Amelioration of severe hereditary spherocytosis in nonablated adult mice by marrow transplantation

Objective Human severe hereditary spherocytosis (sHS) is life threatening and transfusion dependent. sHS is lethal within 6 days of birth for 99% of jaundiced (ja/ja) mice, making these mice excellent models for early therapeutic interventions. Nonablated ja/ja neonates simultaneously transfused and given intravenous injections of normal marrow become chimeric for donor cells. Significant improvement of red blood cell parameters occurs but is temporary because the donor marrow-derived cells gradually disappear from the circulation. The average lifespan, however, is increased to 8.7 months. We postulate that donor cells are diluted by rapidly proliferating host cells during postnatal growth. Here, we test this hypothesis by determining whether treatment of adults improves long-term therapy. Materials and Methods Nonablated ja/ja adults rescued by a single neonatal transfusion were injected intravenously with 1 × 1010 normal, genetically marked donor marrow cells/kg body weight. Donor cell implantation and blood parameters were monitored periodically and tissue histopathology was determined at necropsy. Results sHS recipients with 100% donor erythroid cells have significantly improved red blood cell counts throughout life when compared with ja/ja controls transfused once at birth. Total serum iron and bilirubin levels are corrected in ja/ja marrow recipients. Donor-implanted HS mice necropsied at 16 to 21 months of age have normal mean cell hemoglobin concentration and dramatically decreased tissue iron deposits. Reticulocyte counts but not red cell counts normalize, suggesting the HS mice reset their response to hypoxia. Conclusion Nonablative transplantation performed after cessation of host postnatal red blood cell amplification can be therapeutic long term for transfusion-dependent hemolytic anemias.