a mouse model of Sjögren's syndrome

Kohashi¹,

Ishimaru²,

Arakaki³

et al. 2008

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To determine whether oral administration of rebamipide, a mucosal protective agent, is effective in the treatment of Sjögren's syndrome (SS) in the NFS/sld mouse model of the disease.Methods. NFS/sld mice were given daily oral doses of rebamipide (0.3 mg/kg of body weight or 3 mg/kg) or vehicle alone starting from the age of 4 weeks to the age of 8 weeks. The volume of saliva and tears was monitored during and after treatment. After the final dose, histologic features of the tissues, TUNEL؉ apoptotic duct cells in affected glands, T cell and cytokine function, and levels of immunoglobulin isotypes and serum autoantibodies were examined.Results. The 3-mg/kg dose of rebamipide prevented the development of autoimmune lesions. The average volume of saliva in rebamipide-treated mice was significantly higher than that in control mice. We found decreased TUNEL؉ apoptotic duct cells in the salivary and lacrimal glands of rebamipide-treated mice as compared with control mice. Rebamipide treatment suppressed the activation of CD4؉ T cells and Th1 cytokines (interleukin-2, interferon-␥) associated with impaired NF-B activity. Production of serum autoantibodies, IgM, and IgG1 was clearly inhibited.Conclusion. Our findings demonstrate the efficacy of oral administration of rebamipide in the treatment of SS. Rebamipide represents a new therapeutic strategy for the treatment of patients with sicca symptoms caused by SS, as well as for patients with other diseases.

show abstract

“…24 However, subjects with active autoimmune disease are more likely to have a higher frequency of activated T cells than healthy control subjects. [25][26][27] Therefore, we designed a FACS isolation strategy in which non-CD4 þ T cells were eliminated and only the top 1% of CD4 þ CD25 þ high T cells were collected as the regulatory T-cell subset. We have reported elevated apoptosis levels and decreased function of the CD4 þ CD25 þ high T-cell subset isolated from subjects with recent-onset T1D and from multiple autoantibody-positive subjects.…”

Section: Discussionmentioning

confidence: 99%

Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes

et al. 2009

View full text Add to dashboard Cite

Type 1 diabetes (T1D) has a strong genetic component and the major locus lies in the HLA DQB1 region. We found earlier an increased apoptosis with decreased viability and function of the CD4 þ CD25 þ high T-cell subset (Treg) in human subjects with recent-onset T1D and in multiple autoantibody-positive, high at-risk individuals. Tregs normally inhibit or delay onset of T1D in animal models and increased Treg apoptosis could bring on or accelerate disease from effector T-cell-mediated destruction of insulin-producing beta cells. In this study, we test the hypothesis that HLA DQB1 genotypes are associated with increased CD4 þ CD25 þ high T-cell apoptosis. HLA DQ-based genetic risk status was significantly associated with CD4 þ CD25 þ high T-cell apoptosis, after adjustment for age, gender and phenotypic status (n ¼ 83, F ¼ 4.04 (d.f. ¼ 3), P ¼ 0.01). Unaffected, autoantibody-negative high risk HLA DQB1 control subjects showed increased CD4 þ CD25 þ high apoptosis levels compared with low risk HLA DQB1 control subjects (n ¼ 26, P ¼ 0.002), confirming that the association precedes disease. The association of specific HLA DQB1 genotypes with Treg apoptosis was also tested, showing significance for HLA DQB1*0302, DQB1*0201 and HLA DQB1*0602 alleles. Our study shows an association of HLA DQB1 genotypes with CD4 þ CD25 þ high T-cell apoptosis, which implicates CD4 þ CD25 þ high T-cell apoptosis as a new intermediate trait for T1D.

show abstract

Direct Ex Vivo Analysis of Activated, Fas-sensitive Autoreactive T Cells in Human Autoimmune Disease

Cited by 95 publications

References 32 publications

Modulation of systemic antigen‐specific immune responses by oral antigen in humans

Modulation of systemic antigen‐specific immune responses by oral antigen in humans

Effective treatment with oral administration of rebamipide in a mouse model of Sjögren's syndrome

Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes

Contact Info

Product

Resources

About