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A tumor-derived protein which provides T-cell costimulation through accessory cell activation.

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  • 1SUGEN, Inc., Redwood City, CA 94063, USA.


A recently described tumor-derived glycoprotein, designated 90K, has been shown to have positive effects on the generation of cytotoxic effector cells (NK/LAK) from human PBMC. To determine the mechanism of these effects, we have examined the effects of 90K on cytokine production by human PBMC. A culture of normal PBMC with 90K alone did not result in IL-2 secretion; however, in coculture with suboptimal doses of ConA, 90K increased IL-2 secretion by PBMC. Coculture of PBMC with 90K and ConA also resulted in increased production of the cytokines IL-1, IL-6, GM-CSF, and TNF alpha. T cells depleted of accessory cells failed to respond to ConA alone, 90K alone, or the combination of ConA and 90K, suggesting that this protein does not have a direct effect on T cells. However, 90K alone was sufficient to induce cytokine production by unfractionated PBMC (IL-1, IL-6, GM-CSF, and TNF alpha) or by CD14-enriched PBMC (IL-1 and IL-6). In addition, expression of ICAM-1 was increased on a human monocytic cell line cultured with purified 90K in the absence of any other stimulus. This 90K-induced upregulation of ICAM-1 expression was accompanied by an increased accessory function of the monocytes, demonstrated by their ability to support ConA-induced activation of peripheral blood T cells. Based on the current data, we propose a model in which 90K activates accessory cells, resulting in the secretion of cytokines and the expression of adhesion molecules, which in turn act as costimulatory signals for T-cell activation. Activated T cells then produce cytokines such as IL-2, which lead to a more vigorous cell-mediated immune response to tumor cells and virus-infected cells. Thus, 90K shows promise as an immunotherapeutic reagent for diseases such as cancer and viral infection.

[PubMed - indexed for MEDLINE]
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