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 (globoid cell leukodystrophy) mice, which suffer from a genetic deficiency of the lysosomal enzyme galactosylceramidase that leads to progressive demyelination and early death. Preliminary investigations indicated that a semiallogeneic BMT resulted in graft vs. host disease (GVHD) in twitcher mice but not normal mice. Increased production of the cytokine IL-6 has been demonstrated in twitcher mice, and it has been linked with induction of GVHD. We investigated the effects of BMT in twitcher/IL-6 deficient mice and compared these findings with those from transplanted twitcher and control mice. After a semiallogeneic BMT, 11.4% of controls died within few weeks while the rest survived >100 days without GVHD. In contrast, 85% of the transplanted twitcher mice died by 70 days and 65% developed clinical signs of GVHD, e.g., alopecia and weight loss. In transplanted twitcher/IL-6 deficient mice, only 21% died by Day 70, none had alopecia, and 23% had weight loss. There was no difference in the onset day and severity of twitching between twitcher 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 globoid cell number compared with nontransplanted twitcher/IL-6 deficient mice. In summary, these results demonstrate that an underlying pathology like globoid cell leukodystrophy leads to activation of GVHD responses in a donor-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 prognosis.
Biswas
S
S
Department of Molecular and Integrative Physiology and Mental Retardation, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
Pinson
D M
DM
Bronshteyn
I G
IG
LeVine
S M
SM
D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001812:Blood-Brain Barrier; D001835:Body Weight; D016026:Bone Marrow Transplantation / Q000276:immunology*; D001921:Brain / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D003711:Demyelinating Diseases / Q000276:immunology / Q000473:pathology; D005260:Female; D005911:Gliosis / Q000473:pathology; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000235:genetics* / Q000276:immunology; D037102:Lectins; D007965:Leukodystrophy, Globoid Cell / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D004676:Myelin Basic Protein / Q000032:analysis; D012709:Serum Albumin / Q000032:analysis / Q000378:metabolism; D015996:Survival Rate; D001616:beta-Galactosidase / Q000235:genetics
D015850:Interleukin-6; D037102:Lectins; D015778:Minor Histocompatibility Antigens; D004676:Myelin Basic Protein; D012709:Serum Albumin; D001616:beta-Galactosidase