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- Botling, Johan, et al.
(författare)
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CD49f (alpha 6 integrin) and CD66a (BGP) are specifically induced by retinoids during human monocytic differentiation
- 1995
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Ingår i: Leukemia. - 0887-6924 .- 1476-5551. ; 9:12, s. 2034-41
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Tidskriftsartikel (refereegranskat)abstract
- Retinoic acid (RA) and 1,25(OH)2-cholecalciferol (VitD3) are potent regulators of normal and malignant myeloid cells. In the human monoblast cell line U-937 they induce terminal differentiation, and the resulting phenotypes display both common and distinct, inducer-specific, properties. This paper shows that in U-937 cells the two retinoids, all-trans and 9-cis RA, induced the expression of CD49f (alpha 6 integrin subunit) and CD66a (biliary glycoprotein, BGP) mRNA and protein. In contrast, expression of CD49f and CD66a was not found in untreated or VitD3-induced cells. Cytokine-induced modulation of CD49f and CD66a expression was restricted to the retinoid-induced U-937 cells. The retinoid specific induction of CD49f and CD66a was confirmed in the related monoblastic cell line THP-1. Human blood monocytes and the monocytic cell line Mono Mac 6 responded poorly to RA, with respect to the regulation of CD49f and CD66a expression, indicating that early monocytic precursors were targets for the retinoid-specific regulation. Thus, the expression of CD49f and CD66a is developmentally regulated and specifically induced by all-trans and 9-cis Ra in human monocytic cells.
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- Gidlöf, Cecilia, et al.
(författare)
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Antibodies can direct superantigen-mediated T cell killing of chronic B-lymphocytic leukemia cells
- 1995
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Ingår i: Leukemia. - 0887-6924 .- 1476-5551. ; 9:9, s. 1534-1542
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Tidskriftsartikel (refereegranskat)abstract
- The bacterial superantigen staphylococcal enterotoxin A (SEA) is a highly potent activator of cytotoxic T cells when presented on MHC class II molecules of target cells. Our earlier studies showed that such SEA-directed T cells efficiently killed chronic B lymphocytic leukemia (B-CLL) cells. With the ultimate goal to replace the natural specificity of SEA for MHC class II molecules with the specificity of a monoclonal antibody (mAb), we initially made a mutated protein A-SEA (PA-SEAm) fusion protein with > 100-fold reduced binding affinity for MHC class II compared to native SEA. The fusion protein was successfully used to direct T cells to B-CLL cells coated with different B lineage specific (CD19, CD20) or associated (CD37, CD40) mAbs. The PA-SEAm protein was 10-100-fold more potent against mAb coated compared to uncoated HLA class II+ B-CLL cells. No correlation was seen between the amount of mAb bound to the cell surface and sensitivity to lysis. Preactivation of B-CLL cells by phorbol ester increased their sensitivity, and lysis was dependent on ICAM-1 molecules. However, no preactivation of the target cells was needed when a cocktail of two or four mAbs was used. Circulating leukemia and spleen cells were equally well killed. We conclude that the natural target specificity of SEA, MHC class II, can be reduced by mutagenesis and novel binding specificity can be introduced by linkage to tumor reactive mAbs. Our findings encourage the construction of recombinant SEA mutant fusion proteins for specific T cell therapy of hematopoietic tumors such as B-CLL.
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