Intra–bone marrow injection of allogeneic bone marrow cells: a powerful new strategy for treatment of intractable autoimmune diseases in MRL/lpr mice

• Published in: Blood Vol. 97; no. 10; pp. 3292 - 3299
• Main Authors: Kushida, Taketoshi, Inaba, Muneo, Hisha, Hiroko, Ichioka, Naoya, Esumi, Takashi, Ogawa, Ryokei, Iida, Hirokazu, Ikehara, Susumu
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.05.2001; The Americain Society of Hematology
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Autoantibodies - blood; Autoimmune Diseases - mortality; Autoimmune Diseases - surgery; Biological and medical sciences; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation - methods; Bone marrow, stem cells transplantation. Graft versus host reaction; Cell Count; Female; Hematopoietic Stem Cells; Injections; Liver - cytology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Spleen - cytology; Stromal Cells; Survival Rate; T-Lymphocytes - pathology; Tissue Donors; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Animal model; Stem cell; Rodentia; Hematopoietic cell; Homograft; Autoimmune disease; Injection; Vertebrata; Mammalia; Treatment; Mouse; Animal; Bone marrow; Technique
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V97.10.3292

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 × 2, followed by intra–bone marrow (IBM) injection of whole bone marrow cells (BMCs) from allogeneic normal C57BL/6 (B6) mice (5.5 Gy × 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 × 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.