A mouse model of lymphocyte infusion-induced bone marrow failure

Exp Hematol. 2004 Dec;32(12):1163-72. doi: 10.1016/j.exphem.2004.08.006.


Objective: To develop a mouse model for the study of the pathophysiologic mechanism and treatment of human bone marrow (BM) failure.

Materials and 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.

Conclusion: This mouse model indicates that activated lymphocytes and type I cytokines play important roles in marrow destruction in lymphocyte infusion-induced BM failure.

MeSH terms

  • Anemia, Aplastic / drug therapy
  • Anemia, Aplastic / etiology
  • Anemia, Aplastic / therapy
  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antilymphocyte Serum / administration & dosage
  • Bone Marrow / metabolism
  • Bone Marrow / pathology*
  • Bone Marrow / radiation effects
  • Bone Marrow Transplantation*
  • Colony-Forming Units Assay
  • Cyclosporine / administration & dosage
  • Disease Models, Animal
  • Gamma Rays / therapeutic use
  • Hematopoiesis / drug effects
  • Hematopoiesis / radiation effects
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology*
  • Hematopoietic Stem Cells / radiation effects
  • Immunosuppressive Agents / administration & dosage
  • Interferon-gamma / blood
  • Lymph Nodes / cytology
  • Lymphocyte Transfusion*
  • Mice
  • Pancytopenia / blood
  • Pancytopenia / etiology
  • Pancytopenia / therapy
  • Receptors, Antigen, T-Cell, alpha-beta / biosynthesis
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / pathology


  • Antibodies, Monoclonal
  • Antilymphocyte Serum
  • Immunosuppressive Agents
  • Receptors, Antigen, T-Cell, alpha-beta
  • Interferon-gamma
  • Cyclosporine