Bystander destruction of hematopoietic progenitor and stem cells in a mouse model of infusion-induced bone marrow failure

Abstract

Infusion of parental lymph node (LN) cells into sublethally irradiated hybrid F1 recipients created a murine model for bone marrow (BM) failure. Affected animals developed fatal pancytopenia within 2 to 3 weeks, accompanied by BM oligoclonal T-cell infiltration and severe marrow hypoplasia indicated by approximately 10-fold declines in total BM cellularity, 15-fold declines in BM Lin^-Sca1⁺c-Kit⁺ cells, 100-fold declines in spleen colony-forming units, and 100-fold declines in hematopoietic progenitor and stem cells as estimated by irradiation protection in vivo. LN cells of both H2^b/b and H2^d/d haplotypes were effectors. Serum interferon-γ (IFN-γ) concentration increased 2- to 3-fold. Marrow cells were severely apoptotic, with high proportions of Fas⁺ and annexin V⁺ cells. Cotransplantation of 5 × 10⁵ BM cells from clinically affected donors and 10⁶ BM cells from H2 identical healthy mice could not rescue lethally irradiated recipients. Recipients had significantly lower cellularity in peripheral blood and BM, and cell mixtures failed to produce a stromal feeder layer to support marrow cell growth in vitro. Pathogenic T cells from donors after BM failure appeared capable of destroying hematopoietic progenitor, stem, and stromal cells from fully compatible healthy donors as “innocent bystanders.” This effect can be partially abrogated by anti-IFN-γ antibody. (Blood. 2004;104:1671-1678)