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Apoptotic Effect of Rituximab on Peripheral Blood B Cells in Rheumatoid Arthritis (2004)

Szodoray, P. ; Alex, P. ; Dandapani, V. ; [et al.]

Oxford, UK; Malden, USA : Blackwell Publishing Ltd/Inc.

Scandinavian journal of immunology 60 (2004), S. 0

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ISSN: 1365-3083

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: Rituximab (RTX) has proven efficacious in the treatment of rheumatoid arthritis (RA). Herein, we assessed the apoptosis-inducing capability of RTX in vitro on RA peripheral blood B-cell subsets and also compared the effects of RTX on B cells from rheumatoid factor-positive (RF+) and RF– patients. The likely relevance of B cells in disease was assessed by measuring B-cell-modulating serum cytokines. Peripheral blood B cells were isolated and cultured with the presence or absence of RTX. The levels of apoptosis within the naïve, memory and IgD+CD27+ B-cell subpopulations were determined by cytofluorometric analysis and caspase 3/7 assays. Levels of serum cytokines were measured with a multiplex cytokine array system. RTX induced significant apoptosis in all B-cell subsets in both RA and controls. In naïve and memory B cells from RA patients, RTX induced significantly higher levels of apoptosis than in controls. RTX induced apoptosis of B cells in RF+ and RF– patients. Serum levels of interleukin-1β (IL-1β), IL-4, IL-10 and IL-13 were profoundly increased in RF+ patients compared to RF− patients and controls. Although our cohort was small (10 RA patients), the data suggest that RTX induces apoptosis in all investigated subsets of B cells from RA patients. Interestingly, memory B cells from RA patients were more sensitive to RTX than memory cells from normal controls, suggesting that the delay in treatment response to RTX observed in clinical trials may be due in part to memory cell depletion. The apoptotic effects of RTX were similar in RF+ and RF– patients, but serum levels of B-cell-activating cytokine levels were only elevated in RF+ but not RF– patients. These data suggest that RTX is less effective in RF– RA because B cells play a less significant role in RA pathogenesis in RF– patients.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1111/j.0300-9475.2004.01441.x

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Bone morphogenetic proteins inhibit adipocyte differentiation by bone marrow stromal cells (1995)

Gimble, J. M. ; Morgan, C. ; Kelly, K. ; [et al.]

New York, N.Y. : Wiley-Blackwell

Journal of Cellular Biochemistry 58 (1995), S. 393-402

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ISSN: 0730-2312

Keywords: adipocytes ; bone morphogenetic proteins ; differentiation ; bone marrow stromal cells ; transforming growth factor β ; Life and Medical Sciences ; Cell & Developmental Biology

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Biology , Chemistry and Pharmacology , Medicine

Notes: The bone morphogenetic proteins were originally identified based on their ability to induce ectopic bone formation in vivo and have since been identified as members of the transforming growth factor-β gene superfamily. It has been well established that the bone morphogenetic cytokines enhance osteogenic activity in bone marrow stromal cells in vitro. Recent reports have described how bone morphogenetic proteins inhibited myogenic differentiation of bone marrow stromal cells in vitro. In vivo, bone marrow stromal cells differentiate along the related adipogenic pathway with advancing age. The current work reports the inhibitory effects of the bone morphorphogenetic proteins on adipogenesis in a multipotent murine bone marrow stromal cell line, BMS2. When exposed to bone morphogenetic protein-2, the pre-adipocyte BMS2 cells exhibited the expected induction of the osteogenic-related enzyme, alkaline phosphatase. Following induction of the BMS2 cells with adipogenic agonists, adipocyte differentiation was assessed by morphologic, enzymatic, and mRNA markers. Flow cytometric analysis combined with staining by the lipophilic fluorescent dye, Nile red, was used to quantitate the extent of lipid accumulation within the BMS2 cells. By this morphologic criteria, the bone morphogenetic proteins inhibited adipogenesis at concentrations of 50 to 500 ng/ml. This correlated with decreased levels of adipocyte specific enzymes and mRNAs. The BMS2 pre-adipocytes constitutively expressed mRNA encoding bone morphogenetic protein-4 and this was inhibited by adipogenic agonists. Together, these findings demonstrate that bone morphogenetic proteins act as adipogenic antagonists. This supports the hypothesis that adipogenesis and osteogenesis in the bone marrow microenvironment are reciprocally regulated.

Additional Material: 4 Ill.