We have shown that systemic administration of CTLA4Ig is effective in preventing experimental autoimmune encephalomyelitis (EAE) in Lewis rats (J Iminimol 1995; 155:4521). In this study we investigated the mechanisms of CD28-B7 blockade in EAE. Naive APCs (nylon wool adherent splenocytes) incubated in vitro with CTLA4Ig and the encephalitogenic peptide of MBP (p71-90) protect recipients from EAE: Lewis rats were immunized with MBP/CFA 48 hours after receiving 40x10APCs i.v. Animals received APCs incubated with CTLA4Ig+p71-90, control animals received APCs incubated with CTLA4Ig with no peptide, or no APCs. Grade Incidence Mean Duration Index Control (n=15) 2.60 ± 0.18 100% 4.40 ± 0.25 11.44 APC + peptide + CTLA4-Ig (n=12) 0.75 ± 0.21 58% 1.75 ± 0.46 0.77 APC + CTLA4-Ig control (n=7) 2.29 ± 0.52 100% 4.57 ± 0.30 10.47 In vitro, lymphocytes from protected animals had decreased proliferation to MBP, as compared to controls. We then investigated which APC is mediating protection. The dendritic-enriched population of splenocytes, but not T or B cell-enriched preparations, was able to induce tolerance when pre-incubated with CTLA4Ig and p71-90. Incubating dendritic-enriched cells with p71-90 alone was not protective. Immunohistologically, protected animals had decreased inflammatory response with inhibition of Thl cytokines and sparing of Th2 cytokines in the brain. These results suggest that ex-vivo blockade of CD28-B7 leads to the generation of regulatory cells, presumably Th2, which inhibit priming of T cells and suppress the autoimmune response to the specific antigen in vivo.
|Original language||English (US)|
|State||Published - Dec 1 1996|
ASJC Scopus subject areas
- Agricultural and Biological Sciences (miscellaneous)
- Biochemistry, Genetics and Molecular Biology(all)
- Cell Biology