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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4439-4445
Correction of the PNH Defect by GPI-Anchored Protein Transfer
Elaine M. Sloand,
Jaroslaw P. Maciejewski,
Daniel Dunn,
Joel Moss,
Bryan Brewer,
Martha Kirby, and
Neal S. Young
From the Hematology Branch, Pulmonary Critical Care Medicine Branch,
and Molecular Disease Branch, National Heart, Lung, and Blood
Institute, Bethesda, MD.
Hemolytic anemia is a major feature of paroxysmal nocturnal
hemoglobinuria (PNH). Intravascular red blood cell (RBC)
destruction is caused by increased sensitivity of the abnormal
erythrocyte to complement-mediated lysis, due to the GPI absence of a
membrane-bound glycosylphosphatidylinositol (GPI)-linked protein,
which functions as an inhibitor of reactive lysis (CD59). Both in vivo
and in vitro models have suggested the feasibility of cell-to-cell
transfer of GPI proteins, and patients with hemolysis could potentially benefit from transfer of CD59 to their deficient erythrocytes. We
studied the ability of RBC components prepared from outdated packed RBC
collections, as well as high-density lipoprotein (HDL) preparations,
rich in CD55 and CD59, to promote protein transfer, as assessed by flow
cytometry, immunoblotting, and susceptibility to complement-mediated
lysis. By flow cytometry, CD55 and CD59 were present on RBC-derived
microvesicles that stained with an antiglycophorin antibody Ab; in
addition, soluble CD59 and CD55 were detected by immunoblot in soluble
fractions eluated from RBC units stored for more than 35 days, but not
in fresh blood. Both commercial HDL preparations and those prepared in
our laboratory contained CD55 and CD59, as assayed by immunoblot. When
RBC that were deficient (GPI)-anchored protein, obtained from five
patients, with PNH were incubated with HDL preparations for 2 to 4 hours, there was significant transfer of both proteins to the cell
surface, as demonstrated by flow cytometry. Washed RBC microvesicles,
prepared by ultrasonification, also mediated transfer of GPI-linked
proteins to deficient RBC. Pretreatment of microvesicles, RBC eluate
preparations, and HDL with phosphatidylinositol-specific, phospholipase
C, abrogated protein transfer to deficient cells, indicating that
increased cell-associated CD55 and CD59 levels were related to
insertion of the intact GPI moiety, rather than to simple adhesion. PNH RBC that were exposed to HDL, RBC eluate preparations, or microvesicles demonstrated decreased in vitro complement-mediated hemolysis in the
Ham test. Transfer of GPI-linked proteins from soluble preparations
containing CD55 and CD59 to PNH erythrocytes is feasible and may have
clinical utility.
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