Treatment of intractable autoimmune diseases in MRL/lpr mice using a new strategy for allogeneic bone marrow transplantation.
A new bone marrow transplantation (BMT) method for treating severe autoimmune diseases in chimeric resistant MRL/lpr mice is presented. The method consists of fractionated irradiation (5.5 Gy x 2), followed by portal venous (PV) injection of whole bone marrow cells (BMCs) from allogeneic normal C57BL/6 (B6) mice and intravenous (IV) injection of whole B6 BMCs 5 days after the PV injection (abbreviated as 5.5 Gy x 2 + PV + IV). All recipients survived more than 1 year after this treatment (more than 64 weeks after birth). Abnormal T cells (Thy1.2(+)/B220(+)/CD3(+)/CD4(-)/CD8(-)) present in MRL/lpr mice before the treatment disappear, and hematolymphoid cells are reconstituted with donor-derived cells. The treated mice are free from autoimmune diseases. Levels of autoantibodies (IgG/IgM anti-ssDNA antibodies and IgG/IgM rheumatoid factors) decrease to normal levels. Successful cooperation is achieved among T cells, B cells, and antigen-presenting cells (APCs) of the treated MRL/lpr mice when evaluated by in vitro anti-SRBC responses. Newly developed T cells are tolerant to both donor (B6)-type and host (MRL/lpr)-type major histocompatibility complex (MHC) determinants. These findings clearly indicate that severe autoimmune diseases in MRL/lpr mice are completely ameliorated by the treatment without recourse to immunosuppressants, and that the treated MRL/lpr mice show normal immune functions, strongly suggesting that this strategy would be applicable to humans. (Blood. 2000;95:1862-1868)
Kushida
T
T
First Department of Pathology, Kansai Medical University, Moriguchi City, Osaka, Japan.
Inaba
M
M
Takeuchi
K
K
Sugiura
K
K
Ogawa
R
R
Ikehara
S
S
D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016026:Bone Marrow Transplantation / Q000379:methods*; D003520:Cyclophosphamide / Q000494:pharmacology; D019583:Dose Fractionation, Radiation; D005260:Female; D007275:Injections, Intravenous; D007668:Kidney / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D011169:Portal Vein; D011828:Radiation Chimera; D019172:Transplantation Conditioning / Q000379:methods*; D014916:Whole-Body Irradiation / Q000379:methods
D001323:Autoantibodies; D003520:Cyclophosphamide