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Anti-CD20 Therapy Reduces Microglial Activation and Lesion Volume in Focal Models of Pattern I and Pattern II Multiple Sclerosis

Objective: We sought to determine whether anti-CD20 would inhibit lesion development and microglial activation in the focal (pattern I) Th1-type delayed type hypersensitivity (BCG-DTH) model and in an antibody-mediated focal (pattern II) fMOG-EAE of MS. We also compare the effects of anti-CD20 against those of FTY720. Background Pattern II MS lesions are associated with deposition of antibody and complement, but pattern I lesions are thought to be mediated principally by Th1/Th17 T cells and macrophages in a B-cell independent manner. However, there is evidence to suggest that B cells play a role in MS in an antibody independent fashion and B cell directed therapy is proving effective in a broader MS population than expected. Design/Methods: ocal pattern I-like lesions, were induced by the injection of heat-killed BCG into the striatum, followed by intradermal injection of BCG in CFA 28 days later. Focal pattern II lesions were induced by the injection of MOG35-55(25 μg) in IFA, followed by the stereotaxic injection of TNF/IFNg into the corpus callosum 21 days after. Animals (n=6) received anti-CD20 or FTY or vehicle on d1 and d7. The animals were killed on d12. Microglial activation as assessed by the binding of the TSPO ligand [125I]-DPA-713. Results: Anti-CD20-treated rats displayed significantly reduced lesion volume in both the pattern I (65.7%, p≤0.001) and pattern II (56.8%, p≤0.013) models. For the pattern I lesion, [125I]-DPA-713 binding was reduced to the same extent in the FTY720 treated animals compared to the anti-CD20. Thus the anti-CD20 treatment blocked the development of both an aggressive Th1 pattern I-type MS lesion, and the pattern II fMOG-EAE lesion. Conclusions: This suggests that B cells play an important role in lesion development that is independent of local CNS antibody production. Supported by: F. Hoffmann-La Roche Ltd. Disclosure: Dr. Leppert has received personal compensation for activities with Roche Diagnostics Corporation as an employee. Dr. Leppert has received compensation for serving on the University of British Columbia MS/MRI Research Group of Angiotech, Bayer, Berlex-Schering, Bio-MS, Centocor, Daiichi Sankyo, Genentech, Hoffmann-LaRoche, Merck-Serono, Perceptives, Schering-Plough, Teva Neurosciences, Sanofi-Aventis, and Transition Therapeutics. Dr. Leppert holds stock and/or stock options in F. Hoffmann La Roche Ltd., which sponsored research in which Dr. Leppert was involved as an investigator. Dr. Campbell has nothing to disclose. Dr. Seneca has received personal compensation for activities with Roche as an employee. Dr. Warren has nothing to disclose. Dr. Balazs has received personal compensation for activities with Genentech as an employee. Dr. Anthony has nothing to disclose.