Expression of immune-related molecules is downregulated in twitcher mice following bone marrow transplantation.
Twitcher (twi/twi) is a murine model of a human genetic demyelinating disease, globoid cell leukodystrophy (Krabbe disease). The affected mice usually die before reaching age 45 days, having demyelination associated with extensive glial activation. The twi/twi mice that receive wild-type bone marrow transplantation (BMT) survive up to 3 times longer with improved pathology. We hypothesize that immune-related molecules such as cytokines and chemokines are partly responsible for the demyelination in twi/twi, and that the decrease in the expression of such molecules following BMT contributes to clinico-pathological improvement. Cells expressing TNF-alpha, MCP-1, and MIP-1beta were conspicuous in the twi/twi CNS accompanied by infiltration of Ia+ and CD8+/CD3- hematogenous cells. These cells decreased gradually after BMT TNF-alpha mRNA and mRNA of C-C chemokine families, including MCP-1, IP-10, MIP-1alpha, MIP-1beta, and RANTES, were upregulated in the twi/twi CNS but downregulated gradually following BMT. In twi/twi that survived to 20 wk of age, cells expressing TNF-alpha, MCP-1, MIP-1beta, Ia, or CD8 were hardly detected and pathology was clearly improved. These results are consistent with the hypothesis that cytokine expression in glial cells contributes (to some extent) to the pathogenesis of demyelinating lesions in the twi/twi mice.
Wu
Y P
YP
Department of Pathology, University of North Carolina, Chapel Hill 27599-7525, USA.
McMahon
E J
EJ
Matsuda
J
J
Suzuki
K
K
Matsushima
G K
GK
Suzuki
K
K
D000818:Animals; D001253:Astrocytes / Q000737:chemistry / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000276:immunology*; D017252:CD3 Complex / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D018932:Chemokine CCL2 / Q000032:analysis / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines / Q000032:analysis / Q000378:metabolism*; D015536:Down-Regulation / Q000276:immunology; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000032:analysis / Q000378:metabolism; D007965:Leukodystrophy, Globoid Cell / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D019402:Macrophage Inflammatory Proteins / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D017628:Microglia / Q000737:chemistry / Q000473:pathology; D008854:Microscopy, Electron; D009413:Nerve Fibers, Myelinated / Q000276:immunology / Q000648:ultrastructure; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
D017252:CD3 Complex; D016827:CD8 Antigens; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10