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 therap eutic interventions. Nonablated ja/ja neonates simultaneously transfused an d given intravenous injections of normal marrow become chimeric for donor c ells, Significant improvement of red blood cell parameters occurs but is te mporary 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 whet her 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 x 10(10) normal, geneticall y marked donor marrow cells/kg body weight. Donor cell implantation and blo od parameters were monitored periodically and tissue histopathology was det ermined at necropsy. Results. sHS recipients with 100% donor erythroid cells have significantly improved red blood cell counts throughout life when compared with ja/ja con trols transfused once at birth. Total serum iron and bilirubin levels are c orrected in ja/ja marrow recipients, Donor-implanted IIS 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 re d cell counts normalize, suggesting the HS mice reset their response to hyp oxia, Conclusion. Nonablative transplantation performed after cessation of host p ostnatal red blood cell amplification can be therapeutic long term for tran sfusion-dependent hemolytic anemias. (C) 2000 International Society for Exp erimental Hematology, Published by Elsevier Science Inc.