Autologous bone marrow transplantation in autoimmune arthritis restores immune homeostasis through CD4(+)CD25(+)Foxp3(+) regulatory T cells

Department of Pediatric Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, USA.
Blood (Impact Factor: 10.45). 06/2008; 111(10):5233-41. DOI: 10.1182/blood-2007-12-128488
Source: PubMed

ABSTRACT Despite the earlier use of potent immunosuppressive or cytostatic drugs and the recent emergence of biologicals as treatment for human autoimmune diseases (AIDs), some patients still remain unresponsive to treatment. To those severely ill patients, autologous bone marrow transplantation (aBMT) is applied as a last resource, leading to disease remission in a majority of patients. The underlying mechanism of action of aBMT is still largely unknown. Here, we showed that regulatory T cells (Tregs) play a role in the natural disease course of proteoglycan-induced arthritis (PGIA) and in disease remission by aBMT. aBMT led to an initial phase of rapid disease improvement corresponding with a relative increase in CD4(+)CD25(+) T cells. At this time, the CD4(+)CD25(+) cells did not yet show an increase in Foxp3 expression and showed less potent suppression. After this initial improvement, disease relapsed but stabilized at a level below the severity before aBMT. This second phase was actively regulated by potently suppressive CD4(+)CD25(+)Foxp3(+) Tregs. This work provided further insight into the role of Tregs in restoration of the immune balance by aBMT and can open the way to explore therapeutic interventions to further improve treatment of AID and disease relapses.

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    • "To identify the Treg cells in murine splenocytes and TACs, splenocytes and TACs were first stained with PE/Cy5-conjugated anti-mouse CD4 (eBioscience) and PE-conjugated anti-mouse CD25 (eBioscience) for cell surface markers. Fluorescein isothiocyanate-conjugated anti-mouse FoxP3 (eBioscience) for intracellular staining were performed as described previously [24]. Staining was characterized by flow cytometric analysis as described earlier. "
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    ABSTRACT: The regulatory T cells (Tregs) can actively suppress the immune responses. However, literature about detailed changes of host effective and suppressive immunities before and after depletion of Tregs in ovarian carcinomas, is rare. Ovarian cancer patients and the ascitogenic animal model were employed. Immunologic profiles with flow cytometric analyses, immunohistochemistric staining, RT-PCR, ELISA, and ELISPOT assays were performed. In vivo depletion of Treg cells with the mAb PC61was also performed in the animal model. The cytokines, including IL-4 (p = 0.017) and TNF-α (p = 0.046), significantly decreased while others such as TGF-β (p = 0.013), IL-6 (p = 0.016), and IL-10 (p = 0.018) were elevated in ascites of ovarian cancer patients, when the disease progressed to advanced stages. The ratio of CD8(+) T cell/Treg cell in ascites was also lower in advanced diseases than in early diseases (advanced 7.37±0.64 vs. early 14.25±3.11, p = 0.037). The kinetic low-dose CD25 Ab depletion group had significantly lower intra-peritoneal tumor weight (0.20±0.03 g) than the sequential high-dose (0.69±0.06 g) and sequential low-dose (0.67±0.07 g) CD25 Ab deletion groups (p = 0.001) after 49 days of tumor challenge in the animal. The kinetic low-dose CD25 Ab depletion group generated the highest number of IFN-γ-secreting, mesothelin-specific T lymphocytes compared to the other groups (p<0.001). The imbalance between effective and suppressive immunities becomes more severe as a tumor progresses. The depletion of Treg cells can correct the imbalance of immunologic profiles and generate potent anti-tumor effects. Targeting Treg cells can be a new strategy for the immunotherapy of ovarian carcinoma.
    PLoS ONE 10/2012; 7(10):e47190. DOI:10.1371/journal.pone.0047190 · 3.23 Impact Factor
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    • "In some studies there is a suggestion that the resulting expansion from the memory T-cell pool favours development of autoimmunity . Additionally, to date, there is good evidence for the crucial role of Tregs in the restoration of immune regulation post-HSCT, both in autologous and allogeneic setting (Roord et al, 2008; Seidel et al, 2009). Lymphodepletion can temporarily inhibit the mechanisms of tolerance, thus leading to the expansion of autoreactive naı¨ve-and/or memory T-cells (Minamimura et al, 2006). "
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    ABSTRACT: Autologous and allogeneic haematopoietic stem cell transplantation (HSCT) is an option for the treatment of malignant and non-malignant diseases, including the severe autoimmune diseases. Intriguingly, the 'new' autoimmunity developing after transplantation is a constantly recognized phenomenon, which has to be differentiated from original disease relapse, toxicity, infection and graft-versus-host disease. The reported autoimmune diseases occurring in this setting are mainly antibody-associated and organ-specific, with scarce evidence in support for specific treatment options. This review focuses on current concepts on the pathogenesis, the available data on incidence, risk factors, manifestations and treatment of post-HSCT autoimmune diseases.
    British Journal of Haematology 02/2012; 157(3):281-90. DOI:10.1111/j.1365-2141.2012.09070.x · 4.71 Impact Factor
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    • "In the months and years posttransplant , there is now evidence of thymic reprocessing with generation of na¨ıve CD4 + cells with increased clonal T-cell receptor diversity and loss of memory cells (Muraro et al., 2005). In addition, there is support for a role of T-regulatory cells in the restoration of immune regulation following autologous HSCT (de Kleer et al., 2006; Roord et al., 2008). The precise role of such immune reconstitution has yet to be fully defined. "
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    ABSTRACT: Severe autoimmune diseases (ADs) are a major source of disability and reduced quality of life and may result in shortened life expectancy, particularly in treatment-resistant patients. For several decades, allogeneic and autologous haematopoietic stem cell transplantation (HSCT) has been the focus of scientific investigation as a potential means of delivering 'one-off' intensive treatment in severe ADs. Improvements in the clinical safety of HCST were followed by its increasing use in recent years as an experimental treatment for severe and resistant ADs. European and North American registries have accumulated between one and two thousand procedures. Retrospective analyses and prospective studies have demonstrated the feasibility, safety and initial efficacy data in various ADs. Profound cell biological changes induced by HSCT leading to stabilization or reversal of organ damage have been characterized. These have also shed light on basic disease mechanisms and support investigation of more specific cellular therapy in ADs. There is clear potential for harnessing a profound immunological effect through HSCT. However, there is a need for an ongoing balance against evolving non-transplant treatments for ADs. Ideally, these issues should be resolved in phase III studies, in which HSCT approaches are compared with the best comparator.
    Transfusion Medicine 10/2009; 19(5):223-34. DOI:10.1111/j.1365-3148.2009.00927.x · 1.65 Impact Factor
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