Systemic IFN-beta treatment induces apoptosis of peripheral immune cells in MS patients.
ABSTRACT In multiple sclerosis (MS), an impaired apoptotic deletion of activated CNS-specific immune cells, leading to their pathogenic persistence, has been suggested to maintain chronic brain inflammation. We here investigated whether interferon-beta (IFN-beta) therapy induces apoptosis of peripheral immune cells. Serial blood samples from 127 relapsing-remitting MS patients were analyzed prior to the initiation of a weekly IFN-beta 1a therapy and 4, 26, and 52 weeks thereafter. Peripheral immune cells were investigated for apoptosis and for the expression of apoptosis-regulatory genes CD95, CD95 ligand, FLIP, Bcl-2, Bcl-X(L), Bag-1, and caspase 3 by quantitative real-time PCR. Biological efficacy of IFN-beta treatment was checked by quantification of Mx expression (ELISA and real-time PCR). We found a significant increase in the apoptosis rate of immune cells in response to IFN-beta treatment, compared to baseline levels. While Bcl-2 levels were permanently and Bag-1 levels transiently elevated upon therapy, other apoptosis-regulatory genes revealed no alterations. Upregulation of Mx expression confirmed the activity of IFN-beta in vivo. These findings indicate that immunomodulatory IFN-beta therapy involves the induction of apoptotic cell death with the observed RNA upregulation of Bcl-2 family members rather reflecting a possible compensatory mechanism. The increased apoptosis susceptibility of peripheral immune cells may contribute to the known reduction of brain inflammatory lesions during IFN-beta treatment.
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ABSTRACT: Hot torsion tests to fracture to simulate thermomechanical processing were carried out on a solution-treated Al–Cu–Mg alloy (Al 2024-T351) at constant temperature. Torsion tests were conducted in the range 278–467 °C, and at two strain rates, 2.1 and 4.5 s−1. Electron backscatter diffraction (EBSD) was employed to characterize the microtexture and microstructure before and after testing. The microstructural evolution during torsion deformation at different temperatures and strain rate conditions determines the mechanical properties at room temperature of the Al 2024 alloy since grain refining, dynamic precipitation and precipitate coalescence occur during the torsion test. These mechanical properties were measured by Vickers microhardness tests. At 408 °C and 2.1 s−1 the optimum combination of solid solution and incipient precipitation gives rise to maximum ductility and large fraction of fine and misoriented grains (fHAB = 54%). In contrast, the increase in test temperature to 467 °C produces a sharp decrease in ductility, attributed to the high proportion of alloying elements in solid solution. Both the stress–strain flow curves obtained by torsion tests and the final microstructures are a consequence of recovery phenomena and the dynamic nature of the precipitation process taking place during deformation.Research highlights▶ The most favourable conditions for hot workability have been determined. ▶ EBSD was employed to characterize the obtained microtexture and microstructure. ▶ The Al 2024 alloy torsion tested at 408 °C and 2.1 s−1 showed maximum ductility. ▶ Solid solution and fine precipitates favour a fine microstructure at 408 °C. ▶ The increase in test temperature to 467 °C produces a sharp decrease in ductility.Materials Science and Engineering: A. 01/2011; 528:3161-3168.
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ABSTRACT: Multiple sclerosis is a clinically heterogeneous autoimmune disease leading to severe neurological disability. Although during the last years many disease-modifying agents as treatment options for multiple sclerosis have been made available, their mechanisms of action are still not fully determined. In the present study radiosensitivity in lymphocytes of patients with relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis and healthy controls was investigated. Whole blood cultures from multiple sclerosis patients and healthy controls were used to analyse the spontaneous and radiation-induced micronuclei in binucleated lymphocytes. A subgroup of patients with relapsing-remitting multiple sclerosis was treated with immunomodulatory agents, interferon β or glatiramer acetate. The secondary progressive multiple sclerosis patients group was not receiving any treatment. Our results reveal that the basal DNA damage was not different between relapsing-remitting and secondary progressive multiple sclerosis patients, and healthy controls. No differences between gamma-irradiation induced micronuclei frequencies in binucleated cells from relapsing-remitting and secondary progressive multiple sclerosis patients, and healthy controls were found either. Nevertheless, when we compared the radiation induced DNA damage in binucleated cells from healthy individuals with the whole group of patients, a reduction in the frequency of micronuclei was obtained in the patients group. Induced micronuclei yield was significantly lower in the irradiated samples from treated relapsing-remitting multiple sclerosis patients than in healthy controls and relapsing-remitting not treated patients. Intrinsic sensitivity of lymphocytes subpopulations to the apoptotic effect of immunomodulatory treatment could be responsible for this result.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 08/2013; · 3.90 Impact Factor
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ABSTRACT: Introduction: MS is a heterogeneous disorder that requires the development of better diagnostics to identify disease subtypes enabling appropriate therapeutic intervention at an early stage of the disease. Accumulating evidence indicates that members of the inhibitor of apoptosis (IAP) family play an important role in the pathogenesis of MS by reducing the apoptotic elimination of autoreactive immune cells. Areas covered: The authors describe improved animal modeling strategies to identify compounds that have immunomodulatory, neurorestorative and neuroprotective properties. In addition, the authors propose new approaches to better model cognitive dysfunction in MS, which will aid the development of novel therapeutics for this complex disorder. The paper provides the reader with an appreciation for the diagnostic and therapeutic potential of apoptosis-related proteins for MS. Expert opinion: Recent evidence suggests that increased resistance of autoreactive immune cells to apoptotic elimination is a contributing factor to both disease susceptibility and progression in MS. This occurs, at least in part, because of elevated levels of the IAP family of anti-apoptotic genes that display distinct expression profiles associated with different subtypes of MS. The authors believe that the detection and targeting of members of the IAP family can provide better drugs for MS. Particularly, the authors feel that the overexpression of IAPs in animal models can provide novel insights into MS for both its pathogenesis and the discovery of new lead compounds.Expert Opinion on Drug Discovery 07/2011; 6(7):689-99. · 2.30 Impact Factor