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Biotech / Medical : Cistron Biotechnology(CIST)$.30

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To: Rudy Saucillo who wrote (1119)	4/29/1998 1:33:00 PM
From: Rudy Saucillo	Read Replies (2) of 2742

A couple of notes... (1) I spoke with Hal Smith again this morning. We had a miscommunication about the status of CIST's cancer vaccine research. Yes, they have reacquired the GTI sublicense as noted in the last quarterly report. No, they are not actively involved in new research with another company. I would be surprised if they're not pursuing this, however, since that's the only reason to reacquire the (long dormant) sublicense. (2) I found a description (below) of current IL-1b research being performed at Wash. U. Interesting stuff...researchers are investigating the therapeutic potential of IL-1. Rudy PHYSIOLOGIC AND THERAPEUTIC ROLES OF TUMOR NECROSIS FACTOR AND INTERLEUKIN-1 Robert D. Schreiber, Ph.D. Keywords: immunology, cytokines, TNF, IL-1, cell biology Tumor Necrosis Factor (TNF) and Interleukin-1 (IL-1) are pleiotropic cytokines that play important roles in promoting inflammatory reactions. We have initiated two research projects aimed at defining the physiologic roles of TNF and IL-1 in vivo and evaluating the therapeutic potential of these agents in the treatment of immunopathological diseases. Our recent work has demonstrated that TNF or IL-1 can completely and reversibly suppress immune responses if the agents are supplied to an individual prior to an immunologic challenge. Working in murine model systems we have blocked xenograft islet rejection and inhibited T cell priming to protein antigens by daily administration of TNF or IL-1. Our goal in this first project is to define the molecular mechanisms that underlie the immunosuppressive effects of these agents and explore whether the actions of these cytokines can be exploited to generate novel immunosuppressive therapeutics. The second project focuses on developing novel approaches to define the functional roles of TNF and IL-1 in vivo. Our laboratory has been one of the leaders in using neutralizing cytokine-specific monoclonal antibodies to elucidate the physiologic roles of endogenously produced cytokines in animal models. While these approaches have helped to document the general in vivo importance of TNF and IL-1, they have not defined the individual functional responses induced by these proteins in specific cellular targets in vivo. Recently, we ablated cellular responsiveness to particular cytokines in vitro by introducing functionally inactive cytokine receptors into homologous cells. The inactive receptors act as a dominant negative mutation and thereby completely paralyze the ability of the cell to respond to its cytokine agonist. We wish to capitalize on this observation and explore whether we can generate mice with tissue-specific defects in responsiveness to TNF and IL-1 by expressing inactive TNF- or IL-1-receptor mutants behind tissue-specific promoters. This approach will allow us to define the actions of each cytokine directly on specific tissues in an environment in which responses of other tissues to TNF and/or IL-1 are unaltered. These experiments should provide new insights into the biology of TNF and IL-1 and may result in the development of novel therapeutic approaches to regulate immune and inflammatory responses.

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