Modulation of TLR-4 Using a MD-2:Endotoxin Complex
A wild-type or mutant MD-2:Endotoxin covalently cross-linked complex can be used to activate or inhibit the TLR-4 receptor, thus modulating an innate immune response.
UIRF Case #:07003
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Teghanemt A, Prohinar P, Gioannini TL, Weiss JP. Transfer of monomeric endotoxin from MD-2 to CD14: characterization and functional consequences. J Biol Chem. 2007 Dec 14;282(50):36250-6.
Level of Development
General: in vitro
Researchers at the University of Iowa have created a complex that includes a wild-type or mutated protein and endotoxin which serves as a specific modulator of the TLR-4 receptor. This complex consists of an endotoxin, such as lipopolysaccharide (LPS), and the MD-2 protein (wild-type or mutant), the well-characterized co-factor for the TLR-4 receptor. The association of these co-ligands via a covalently cross-linked chimera creates a therapeutic compound that can up- or down-regulate activation of the TLR-4 receptor which serves to increase, decrease or prevent subsequent efforts to activate the host's immune system. Activation of TLR-4 has been associated with release of cytokines, most notably IL-8 and IFN-beta. These cytokines attract other immune cells and prime them to respond to an unknown invader, typically of bacterial origin. Activation of TLR-4 primes the immune system to rapidly respond to newly encountered bacteria and could be used to treat infections, in biodefense, or to increase the efficacy of a given vaccine. Inhibition of this pathway depresses the patients response to TLR-4 activating compounds and prevents the key cytokine-mediated signaling associated with TLR-4 activation and could be used for biodefense or other applications. The MD-2 mutation residues associated with this technology include: 25, 37, 51, 55, 58, 68, 69, 90, 91, 95, 99, 102, 103, 105, 114, 121, 122, 125, 126, 127, 128, 129, 130, 131, 132, 133 and/or 148.