In:
The Journal of Immunology, The American Association of Immunologists, Vol. 186, No. 1_Supplement ( 2011-04-01), p. 57.8-57.8
Abstract:
IL-4 supports the differentiation and function of B and T cells, but also induces a response in virtually all cell types. Lymphocytes express mostly the IL-4 type I receptor (IL-4Ra and common gamma (CG) chains), and non-hematopoietic cells express primarily the type II receptor (IL-4Ra and IL-13Ra1 chains; also receptor for IL-13), while other leukocytes express both. We have engineered human IL-4 variants with up to 3-logs higher affinity for CG, or up to 2-logs increased binding to IL-13Ra1. Binding of these variants did not perturb receptor orientation. Selected variants were tested on various human cell lines or peripheral blood cells for their ability to differentially induce phospho-STAT6. The RGA variant, which has the highest affinity for CG and lost 1-log binding affinity to IL-13Ra1, induced significantly more pSTAT6 in the Ramos B cell line and in primary lymphocytes, and less pSTAT6 in epithelial and fibroblastic cells, compared to IL-4. Conversely, the KFR variant, which had the highest affinity to IL-13Ra1, had the opposite effect on these cells. Relative abundance (or scarcity) of CG and IL-13Ra1 on the cell surface dictated the potency of each variant: cells expressing high levels of both receptors were not affected, whereas cells expressing limited CG benefited most from the increased affinity afforded by RGA. These new variants have potential therapeutic application in targeting selective cell types, and thereby reducing toxic effects in vivo.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.186.Supp.57.8
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2011
detail.hit.zdb_id:
1475085-5
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