Autoimmune diseases as stem cell disorders.
Using an animal model for insulin-dependent diabetes mellitus (IDDM), the NOD mouse, we have demonstrated that allogeneic bone marrow transplantation (BMT) has a preventative effect on IDDM, and that a combined transplantation of pancreas and bone marrow can be used to treat IDDM. We have also shown that BMT has a curative effect on systemic autoimmune disease in (NZB x NZW) F1, BXSB, and (NZW x BXSB) F1 mice but not in MRL/lpr mice. Since MRL/lpr mice possess abnormal radioresistant hemopoietic stem cells (HSCs), they suffer a relapse 5 months after BMT. Recently, we have found that major histocompatibility complex (MHC)-matched stromal cells in the bone marrow are essential to the support of HSCs in the Go phase. We therefore attempted to treat autoimmune diseases in MRL/lpr mice by the transplantation of stromal cells with HSCs. Transplantation of HSCs with bone to recruit stromal cells was indeed found to have a curative effect on autoimmune diseases in the mice. These results indicate that BMT with bone graft will become a valuable strategy for the treatment of patients with both systemic and organ-specific autoimmune diseases. To prove that autoimmune diseases originate from defects in HSCs, we transferred the HSCs of autoimmune-prone mice to normal mice. BMT or transplantation of stem-cell concentrates induced organ-specific and/or systemic autoimmune diseases in [NOD-->C3H/HeN] and [(NZW x BXSB)F1-->C3H/HeN or C57BL/6J] chimeric mice. These results provide direct evidence that the etiopathogenesis of autoimmune diseases, including both organ-specific and systemic autoimmune diseases, is attributable to defects in the HSCs themselves. We further provide that various intractable diseases such as non-insulin-dependent diabetes mellitus and chronic nephritis (focal glomerulosclerosis) are also organ-specific autoimmune diseases, and that BMT can be used to treat them.
Ikehara
S
S
First Department of Pathology, Kansai Medical University, Osaka, Japan.
Inaba
M
M
Yasumizu
R
R
Nagata
N
N
Toki
J
J
Hisha
H
H
Sugiura
K
K
Oyaizu
N
N
Kawamura
M
M
Than
S
S
D000818:Animals; D001327:Autoimmune Diseases / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D016026:Bone Marrow Transplantation; D017690:Cell Transplantation; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control; D051379:Mice; D008815:Mice, Inbred Strains; D011315:Preventive Medicine / Q000379:methods; D013234:Stem Cells / Q000502:physiology*; D017154:Stromal Cells / Q000637:transplantation