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Induced T regulatory cells suppress osteoclastogenesis and bone erosion in collagen-induced arthritis better than natural T regulatory cells.

ABSTRACT: Although natural regulatory T cells (nTregs) can suppress osteoclastogenesis, the role of TGF-?-induced CD4+Foxp3+ Tregs (iTregs) in osteoclastogenesis remains unknown.To determine the effects of iTregs on osteoclastogenesis in vitro and on bone erosion in vivo in collagen-induced arthritis (CIA).Osteoclastogenesis was induced in bone marrow CD11b+ cells with receptor activator of nuclear factor ? B (NF-?B) ligand (RANKL) and macrophage colony stimulating factor. Graded doses of Tregs were added to inhibit osteoclastogenesis. Transwell and antibody blockade experiments were performed to assess the roles for cell contact and soluble cytokines. NF-?B activation was determined by western blot. iTregs or nTregs were adoptively transferred to mice with CIA to assess in vivo effects on disease incidence and bone erosion, the latter determined by CT scanning.Both nTregs and iTregs greatly suppressed osteoclastogenesis in vitro, but only iTregs sustained this effect when interleukin-6 was present. iTregs, but not nTregs, significantly suppressed development of CIA. Bone erosions in iTregs-treated mice were diminished compared with untreated mice or nTregs-treated mice. Treatment with iTregs, but not with nTregs, dramatically decreased NF-?B p65/p50 levels in osteoclasts in vitro and p65/50 and RANKL expression by synovial tissues in vivo.iTregs may be therapeutically beneficial in rheumatoid arthritis and related diseases associated with bone erosions.

SUBMITTER: Kong N

PROVIDER: S-EPMC4038329 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Induced T regulatory cells suppress osteoclastogenesis and bone erosion in collagen-induced arthritis better than natural T regulatory cells.

Kong Ning N Lan Qin Q Su Wenru W Chen Maogen M Wang Julie J Yang Ziyan Z Park Ryan R Dagliyan Grant G Conti Peter S PS Brand David D Liu Zhongmin Z Stohl William W Zou Hejian H Zheng Song Guo SG

Annals of the rheumatic diseases 20120704 9

<h4>Background</h4>Although natural regulatory T cells (nTregs) can suppress osteoclastogenesis, the role of TGF-β-induced CD4+Foxp3+ Tregs (iTregs) in osteoclastogenesis remains unknown.<h4>Objective</h4>To determine the effects of iTregs on osteoclastogenesis in vitro and on bone erosion in vivo in collagen-induced arthritis (CIA).<h4>Methods</h4>Osteoclastogenesis was induced in bone marrow CD11b+ cells with receptor activator of nuclear factor κ B (NF-κB) ligand (RANKL) and macrophage colony ...[more]

PMID: 22764040

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Project description:Regulatory T (Treg) cells have anti-inflammatory functions and heighten immune tolerance. The proportion and functions of Treg cells are perturbed in rheumatoid arthritis (RA), contributing to the excessive immune activation associated with this disease. We therefore hypothesized that supplementation with foreign Treg cells could be used to treat RA. To investigate the therapeutic effects of exogenous Treg cells on RA and its mechanism, we used human Treg cells to treat collagen-induced arthritis (CIA) in a rat model to observe whether exogenous Treg cells can treat the disease across species. Successful treatment would indicate that Treg cell transplantation in humans is more likely to affect RA. In the present study, human Treg cells were collected from healthy human peripheral blood and culture-expanded in vitro. Induced human Treg cells were injected into CIA rats via the tail vein. The rats' lymphocyte subtypes, cytokines, and Th1/Th2 ratios were measured using flow cytometry. In the rats, following injection of the human Treg cells, the severity of CIA was significantly reduced (P < 0.01), the proportion of endogenous Treg cells increased in the peripheral blood and spleen (P = 0.007 and P < 0.01, respectively), and the proportion of B cells decreased (P = 0.031). The IL-5 level, IL-6 level, and Th1/Th2 ratio in the peripheral blood were decreased (P = 0.013, 0.009, and 0.012, respectively). The culture-expanded human Treg cells were also cultured with synovial fibroblast cells from RA patients (RASFs). After coculture with Treg cells, RASFs showed reduced proliferation (P < 0.01) and increased apoptosis (P = 0.037). These results suggest that exogenous and induced Treg cells can produce a therapeutic effect in RA and CIA by increasing endogenous Treg cells and RASF apoptosis and reducing B cells, the Th1/Th2 ratio, and secretion levels of IL-5 and IL-6. Treg cell transplantation could serve as a therapy for RA that does not cause immune rejection.

Dataset Information

Induced T regulatory cells suppress osteoclastogenesis and bone erosion in collagen-induced arthritis better than natural T regulatory cells.

Publications

Induced T regulatory cells suppress osteoclastogenesis and bone erosion in collagen-induced arthritis better than natural T regulatory cells.

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