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Lymphocytes with Aberrant Expression of Fas or Fas Ligand Attenuate Immune Bone Marrow Failure in a Mouse Model¹

Stephanie O. Omokaro^2,*, Marie J. Desierto^*, Michael A. Eckhaus, Felicia M. Ellison^*, Jichun Chen^* and Neal S. Young^*

^* Hematology Branch, National Heart, Lung, and Blood Institute, and Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, MD

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-H2^b/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.

¹ S.O. designed the study, performed the experiments, and wrote the paper. M.J.D. and F.M.E. performed the experiments, M.A.E. performed pathological examinations, and J.C. and N.S.Y. designed the study and wrote the paper.

² Address correspondence and reprint requests to Stephanie O. Omokaro, M.D., Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10 Clinical Research Center Room 3E-5140, 10 Center Drive, Bethesda, MD 20892. E-mail address: omokaros{at}mail.nih.gov

³ Abbreviations used in this paper: AA, aplastic anemia; BM, bone marrow; CBC, complete blood count; DN, double negative; FasL, Fas-ligand; gld, generalized lymphoproliferative disease; LN, lymph node; lpr, lymphoproliferation; PB, peripheral blood; PE-Cy5, PE-Cyanin 5; RBM, residual BM; SP, spleen; TBI, total body irradiation; TH, thymus; Treg, regulatory T cell.