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Blood, 15 February 2004, Vol. 103, No. 4, pp. 1383-1390.
Prepublished online as a Blood First Edition Paper on October 2, 2003; DOI 10.1182/blood-2003-04-1281.
Submitted April 24, 2003
Accepted September 6, 2003
In vitro and in vivo evidence of PNH cell sensitivity to immune attack after nonmyeloablative allogeneic hematopoietic cell transplantation
Yoshiyuki Takahashi, J Philip McCoy, Cristian Carvallo, Candido Rivera, Takehito Igarashi, Ramaprasad Srinivasan, Neal S Young, and Richard W Childs*
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Flow Cytometry Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Urologic Oncology Branch, National Cancer Institute, National Institues of Health, Bethesda, MD, USA
Department of Laboratory Medicine, the Warren Magnusson Clinical Center, National Institues of Health, Bethesda, MD, USA
* Corresponding author; email: childsr{at}nhlbi.nih.gov.
It has been proposed that paroxysmal nocturnal hemoglobinuria (PNH) cells may proliferate through their intrinsic resistance to immune-attack. To evaluate this hypothesis, we examined the impact of allo-immune pressure on PNH and normal cells in the clinical setting of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Five patients with severe PNH underwent HCT from an HLA-matched sibling after conditioning with cyclophosphamide and fludarabine. PNH neutrophils (CD15+/CD66b-/CD16-) were detected in all patients at engraftment, but they subsequently declined to undetectable levels in all cases by 4 months post-transplant. In order to test for differences in susceptibility to immune pressure, minor histocompatibility antigen (mHa) specific T-cell lines or clones were targeted against glycosylphosphatidylinositol (GPI)-negative and GPI-positive monocyte and B-cell fractions purified by FACS sorting. Equivalent amounts of IFN-gamma were secreted following co-culture with GPI-negative and GPI-positive targets. Furthermore, mHa specific T-cell lines and CD8+ T-cell clones showed similar cytotoxicity against both GPI-positive and GPI-negative B-cells. Presently, all five patients survive without evidence of PNH 5-39 months post-transplant. These in vitro and in vivo studies show PNH cells can be immunologically eradicated following nonmyeloablative HCT. Relative to normal cells, no evidence for a decreased sensitivity of PNH cells to T-cell mediated immunity was observed.
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