Human cytotoxic T lymphocytes specific for Wilms' tumor antigen-1 inhibit engraftment of leukemia-initiating stem cells in non-obese diabetic-severe combined immunodeficient recipients.
Leukemia is a disease characterized by the malignant transformation of hematopoietic stem cells. Previous studies have shown that the Wilms' tumor antigen-1 (WT1) transcription factor is expressed at elevated levels in hematopoietic stem cells of leukemia patients compared with normal stem cells. In the past, we have generated cytotoxic T lymphocytes (CTL) specific for WT1, and we have shown that they killed WT1-expressing leukemia cell lines and inhibited the in vitro colony-forming activity of leukemia cells of patients. We used a xenotransplantation model to address whether WT1-specific CTL can selectively inhibit engraftment of malignant but not normal stem cells. CD34+ hematopoietic cells isolated from individuals with chronic myeloid leukemia or normal hematopoiesis were treated with WT1-specific CTL and injected into immunodeficient non-obese diabetic-severe combined immunodeficient mice. After 5 to 8 weeks, engraftment of leukemic or normal human cells was analyzed using immunohistology, flow cytometry, and polymerase chain reaction amplification of human sequences. The data showed that exposure of chronic myeloid leukemia CD34+ cells to WT1-specifc CTL completely prevented the development of leukemia in the recipient mice, whereas CTL treatment did not inhibit engraftment of normal CD34+ stem cells. The experiments indicate that WT1-specific CTL can discriminate between stem cells that give raise to leukemia and normal hematopoiesis in the xenogenic transplantation model. This supports the use of CTL with this specificity for treatment of leukemia patients undergoing stem-cell transplantation.
Gao
Liquan
L
Department of Immunology and Haematology, Imperial College of Science Technology and Medicine, Faculty of Medicine, Hammersmith Hospital, London.
Xue
Shao-An
SA
Hasserjian
Robert
R
Cotter
Finbarr
F
Kaeda
Jaspal
J
Goldman
John M
JM
Dazzi
Fancesco
F
Stauss
Hans J
HJ
D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D025721:WT1 Proteins / Q000276:immunology*
D018952:Antigens, CD34; D025721:WT1 Proteins