A mouse model of lymphocyte infusion-induced bone marrow failure.
OBJECTIVE
To develop a mouse model for the study of the pathophysiologic mechanism and treatment of human bone marrow (BM) failure.


METHODS
Unmanipulated B6D2F1 or CByB6F1 hybrid mice were infused with 10-40 x 10(6) lymph node (LN) cells from their C57BL/6 (B6) parent. Pancytopenia was monitored by cell counting, while marrow damage was assessed by histological staining. Destruction of BM hematopoietic progenitor/stem cells was measured by colony formation in vitro and irradiation protection in vivo. Serum interferon-gamma (IFN-gamma) concentration was measured by enzyme-linked immunosorbent assay. BM T cell Vbeta and Fas expressions were analyzed by flow cytometry. Treatment effects of immunosupressive agents cyclosporine, antithymocyte globulin (ATG), anti-IFN-gamma, and anti-tumor necrosis factor-alpha (anti-TNF-alpha) were tested.


RESULTS
Infusion of 30-40 x 10(6)B6 LN cells led to rapid development of severe pancytopenia, BM hypoplasia, and death. Affected mice had drastically reduced hematopoietic progenitor and stem cells. BM of affected mice showed lymphocyte infiltration, oligoclonal T cell expansion, and upregulated Fas expression. Serum IFN-gamma concentration increased two- to three-fold. Timed administration of cyclosporine or ATG abrogated pancytopenia. Treatment with anti-IFN-gamma antibody reliably rescued mice, and treatment with anti-TNF-alpha antibody extended animal survival significantly.


CONCLUSIONS
This mouse model indicates that activated lymphocytes and type I cytokines play important roles in marrow destruction in lymphocyte infusion-induced BM failure.
Bloom
Michael L
ML
Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD 20892-1652, USA.
Wolk
Adam G
AG
Simon-Stoos
Karen L
KL
Bard
Julie S
JS
Chen
Jichun
J
Young
Neal S
NS
D000741:Anemia, Aplastic / Q000188:drug therapy / Q000209:etiology / Q000628:therapy; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000961:Antilymphocyte Serum / Q000008:administration & dosage; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D016026:Bone Marrow Transplantation; D003114:Colony-Forming Units Assay; D016572:Cyclosporine / Q000008:administration & dosage; D004195:Disease Models, Animal; D005720:Gamma Rays / Q000627:therapeutic use; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology* / Q000528:radiation effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007371:Interferon-gamma / Q000097:blood; D008198:Lymph Nodes / Q000166:cytology; D017710:Lymphocyte Transfusion; D051379:Mice; D010198:Pancytopenia / Q000097:blood / Q000209:etiology / Q000628:therapy; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology
D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D016693:Receptors, Antigen, T-Cell, alpha-beta; D007371:Interferon-gamma; D016572:Cyclosporine