Nadkarni, S., Mauri, C. & Ehrenstein, M. R. Anti-TNF- therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-. J. Exp. Med. 204, 33-39

Centre For Rheumatology, Department of Medicine, Windeyer Institute, University College London, London W1T 4JF, England, UK.
Journal of Experimental Medicine (Impact Factor: 12.52). 02/2007; 204(1):33-9. DOI: 10.1084/jem.20061531
Source: PubMed


The induction of regulatory T (T reg) cells holds considerable potential as a treatment for autoimmune diseases. We have previously shown that CD4+CD25hi T reg cells isolated from patients with active rheumatoid arthritis (RA) have a defect in their ability to suppress proinflammatory cytokine production by CD4+CD25- [corrected] T cells. This defect, however, was overcome after anti-tumor necrosis factor (TNF)-alpha antibody (infliximab) therapy. Here, we demonstrate that infliximab therapy gives rise to a CD4+CD25hiFoxP3+ T reg cell population, which mediates suppression via transforming growth factor (TGF)-beta and interleukin 10, and lacks CD62L expression, thereby distinguishing this T reg cell subset from natural T reg cells present in healthy individuals and patients with active RA. In vitro, infliximab induced the differentiation of CD62L- T reg cells from CD4+CD25- T cells isolated from active RA patients, a process dependent on TGF-beta. In spite of the potent suppressor capacity displayed by this CD62L- T reg cell population, the natural CD62L+ T reg cells remained defective in infliximab-treated patients. These results suggest that anti-TNF-alpha therapy in RA patients generates a newly differentiated population of T reg cells, which compensates for the defective natural T reg cells. Therefore, manipulation of a proinflammatory environment could represent a therapeutic strategy for the induction of T reg cells and the restoration of tolerance.

Download full-text


Available from: Suchita Nadkarni, Oct 06, 2015
56 Reads
  • Source
    • "Deficiencies in the functions of Treg cells have been identified in a number of autoimmune diseases including RA. A number of studies suggested that stem cell therapy or biological therapy induced a potent population of CD4+CD25+ Treg cells in patients with RA (44); however, the deficit of nTreg cells persisted in the patients even after the treatment with anti-TNF-α (45). CD4+CD25+ Treg cells isolated from active RA patients were capable of suppressing the proliferation of conventional T cells; however, these Treg cells could not suppress the cytokine production. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Regulatory T (Treg) cells are essential for normal immune surveillance systems, and their dysfunction leads to development of diseases, such as autoimmune disorders. CD4(+)CD25(+) Treg cells are well-known suppressive cells, which express the transcription factor Foxp3, are indispensable for the maintenance of immune self-tolerance and homeostasis by suppressing aberrant or excessive immune response. Other Foxp3(-) Treg cells include Tr1, Th3, CD8(+)CD28(-/-), and Qa1-restricted T cells; however, the contribution of these Treg cells to self-tolerance, immune homeostasis as well as preventing autoimmunity is not well defined. Here, we discuss the phenotypes and function of Foxp3(+) Treg cells and the potential use of such Treg cells against rheumatoid arthritis (RA). Of note, even though most expanded populations of Foxp3(+) Treg cells exhibit suppressive activity, tissue-associated or antigen-specific Treg cells appear superior in suppressing local autoimmune disorders such as RA. In addition, utilizing tissue-associated Foxp3(+) Treg cells from stem cells may stable Foxp3 expression and avoid induction of a potentially detrimental systemic immunosuppression.
    Frontiers in Oncology 08/2014; 4:209. DOI:10.3389/fonc.2014.00209
  • Source
    • "In addition, oral tolerization protocols developed several years ago have shown disease reduction in RA murine models and have recently been associated with the development of a population of Treg cells that suppress inflammation via IL-10 production [15,16]. More importantly, treatment of RA patients with anti-TNF antibodies has been shown to induce differentiation of a potent population of Treg cells with suppressive activity that is dependent upon transforming growth factor β (TGF-β) and IL-10 [12,13]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Regulatory T (Treg) cells play a crucial role in preventing autoimmune diseases and are an ideal target for the development of therapies designed to suppress inflammation in an antigen-specific manner. Type 1 regulatory T (Tr1) cells are defined by their capacity to produce high levels of interleukin 10 (IL-10), which contributes to their ability to suppress pathological immune responses in several settings. The aim of this study was to evaluate the therapeutic potential of collagen type II–specific Tr1 (Col-Treg) cells in two models of rheumatoid arthritis (RA) in mice. Methods Col-Treg clones were isolated and expanded from collagen-specific TCR transgenic mice. Their cytokine secretion profile and phenotype characterization were studied. The therapeutic potential of Col-Treg cells was evaluated after adoptive transfer in collagen-antibody– and collagen-induced arthritis models. The in vivo suppressive mechanism of Col-Treg clones on effector T-cell proliferation was also investigated. Results Col-Treg clones are characterized by their specific cytokine profile (IL-10highIL-4negIFN-γint) and mediate contact-independent immune suppression. They also share with natural Tregs high expression of GITR, CD39 and granzyme B. A single infusion of Col-Treg cells reduced the incidence and clinical symptoms of arthritis in both preventive and curative settings, with a significant impact on collagen type II antibodies. Importantly, injection of antigen-specific Tr1 cells decreased the proliferation of antigen-specific effector T cells in vivo significantly. Conclusions Our results demonstrate the therapeutic potential of Col-Treg cells in two models of RA, providing evidence that Col-Treg could be an efficient cell-based therapy for RA patients whose disease is refractory to current treatments.
    Arthritis Research & Therapy 05/2014; 16(3):R115. DOI:10.1186/ar4567 · 3.75 Impact Factor
  • Source
    • "PBMCs were isolated by density gradient centrifugation (Tianjin HY, China) within 2 h after sample collection. There is a linear correlation between CD25 and Foxp3 levels expressed on CD4+CD25+ T cells [7]. To isolate live Treg subsets for functional assays, the PBMCs were stained with CD4 and CD25 Abs and sorted using Moflo-XDP (Beckman Coulter, USA) according to the manufacturer's instructions. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Regulatory T (Treg) cells are potent suppressors that maintain immune homeostasis. Accumulation of Treg can inhibit effective immune responses in cancer patients, leading to tumor development and progression. Despite direct cytotoxicity, several chemotherapeutic drugs have been reported to deplete Treg cells for better prognosis for cancer patients. Treg cells are a heterogenous population with at least three different subsets, nonsuppressive, resting, and activated Treg cells. However, the characteristics of Treg cell subsets in lung cancer patients and how chemotherapy affects Treg cells remain elusive. In this study, we first analyzed Treg cell subsets in peripheral blood samples from 40 nonsmall cell lung cancer (NSCLC) patients and 20 healthy donors. Treg cells, specifically activated Treg cell subset, significantly increased in patients with NSCLC. Compared to nonsuppressive Treg cells, activated Treg cells expressed higher level of CD39 and predominantly produced inhibitory cytokines. In vitro assay showed that docetaxel reduced all three subsets of Treg cells. More importantly, we found docetaxel-based chemotherapy significantly decreased all three Treg subsets after 4 cycles of treatment in 17 NSCLC patients. Taken together, this study revealed dynamic changes of various Treg cell subsets in NSCLC patients before and after chemotherapy, providing activated Treg cells as a potential target for chemotherapy.
    Research Journal of Immunology 04/2014; 2014(3):286170. DOI:10.1155/2014/286170
Show more