CTLA4-Ig modifies dendritic cells from mice with collagen-induced arthritis to increase the CD4+CD25+Foxp3+ regulatory T cell population

Ko, Hyeok-Jae; Cho, Mi‐La; Lee, Seon‐Yeong; Oh, Hye-Jwa; Heo, Yu-Jung; Moon, Young Myoung; Kang, Chang-Suk; Kwok, Seung‐Ki; Ju, Ji Hyeon; Park, Sung-Hwan; Park, Kyung-Su; Kim, Ho-Youn

doi:10.1016/j.jaut.2009.07.006

Cited by 76 publications

(45 citation statements)

References 30 publications

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“…These cytokines are known to play important roles in several inflammatory diseases, including RA (40)(41)(42). Although CTLA-4Ig was demonstrated to reduce serum IL-17 during collagen-induced arthritis (43), this is the first study to show a direct inhibition of Ag-specific T cell IL-17 production by abatacept. Interestingly, IL-13 was shown to be produced by TFH cells in human tonsils (44), and this was significantly reduced by treatment with abatacept.…”

Section: Discussionmentioning

confidence: 71%

Abatacept Limits Breach of Self-Tolerance in a Murine Model of Arthritis via Effects on the Generation of T Follicular Helper Cells

Platt

Gibson

Patakas

et al. 2010

The Journal of Immunology

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Abatacept modulates CD28-mediated T cell costimulation and is efficacious in the treatment of rheumatoid arthritis (RA). Its mechanism of action has not been fully elucidated but will likely reveal critical pathologic pathways in RA. We show that abatacept substantially modulated Ag-specific T and B cell responses in vivo. Ag-specific T cell proliferation was reduced, and the acquisition of an activated phenotype, characterized by upregulation of CD69, OX40, ICOS, and programmed death-1 and downregulation of CD62L, was suppressed. Furthermore, abatacept suppressed the production of inflammatory cytokines, such as IFN-γ and IL-17. These effects were associated with a failure of Ag-specific T cells to acquire the CXCR5+ICOS+ T follicular helper cell phenotype. This, in turn, led to a failure of these cells to enter B cell follicles, resulting in reduced specific Ab responses, despite normal B cell clonal expansion. To test the pathologic significance of this, we used a novel model of RA associated with breach of self-tolerance to self-Ag and demonstrated that abatacept prevented the emergence of self-reactivity. Thus, CD28-dependent signaling is required for optimal T follicular helper cell maturation and expansion, and its inhibition prevents loss of self-tolerance in a model of articular pathology. Thus, we provide a novel mode of action for abatacept with profound implications for its potential usefulness in early inflammatory arthropathies associated with autoantibody expression.

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Section: Discussionmentioning

confidence: 71%

Abatacept Limits Breach of Self-Tolerance in a Murine Model of Arthritis via Effects on the Generation of T Follicular Helper Cells

Platt

Gibson

Patakas

et al. 2010

The Journal of Immunology

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“…Studies in RA patients undergoing abatacept treatment have generated inconclusive results concerning the ability of abatacept to induce Treg cells. While one report suggests that abatacept therapy inhibits activation-induced cell death of Treg cells, which resulted in their increased proportion in the blood (24), others suggest that abatacept therapy diminishes the frequency of Treg cells in RA patients (25). Murine studies have also been equivocal, with systemic administration of CTLA-4Ig being reported as leading to an increase in CD41CD251 Treg cells (45).…”

Section: Discussionmentioning

confidence: 99%

“…No abatacept promotion of inducible Treg cell generation or inhibitory molecule up-regulation. The effect of abatacept-mediated CD28 inhibition on the number and function of Treg cells is controversial (24)(25)(26). Thus, the presence of Treg cells and the expression of the regulatory molecules CTLA-4 and PD-1 were determined.…”

Section: Effect Of Abatacept On T Cells and Apcs During Primary Immunmentioning

confidence: 99%

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Patakas

Weir

et al. 2016

Arthritis & Rheumatology

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Objective. To determine at the phenotypic, functional, and transcriptional levels whether abatacept, a CTLA-4Ig molecule that binds with high affinity to CD80/86 on antigen-presenting cells (APCs) and is used to treat rheumatoid arthritis, induces a state of immunologic tolerance in T cells and dendritic cells in mice.Methods. We investigated the capacity of abatacept to regulate the development of antigen-specific immunologic tolerance in vivo using murine models of priming and tolerance to generate highly purified antigen-specific T cell populations and CD11c1 APCs. These were combined with detailed immunologic and full genome transcriptional analyses.Results. We found that abatacept inhibited T cell activation, but did not render T cells anergic or lead to the generation of Treg cells. However, it induced a sustained inhibition of T cell activation due to the inability of these cells to progress through the cell cycle following T cell receptor stimulation. We also observed that this state was accompanied by an inhibition of dendritic cell activation due to their reduced licensing by T cells.Conclusion. This study provides detailed insight into the mode of action of abatacept, demonstrating that its effectiveness is not due to the induction of T cell tolerance, but rather to a sustained inhibition of T cell activation that results in reduced functionality of APCs, with significant implications for its clinical application.

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“…CTLA4-Ig blocks CD28-mediated co-stimulatory signaling to T cells to induce tolerance (50) and maintain the tolerogenic state of DCs (51). It has previously been demonstrated that the CD4 + CD25 + Foxp3 + Treg population in mouse joints and spleen is increased in CTLA4-Ig-treated collagen-induced arthritis model mice and that DCs are modified to become tolerogenic (52). However, there are few reports on the effects of co-injection with immature DCs and CTLA4-Ig in SLE.…”

Section: Discussionmentioning

confidence: 99%

Effect of immune tolerance induced by immature dendritic cells and CTLA4-Ig on systemic lupus erythematosus: An inï¿½vivo study

et al. 2018

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Abstract. Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease in which tissue damage is caused by autoantibodies. The induction of specific immune tolerance, including the utilization of immune regulatory cells, may enhance the therapeutic effects of organ transplantation in patients with SLE. Furthermore, inhibiting immune responses has been reported to be an effective treatment for SLE. However, few studies have explored the association between an increased immune tolerance and a decreased immune response in SLE treatment. Dendritic cells (DCs), which are highly efficient antigen-presenting cells, are able to induce specific tolerance, while cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4-Ig) inhibits the immune response. In the present study, interleukin (IL)-10-treated DCs and CTLA4-Ig were administered to mice with SLE alone or in combination and the therapeutic effects were investigated. IL-10 was added into the culture medium of bone marrow-derived DCs to prevent them from differentiating into mature cells. Low levels of major histocompatibility complex II, cluster of differentiation (CD)40, CD80 and CD86 were detected, which indicated that the immature state of DCs was maintained. IL-10-treated DCs were subsequently injected into the caudal vein of B6.MRL-Fas lpr /J lupus mice, which are an established animal model of SLE. To amplify the tolerance effect, mice were simultaneously injected with CTLA4-Ig. Compared with the IL-10-treated DC and CTLA4-Ig groups, combined treatment with IL-10-treated DCs and CTLA4-Ig strongly induced immune tolerance in mice with SLE, as indicated by the significantly reduced levels of urine protein, anti-nuclear antibody, double-stranded DNA and IL-17A. A significant decrease in the proportion of T helper cells and an increase in the proportion of CD4 + forkhead box protein P3 + Treg cells was also observed, further confirming the induction of immune tolerance. These results suggest that combined treatment with IL-10-DCs and CTLA4-Ig may be a promising novel therapeutic strategy for the treatment of SLE.

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CTLA4-Ig modifies dendritic cells from mice with collagen-induced arthritis to increase the CD4+CD25+Foxp3+ regulatory T cell population

Cited by 76 publications

References 30 publications

Abatacept Limits Breach of Self-Tolerance in a Murine Model of Arthritis via Effects on the Generation of T Follicular Helper Cells

Abatacept Limits Breach of Self-Tolerance in a Murine Model of Arthritis via Effects on the Generation of T Follicular Helper Cells

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

Effect of immune tolerance induced by immature dendritic cells and CTLA4-Ig on systemic lupus erythematosus: An inï¿½vivo study

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