Intra-bone marrow injection of allogeneic bone marrow cells: a powerful new strategy for treatment of intractable autoimmune diseases in MRL/lpr mice.
Intractable autoimmune diseases in chimeric resistant MRL/lpr mice were treated by a new bone marrow transplantation (BMT) method consisting of fractionated irradiation, 5.5 Gy x 2, followed by intra-bone marrow (IBM) injection of whole bone marrow cells (BMCs) from allogeneic normal C57BL/6 (B6) mice (5.5 Gy x 2 + IBM). In MRL/lpr mice treated with this method, the number of donor-derived cells in the bone marrow, spleen, and liver rapidly increased (almost 100% donor-derived cells by 14 days after the treatment), and the number of donor-derived hemopoietic progenitor cells concomitantly increased. Furthermore, donor-derived stromal cells were clearly detected in the cultured bone pieces from MRL/lpr mice treated with 5.5 Gy x 2 + IBM. All the recipients thus treated survived more than 1 year (> 60 weeks after birth) and remained free from autoimmune diseases. Autoantibodies decreased to almost normal levels, and abnormal T cells (Thy1.2(+)/B220(+)/CD4(-)/CD8(-)) disappeared. Hematolymphoid cells were reconstituted with donor-derived cells, and newly developed T cells were tolerant to both donor (B6)-type and host (MRL/lpr)-type major histocompatibility complex determinants. Successful cooperation was achieved among T cells, B cells, and antigen-presenting cells when evaluated by in vitro antisheep red blood cell responses. These findings clearly indicate that this new strategy (IBM-BMT) creates the appropriate hemopoietic environment for the early recovery of hemopoiesis and donor cell engraftment, resulting in the complete amelioration of intractable autoimmune diseases in chimeric resistant MRL/lpr mice without recourse to immunosuppressants. This strategy would therefore be suitable for human therapy.
Kushida
T
T
First Department of Pathology, Transplantation Center, Kansai Medical University, Moriguchi City, Osaka, Japan.
Inaba
M
M
Hisha
H
H
Ichioka
N
N
Esumi
T
T
Ogawa
R
R
Iida
H
H
Ikehara
S
S
D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000401:mortality / Q000601:surgery*; D001853:Bone Marrow; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation / Q000379:methods*; D002452:Cell Count; D005260:Female; D006412:Hematopoietic Stem Cells; D007267:Injections; D008099:Liver / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology; D017154:Stromal Cells; D015996:Survival Rate; D013601:T-Lymphocytes / Q000473:pathology; D014019:Tissue Donors
D001323:Autoantibodies