Multiple sclerosis: pathogenesis and MR imaging features of T1 hypointensities in a [corrected] murine model.

PURPOSE: To prospectively determine how T1 hypointensities (T1 black holes) on brain magnetic resonance (MR) images are generated by the immune system by using a Theiler murine encephalitis virus-induced model of multiple sclerosis and high-field-strength MR imaging. MATERIALS AND METHODS: All animal protocols and experiments were approved by the institutional animal care and use committee. Volumetric MR imaging studies were conducted at 7 T in six C57BL/6 mice and in immune differentiation marker (recombination activation gene [RAG]-1)-, immune cell (CD4, CD8)-, and immune effector molecule (Fas ligand, perforin)-deficient mice (six mice in each group) to determine which immune cell types and effector molecules lead to T1 hypointensities. The main outcome measure was the total T1 black hole volume per animal, as determined with volumetric analysis, and was analyzed statistically by using software. RESULTS: Compared with C57BL/6 mice, RAG-1-deficient mice showed a significant (P = .003) decrease in total T1 black hole volume, suggesting a clear role for the adaptive immune system. While CD4-deficient mice did not show a significant decrease in T1 black hole volume (P = .33), CD8-deficient mice did (P = .003). Perforin-deficient mice showed a significant reduction of T1 black hole volume (P = .002), whereas Fas ligand-deficient mice did not (P = .77). CONCLUSION: The data suggest that CD8 T cells utilizing perforin effector molecules are responsible for T1 black hole formation.

Role of CTLA-4, IL-18 and IL-10 on the Induction of Low Dose Oral Tolerance.

Oral Tolerance is the temporary loss of systemic immunological responsiveness to a specific soluble antigen after ingestion of that antigen. Results from our lab and others indicated that CTLA-4 and lack of IL-12 played a role in the induction of low dose oral tolerance at the Th1 cell level. Previous literature suggested that IL-18 also played a role in preventing oral tolerance induction while the cytokine IL-10 had been shown to be a factor contributing to suppressed immune responses. To determine the role of CTLA-4 in conjunction with either IL-18 or IL-10 in low dose oral tolerance induction, anti-CTLA-4 mAb and either IL-18 or anti-IL-10 mAb were administered concurrently to mice fed either ovalbumin (OVA) or water. Results showed that the PLN cell proliferation of mice treated with anti-CTLA-4 mAb and IL-18 remained significantly suppressed compared with water-fed controls, while a partial abrogation of suppressed IL-4 and IFN-gamma levels were observed. In contrast, mice treated with anti-CTLA-4 mAb and anti-IL-10 mAb exhibited a reversal of PLN cell proliferation and IL-4 suppression; however, IFN-gamma levels remained suppressed. Results suggest that IL-10, IL-18 and CTLA-4 play roles in the induction of oral tolerance at the cell proliferation and cytokine level.