TY - JOUR
T1 - In vitro and in vivo evidence of PNH cell sensitivity to immune attack after nonmyeloablative allogeneic hematopoietic cell transplantation
AU - Takahashi, Yoshiyuki
AU - McCoy, J. Philip
AU - Carvallo, Cristian
AU - Rivera, Candido
AU - Igarashi, Takehito
AU - Srinivasan, Ramaprasad
AU - Young, Neal S.
AU - Childs, Richard W.
PY - 2004/2/15
Y1 - 2004/2/15
N2 - 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 alloimmune 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 family donor 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 after transplantation. 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 flow cytometry sorting. Equivalent amounts of interferon-γ (IFN-γ) were secreted following coculture 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 5 patients survive without evidence of PNH 5 to 39 months after transplantation. 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.
AB - 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 alloimmune 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 family donor 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 after transplantation. 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 flow cytometry sorting. Equivalent amounts of interferon-γ (IFN-γ) were secreted following coculture 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 5 patients survive without evidence of PNH 5 to 39 months after transplantation. 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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U2 - 10.1182/blood-2003-04-1281
DO - 10.1182/blood-2003-04-1281
M3 - Article
C2 - 14525787
AN - SCOPUS:0842285673
SN - 0006-4971
VL - 103
SP - 1383
EP - 1390
JO - Blood
JF - Blood
IS - 4
ER -