IKEHARA, S., INABA, M., YASUMIZU, R., NAGATA, N., TOKI, J., HISHA, H., SUGIURA, K., OYAIZU, N., KAWAMURA, M., THAN, S., TAKAO, F., ADACHI, Y., NISHIMURA, M., NISHIOKA, N., MIZUTANI, H., KURATA, Y. and Goon, R.A.
Autoimmune Diseases as Stem Cell Disorders. Tohoku J. Exp. Med., 1994,
173 (1), 141-155-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 diseases in (NZB× NZW) F
1, BXSB, and (NZW×BXSB) F
1 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×BXSB)F
1→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.
View full abstract