1. Lymphocytes with aberrant expression of Fas or Fas ligand attenuate immune bone marrow failure in a mouse model
- Author
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Neal S. Young, Stephanie O. Omokaro, Jichun Chen, Felicia M. Ellison, Michael Eckhaus, and Marie J. Desierto
- Subjects
Mice, Inbred MRL lpr ,Fas Ligand Protein ,Lymphocyte ,T cell ,Immunology ,Apoptosis ,Biology ,Fas ligand ,Article ,Mice ,Mice, Congenic ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,fas Receptor ,Bone Marrow Diseases ,Bone marrow failure ,Fas receptor ,medicine.disease ,Lymphocyte Subsets ,Lymphoproliferative Disorders ,Mice, Mutant Strains ,Clone Cells ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Gene Expression Regulation ,Cancer research ,Bone marrow - Abstract
Bone marrow (BM) and lymphocyte samples from aplastic anemia patients show up-regulated Fas and Fas-ligand (FasL) expression, respectively, supporting a relationship between immune-mediated BM destruction and the Fas apoptotic pathway. Mice with spontaneous lymphoproliferation (lpr) and generalized lymphoproliferative disease (gld) mutations exhibit abnormal expression of Fas and FasL, serving as potential models to elucidate underlying mechanisms of BM failure. We examined cellular and functional characteristics of lpr and gld mutants on the C57BL/6 (B6) background. Lymph node (LN) cells from lpr and gld mice produced less apoptosis when coincubated with C.B10-H2b/LilMcd (C.B10) BM cells in vitro. This functional difference was confirmed by infusing lpr, gld, and B6 LN cells into sublethally irradiated CB10 mice. All donor LN cells showed significant T cell expansion and activation, but only B6 LN cells caused severe BM destruction. Mice infused with gld LN cells developed mild to moderate BM failure despite receiving FasL-deficient effectors, thus suggesting the existence of alternative pathways or incomplete penetrance of the mutation. Paradoxically, mice that received Fas-deficient lpr LN cells also had reduced BM failure, likely due to down-regulation of proapoptotic genes, an effect that can be overcome by higher doses of lpr LN cells. Our model demonstrates that abnormal Fas or FasL expression interferes with the development of pancytopenia and marrow hypoplasia, validating a major role for the Fas/FasL cytotoxic pathway in immune-mediated BM failure, although disruption of this pathway does not completely abolish marrow destruction.
- Published
- 2009