Transplantation of retrovirally transduced bone marrow prevents autoimmune disease in aged mice by peripheral tolerance mechanisms.
Transplantation of bone marrow (BM) engineered to express self-antigen has been shown to protect 100% of young mice from myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), with thymic clonal deletion as a tolerance mechanism. Here, we asked whether aged mice can also be tolerised following transplantation with self-antigen-engineered BM and whether castration-induced thymus regrowth can enhance this outcomes. Then, 50% of aged mice were protected from EAE regardless of castration-induced thymus regrowth. EAE-free and diseased mice demonstrated MOG-specific lymphocyte proliferation and antibody production regardless of castration-induced thymus regrowth, consistent with lack of intrathymic deletion of self-antigen-reactive T cells. Although low chimerism levels ( < 4%) were observed, EAE-free mice showed significantly higher chimerism levels in lymphocytes in peripheral lymphoid organs compared with thymus. CD4(+)CD25(+) regulatory T cells were elevated in lymph nodes of EAE-free mice. We conclude that transplantation of self-antigen expressing BM protects 50% of aged mice and castration-induced thymic regrowth had no effect on outcomes. Peripheral tolerance mechanisms are implicated since protection is associated with higher chimerism levels in peripheral T and B lymphocytes and with elevated regulatory T cells.
Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Monash University, Clayton, Melbourne, VIC, Australia.
Xiang T
XT
Chen
Siow T
ST
Chan
Hamid
H
Hosseini
Daniel
D
Layton
Richard
R
Boyd
Frank
F
Alderuccio
Ban-Hock
BH
Toh
James
J
Chan
D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D005260:Female; D005822:Genetic Vectors / Q000235:genetics*; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D008198:Lymph Nodes; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018992:Myelin-Associated Glycoprotein / Q000235:genetics / Q000276:immunology; D012190:Retroviridae / Q000235:genetics*; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology; D014161:Transduction, Genetic; D018183:Transplantation Chimera / Q000235:genetics
D001323:Autoantibodies; D018992:Myelin-Associated Glycoprotein