IL-6 deficiency allows for enhanced therapeutic value after bone marrow transplantation across a minor histocompatibility barrier in the twitcher (globoid cell leukodystrophy) mouse

Bone marrow transplantation (BMT) has therapeutic value for twitcher (globo id cell leukodystrophy) mice, which suffer from a genetic deficiency of the lysosomal enzyme galactosylceramidase that leads to progressive demyelinat ion and early death. Preliminary investigations indicated that a semialloge neic BMT resulted in graft vs. host disease (GVHD) in twitcher mice but not normal mice. Increased production of the cytokine IL-6 has been demonstrat ed in twitcher mice, and it has been linked with induction of GVHD. We inve stigated the effects of BMT in twitcher/IL-6 deficient mice and compared th ese findings with those from transplanted twitcher and control mice. After a semiallogeneic BMT, 11.4% of controls died within few weeks while the res t survived > 100 days without GVHD. In contrast, 85% of the transplanted tw itcher mice died by 70 days and 65% developed clinical signs bf GVHD, e.g., alopecia and weight loss. In transplanted twitcher/IL-6 deficient mice, on ly 21 % died by Day 70, none had alopecia, and 23% had weight loss. There w as no difference in the onset day and severity of twitching between twitche r and twitcher/IL-6 deficient mice after BMT. In transplanted twitcher/IL-6 deficient mice, there was improvement of BBB integrity and a decrease in g loboid cell number compared with nontransplanted twitcher/IL-6 deficient mi ce. In summary, these results demonstrate that an underlying pathology like globoid cell leukodystrophy leads to activation of GVHD responses in a don or-host combination that would not normally induce GVHD. Furthermore, IL-6 seems to play a key role because a deficiency of IL-6 results in a better p rognosis. (C) 2001 Wiley-Liss, Ins.