Anti-CD20 Therapy Down-Regulates Lesion Formation And Microglial Activation In Pattern I And Pattern II Rat Models Of Multiple Sclerosis (P1.182)

OBJECTIVE: The mechanism of action of anti-B cell therapy in multiple sclerosis (MS) is not fully understood. Here we compared the effect of anti-CD20 therapy on focal rat models of pattern I (T cell and macrophage-mediated delayed-type hypersensitivity) [DTH-EAE]) and pattern II (antibody-mediated focal myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalitis [fMOG-EAE]) lesion formation. DESIGN/METHODS: DTH-EAE lesions were induced via an intrastriatal injection of heat-killed BCG, then a peripheral injection of complete Freud’s adjuvant supplemented with TB. The fMOG-EAE lesions were induced by a subcutaneous injection of recombinant rat MOG in incomplete adjuvant and then activated by the injection of cytokines into the striatum. Microglial activation was assessed in situ and vivo using the TSPO SPECT ligand [ 125 I]DPA-713 and by immunostaining for MHCII. The effects of treatment on demyelination and lymphocyte recruitment to the brain were also evaluated. RESULTS: Anti-CD20 therapy reduced extralesional microglial activation, and lesion formation in both patterns I and II EAE, with a greater effect in the former model. Immunohistochemistry for MHCII demonstrated a reduced volume of microglial activation in the brains of anti-CD20 treated DTH-EAE animals, which was accompanied by a reduction in T cell recruitment and demyelination. Ex vivo autoradiography with the TSPO ligand [ 125 I]DPA-713 following the administration of anti-CD20 reduced binding by ~53%. In vivo imaging of [ 123 I]DPA-713 using SPECT/CT showed an increased uptake of radioactivity in the ipsilateral area compared with the contralateral side. Anti-CD20-treated DTH-EAE rodents showed significant reduction of radioligand binding compared with untreated animals. CONCLUSIONS: The suppression of lesion development by anti-CD20 treatment in pattern I MS-like lesions, which were hitherto considered B cell independent, suggests that B cells play an important role in lesion development, independent of auto-antibody production. Thus, CD20-positive B cell depletion has the potential to be effective in MS, independent of the pathogenetic type of lesion formation. Study Supported by: F. Hoffmann-LaRoche, Ltd. Disclosure: Dr. Anthony has received personal compensation for activities with Genentech, Inc. Dr. Dickens has nothing to disclose. Dr. Seneca has received personal compensation for activities with Roche Diagnostics Corp. Dr. Campbell has nothing to disclose. Dr. Checa has nothing to disclose. Dr. Kersemans has nothing to disclose. Dr. Warren has nothing to disclose. Dr. Tredwell has nothing to disclose. Dr. Gouverneur has nothing to disclose. Dr. Leppert has received personal compensation for activities with Roche Diagnostics Corp. as an employee. Dr. Leppert holds stock and/or stock options in Roche Diagnostics Corp.