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1.
Cancer Immunol Immunother ; 53(7): 617-24, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15175906

ABSTRACT

A Wilms' tumor gene WT1 is expressed at high levels not only in most types of leukemia but also in various types of solid tumors, including lung and breast cancer. WT1 protein has been reported to serve as a target antigen for tumor-specific immunotherapy both in vitro in human systems and in vivo in murine models. We have shown that mice immunized with WT1 peptide or WT1 cDNA could reject a challenge from WT1-expressing tumor cells (a "prophylactic" model). However, it was not examined whether WT1 peptide vaccination had the potency to reject tumor cells in a "therapeutic" setting. In the present study, we demonstrated for the first time that WT1 peptide vaccination combined with Mycobacterium bovis bacillus Calmette-Guérin cell wall skeleton (BCG-CWS) was more effective for eradication of WT1-expressing tumor cells that had been implanted into mice before vaccination (a "therapeutic" model) compared with WT1 peptide vaccination alone. An intradermal injection of BCG-CWS into mice, followed by that of WT1 peptide at the same site on the next day, generated WT1-specific cytotoxic T lymphocytes (CTLs) and led to rejection of WT1-expressing leukemia or lung cancer cells. These results showed that BCG-CWS, which was well known to enhance innate immunity, could enhance WT1-specific immune responses (acquired immunity) in combination with WT1 peptide vaccination. Therefore, WT1 peptide vaccination combined with BCG-CWS may be applied to cancer immunotherapy in clinical settings.


Subject(s)
Cancer Vaccines/therapeutic use , Leukemia/therapy , Lipopolysaccharides/immunology , Lung Neoplasms/therapy , Peptide Fragments/immunology , Vaccination , WT1 Proteins/immunology , Animals , Bone Marrow/immunology , Bone Marrow/metabolism , Bone Marrow/pathology , Colony-Forming Units Assay , Immunotherapy , Kidney/immunology , Kidney/metabolism , Kidney/pathology , Leukemia/metabolism , Lung Neoplasms/metabolism , Male , Mice , Mice, Inbred C57BL , Peptide Fragments/therapeutic use , T-Lymphocytes, Cytotoxic/immunology , Tumor Cells, Cultured/transplantation , WT1 Proteins/therapeutic use
2.
Int J Hematol ; 77(5): 463-70, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12841384

ABSTRACT

In the thymi of WT1-transgenic (Tg) mice with the 17AA+/KTS- spliced form of the Wilms tumor gene WT1 driven by the lck promoter, the frequencies of CD4-CD8- double-negative (DN) thymocytes were significantly increased relative to those in normal littermates. Of the 4 subsets of CD4-CD8- DN thymocytes, the DN1 (CD44+CD25-) subset increased in both frequency and absolute cell number, whereas the DN2 (CD44+CD25+) and DN3 (CD44-CD25+) subsets decreased, indicating the blocking of thymocyte differentiation from the DN1 to the DN2 subsets. Furthermore, CD4-CD8+ T-cell receptor (TCR) -gammadelta T-cells increased in both frequency and absolute cell number in the spleen and peripheral blood of the WT1-Tg mice relative to those of normal littermates. The CD8 molecules of these CD4-CD8+ TCRgammadelta T-cells were CD8alphabeta, suggesting that they originated from the thymus. These results are the first direct evidence demonstrating that the WT1 gene is involved in the development and differentiation of T-lineage cells.


Subject(s)
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/genetics , Promoter Regions, Genetic , T-Lymphocytes/cytology , Thymus Gland/cytology , WT1 Proteins/physiology , Animals , Antigens, CD/analysis , CD8 Antigens/analysis , CD8-Positive T-Lymphocytes/cytology , Cell Count , Cell Differentiation , Mice , Mice, Transgenic , Receptors, Antigen, T-Cell, gamma-delta , T-Lymphocyte Subsets/cytology , WT1 Proteins/genetics
3.
Blood ; 101(6): 2261-7, 2003 Mar 15.
Article in English | MEDLINE | ID: mdl-12406893

ABSTRACT

Vascular endothelial growth factor (VEGF) is a major growth factor for developing endothelial cells (ECs). Embryonic lethality due to haploinsufficiency of VEGF in the mouse highlighted the strict dose dependency of VEGF on embryonic vascular development. Here we investigated the dose-dependent effects of VEGF on the differentiation of ES cell-derived fetal liver kinase 1 (Flk-1)/VEGF receptor 2(+) (VEGFR2(+)) mesodermal cells into ECs on type IV collagen under a chemically defined serum-free condition. These cells could grow even in the absence of VEGF, but differentiated mostly into mural cells positive for alpha-smooth muscle actin. VEGF supported in a dose-dependent manner the differentiation into ECs defined by the expression of VE-cadherin, platelet-endothelial cell adhesion molecule 1 (PECAM-1)/ CD31, CD34, and TIE2/TEK. VEGF requirement was greater at late than at early phase of culture during EC development, whereas response of VEGFR2(+) cells to VEGF-E, which is a virus-derived ligand for VEGFR2 but not for Flt-1/VEGFR1, was not dose sensitive even at late phase of culture. Delayed expression of VEGFR1 correlated with increased dose dependency of VEGF. These results suggested that greater requirement of VEGF in the maintenance than induction of ECs was due to the activity of VEGFR1 sequestering VEGF from VEGFR2 signal. The chemically defined serum-free culture system described here provides a new tool for assessing different factors for the proliferation and differentiation of VEGFR2(+) mesodermal cells.


Subject(s)
Embryo, Mammalian/cytology , Endothelial Growth Factors/pharmacology , Endothelium, Vascular/cytology , Intercellular Signaling Peptides and Proteins/pharmacology , Lymphokines/pharmacology , Stem Cells/cytology , Vascular Endothelial Growth Factor Receptor-1/physiology , Vascular Endothelial Growth Factor Receptor-2/analysis , Animals , Antigens, CD , Antigens, CD34/analysis , Cadherins/analysis , Cell Differentiation/drug effects , Cells, Cultured , Culture Media, Serum-Free , Dose-Response Relationship, Drug , Endothelial Growth Factors/administration & dosage , Gene Expression , Intercellular Signaling Peptides and Proteins/administration & dosage , Lymphokines/administration & dosage , Mesoderm/cytology , Mice , Platelet Endothelial Cell Adhesion Molecule-1/analysis , RNA, Messenger/analysis , Stem Cells/chemistry , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factor Receptor-1/genetics , Vascular Endothelial Growth Factors
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