myelin-basic-protein and Graft-vs-Host-Disease

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.

Topics: Animals; Astrocytes; beta-Galactosidase; Blood-Brain Barrier; Body Weight; Bone Marrow Transplantation; Brain; Demyelinating Diseases; Female; Gliosis; Graft vs Host Disease; Immunohistochemistry; Interleukin-6; Lectins; Leukodystrophy, Globoid Cell; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Neurologic Mutants; Minor Histocompatibility Antigens; Myelin Basic Protein; Serum Albumin; Survival Rate

Microglia, a type of tissue macrophage, are the only cells in the central nervous system (CNS) parenchyma to express some major histocompatibility complex (MHC) class II constitutively or to upregulate expression readily. They are thought to play a role in CD4 T cell activation in autoimmune diseases such as multiple sclerosis, as well as in neurodegenerative conditions, Alzheimer's disease in particular. We show here that highly purified MHC class II+ microglia when tested directly ex vivo do indeed support an effector response by an encephalitogenic myelin basic protein-reactive CD4 T cell line from which production of the proinflammatory cytokines, interferon gamma and tumor necrosis factor, is elicited, but not interleukin (IL)-2 secretion or proliferation. After this interaction, the T cells die by apoptosis. Other nonmicroglial but CNS-associated macrophages isolated in parallel stimulate full T cell activation, including IL-2 production, proliferation, and support T cell survival. Neither CNS-derived population expresses B7.1/B7.2. Resident macrophages that terminate effector T cells in tissues constitute a novel and broadly applicable regulatory measure of particular relevance to processes of self-tolerance against sequestered antigens.

Topics: Animals; Antigen-Presenting Cells; Antigens, CD; Apoptosis; Autoimmune Diseases; B7-1 Antigen; B7-2 Antigen; CD4-Positive T-Lymphocytes; Central Nervous System; Clonal Anergy; Graft vs Host Disease; Histocompatibility Antigens Class II; Interferon-gamma; Interleukin-2; Leukocyte Common Antigens; Lymphocyte Activation; Macrophages; Membrane Glycoproteins; Microglia; Myelin Basic Protein; Rats; Tumor Necrosis Factor-alpha

Graft-versus-host disease across minor histocompatibility barriers was induced in two different models by transplanting allogeneic bone marrow and spleen cells into irradiated H-2-compatible recipient mice. In this report, we show that administration of peptides with high binding affinity for the respective class II major histocompatibility complex molecules after transplantation is capable of preventing the development of graft-versus-host disease in two different murine models. The peptides used were myelin basic protein residues 1 through 11 with alanine at position 4 (Ac 1-11[4A]) for I-Au (A alpha uA beta u), and the antigenic core sequence 323 through 339 of ovalbumin with lysine and methionine extension (KM core) for I-As (A alpha sA beta s). In both systems, the mechanism of prevention was found to be major histocompatibility complex-associated, because nonbinding control peptides did not have any effect. Engraftment of allogeneic bone marrow cells was shown by polymerase chain reaction analysis of DNA polymorphisms in a microsatellite region within the murine interleukin-5 gene.

Topics: Amino Acid Sequence; Animals; Base Sequence; Bone Marrow Transplantation; Female; Graft vs Host Disease; H-2 Antigens; Histocompatibility; Histocompatibility Antigens Class II; Interleukin-5; Mice; Molecular Sequence Data; Myelin Basic Protein; Ovalbumin; Peptide Fragments; Polymerase Chain Reaction; Repetitive Sequences, Nucleic Acid; Spleen; T-Lymphocytes