Transplantation studies in mice with congenital hemolytic anemia.

Sphha/sphha anemic mice have an abnormality in the erythroid membrane protein, alpha spectrin, and exhibit multiple related clinical abnormalities, including spherocytosis, shortened red cell survival, chronic hemolysis, hemosiderosis, and extramedullary hematopoiesis. In addition, these mutant mice exhibit a granulocytosis and lymphocytosis, lymph node hyperplasia, elevated serum immunoglobulins, membranoproliferative glomerulonephritis, and decreased lifespan--abnormalities that are less clearly attributable to a spectrin defect. In order to further elucidate the mechanisms of disease in these animals, we undertook a series of bone marrow transplantation experiments. Transplantation of anemic marrow into lethally irradiated congenic +/+ mice resulted in chronic spherocytosis, hemolytic anemia, peripheral leukocytosis, and extramedullary hematopoiesis. Additionally, transplant recipients of anemic marrow which had received a higher radiation dose (12 Gy) had increased numbers of peripheral blood CD4+ and CD8+ lymphocytes, a hypocellcular thymus, and a severe pneumonitis characterized by nodular areas of consolidation and edema. Mice receiving congenic +/+ marrow and irradiated with the same radiation dose exhibited minimal pulmonary abnormalities. Anemic mice transplanted with congenic +/+ marrow usually died, but the survivors exhibited reversal of some clinicopathological changes. These results would suggest that the clinical abnormalities of sphha/sphha mice are in part attributable to abnormalities of hematopoietic stem cells but may also involve defects in other cell types. The pathogenesis of the accompanying lymphoid abnormalities observed in this mutant anemic mouse and any correlation with the erythroid spectrin defect are presently unknown. The pulmonary disease that develops in the transplant recipients of anemic marrow needs to be characterized further but may represent a unique model of lung injury.