Interleukin-12: Basic Principles and Clinical Applications
The most important advance in the last 10 years in our understanding of how to direct the immune response by vaccination or immunotherapy has been the description and subsequent refinement of the T helper type 1/2 (Th 1/2) paradigm. (Mosmann and Coffman 1
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Introduction . . . . . . . . . . . . . . . . . . . . . . . .
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The Interleukin-12 Molecule: Its Genes and Its Receptor
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Cell Types Producing Interleukin-12 . . . . . . .
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Molecular Control of Interleukin-12 Production.
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In Vitro Activities of Interleukin-12
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Interleukin-12 Induction of Th I Responses.
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Role of Interleukin-12 in Infections . . . . .
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Use of Interleukin-12 as an Adjuvant fix Infectious Diseases.
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Use of Interleukin-12 in Tumor Therapy . . . . . . . .
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Use of Interleukin-12 as an Immunotherapeutic Agent
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Interleukin-12: Future Use in Clinical Settings.
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References. . . . . . . . . . . . . . . . . . . . . . . .
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1 Introduction The most important advance in the last 10 years in our understanding of how to direct the immune response by vaccination or immunotherapy has been the description and subsequent refinement of the T helper type I /2 (Th I /2) paradigm (MOSMANN and COFFMAN 1989). This paradigm has provided the framework necessary to formulate basic questions related to defining the cues pathogens provide that shape the immune response. A major advance in this area came with the discovery of interleukin-12 (IL-12) (KOBAYASHI et al. 1989; STERN et al. 1990) and the subsequent demonstration that I L-12 promotes the development of Th I cells in vitro (HSIEH et al. 1993; MANElTl et al. 1993). Thus, in naive T cell populations exposure to antigen in the presence of I L-12 for several days, followed by
IThe Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA 2Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104-6008, USA
R. L. Coffman et al. (eds.), Redirection of Th1 and Th2 Responses © Springer-Verlag Berlin Heidelberg 1999
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G. Trinchieri and P. Scott
restimulation with antigen alone, led to the development of interferon (IFN)-y producing T cells. Moreover, it was found that one could link together I L-12, the innate immune response, pathogens, and Th I cell development. This was done by showing that bacteria, such as Listeria monocytogenes, induced Th I cell development and that this occurred by stimulation of macrophages to produce IL-12 (D'ANDREA et al. 1992; HSIEH et al. 1993). This observation has led to the description of a common pathway leading from the innate immune response to adaptive immunity, in which intracellular pathogens stimulate macrophages to prod uce I L-12, which promotes the development of Th I cells from a naive cell population. This pathway can now be exploited to develop approaches for the design of new immunotherapies and vaccines.
2 The Interleukin-12 Molecule: Its Genes and Its Receptor Interleukin-12 is a heterodimeric cytokine, composed of a heavy chain of 40kDa (p40) and a light chain of 35 kDa (p35), originally described with the names of natural killer stimulatory factor (NKSF) (KOBAYASHI et al. 1989) or cytotoxic lymphocyte maturation factor (CLM F) (STERN et al. 1990). I L-12 is produce
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