The focus of the MRI Multiple Sclerosis project is to elucidate the mechanisms of action of Interferon B1b (IFNB1b) in Early Relapsing Remitting MS patients and the impact of this therapy on a larger cohort of patients followed serially with MRI. There is a considerable debate as to the exact mechanism and site of action of IFNB1b --whether IFNB1b's major effect was centrally within the CNS parenchyma resulting in a down regulation of cytokine release from T-cells and/or macrophage or the interaction with antigen presenting cells, thereby, preventing the destructive inflammatory response, or if IFNB1b plays a more peripheral role at the level of the endothelial cell or at the circulating T-cell. Thirty-three MS patients have been followed for a minimum of 6 to 30 months on IFNB1b with serial monthly MRI examinations. The number and area of contrast enhancing lesions indicative of Blood Brain Barrier (BBB) disruption, the total white matter lesion load volume (WMLL) on T2 weighted images, and the volume of white matter (WM) hypointensities on T1 weighted images (i.e., areas of gliosis or active inflammation in the white matter) have been measured in these patients. The results from the NIH baseline versus treatment trial design MRI studies are as follows: 1) There is a statistically significant decrease in the number of BBB disruptions observed for the patient population-- this decrease occurs within the first 3 months of therapy and usually persists for up to 2.5 years for the patient population studied. However, there are patients that could clearly be considered """"""""MRI Non-Responders"""""""" due to the fact that they continued to have areas of BBB disruptions while on IFNB1b therapy (vide infra); 2) There is a statistically significant decrease in the bulk WMLL and WM hypointensities, however, the change from the respective baseline lesion volume lags by about 3-6 months from the effect of IFNB1b on closing of the blood brain barrier; 3) The decrease in the bulk WMLL and WM hypointensities plateau after 12 months on IFNB1b at the same time the areas of BBB disruptions disappear; and 4) There is a measured up-regulation of soluble variable cellular adhesion molecule 1 (VCAM1) correlating to a decrease in the number of BBB disruptions on MRI. These results suggest that IFNB1b appears to act peripherally by shutting off (interfering or inhibiting) the initial event in the evolution of a MS lesion (the opening of the BBB) by either increasing the release of soluble VCAM1 from endothelial cells blocking receptor sites on activated T-Cells and/or down regulating of other antigens on endothelial cell surface preventing the activated T-Cell from adhering to the endothelial cell and then marginating into the parenchyma. The decrease in the bulk WMLL and WM hypointensities followed by the subsequent plateauing of these measures support the conclusion that IFNB1b is acting peripherally closing the BBB and, with time, the edema is reabsorbed and the inflammation resolves.
