A New Strategy for Treatment of Autoimmune Diseases in Chimeric
Resistant MRL/lpr Mice
Kenji Takeuchi,
Muneo Inaba,
Shigeo Miyashima,
Ryokei Ogawa, and
Susumu Ikehara
From the First Department of Pathology and Department of Orthopedic
Surgery, Kansai Medical University, Moriguchi, Osaka, Japan.
A new strategy for the treatment of autoimmune diseases in chimeric
resistant MRL/lpr mice is established. The strategy includes injection
of cyclophosphamide (CY), fractionated irradiation (5 Gy × 2), bone
grafts (to recruit stromal cells), and two transplantations of whole
bone marrow cells (WBMCs) from allogeneic normal C57BL/6 mice
(CY/2X/Bone/2BMT). MRL/lpr mice, thus treated, survived more than 40 weeks (1 mouse survived for >40 weeks, 7 for >50 weeks, and 4 for
>60 weeks after these treatments). Immunohistological studies showed
that the mice were completely free from both lymphadenopathy and
autoimmune diseases such as systemic lupus erythematosis and rheumatoid
arthritis. The levels of autoantibodies (IgM/IgG rheumatoid factors and
IgM/IgG anti-ssDNA antibodies [Abs]) in the treated mice decreased to
those in the normal mice. In addition, successful cooperation among T
cells, B cells, and antigen-presenting cells (APCs) was observed.
Abnormal T cells with immunophenotypes of B220+/Thy-1+/CD3+/CD4
/CD8
present in untreated MRL/lpr mice disappeared, and the hematolymphoid cells of the treated mice were of donor origin. However, the mice that
had been irradiated with 8.5 Gy and then reconstituted with T-cell-depleted BMCs plus bone grafts died within 2 weeks due to the
side effect of irradiation. The depletion of CD8+ cells
(not CD4+ cells) from WBMCs resulted in graft failure;
60% of the recipient mice, thus treated, died within 2 weeks, and all
recipients died by 15 weeks. Furthermore, limiting dilution assays
showed that approximately more than 0.5% of T cells contained in the
BMCs are necessary not only for engraftment of BMCs but also for
long-term disease-free survival of the recipients. In contrast,
recipients that had received CD4-depleted BMCs with CY plus
fractionated irradiation (5Gy × 2) survived for more than 40 weeks
without showing graft-versus-host reaction (GVHR). This indicates that CD8+cells in the BMCs are essential for the successful
engraftment of the donor-type hematolymphoid cells.
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4616-4623
© 1998 by The American Society of Hematology.
