This invention relates generally to extracellular signal molecules, and more particularly, relates to a member of the tumor necrosis factor (TNF) family of molecules designated as TREPA, reagents and methods for its detection as well as its use in therapeutics.
The TNF (tumor necrosis factor) family is an expanding set of extracellular signaling molecules (ligands) with biological activities that are intimately associated with a variety of disease conditions. The prototypic member of this family, TNF, is well known as a mediator of septic shock, inflammation, and graft versus host disease. See, for example, A. Cerami, Immunol Today, 9:28-31 (1988); M. Revel, Ciba Found Symp, 129:223-233 (1987); J. Cohen, J. Bone Marrow Transplant 3(3):193-197 (1988). Also, because of its beneficial effects on vasculature of solid tumors, isolated perfusion of TNF is being evaluated as a therapeutic agent for cancer patients. M. W. Boehme, Eur. J. Clin. Invest. 26:404-410 (1996).
The important role of the TNF family in immune regulation has been demonstrated by mutations both in mice and humans. For instance, mice with a loss of function mutation in the TNF family member known as Fas ligand present a variety of disorders including lymphadenopathy and autoimmune disease. See, for example, R. Watanabe-Fukunaga, Nature 356:314-317 (1992); Takahishi et al., Cell 76:969-966, (1994); Adiachi et al., PNAS, 90:1756 (1993); Fisher et al., Cell 81:953-946 (1995); F. Rieux-Laucat, Science 268:1347 (1995). Another example of the immune regulation role is mutation of the TNF family member CD40 ligand in humans. Spontaneous CD40 ligand mutations in human patients result in hyper IgM syndrome, demonstrating the requirement of CD40 ligand for B-cell maturation and isotype switching. Also, targeted disruption of TNF family member LTa in mice results in failure to develop peripheral lymph nodes. P. De Togni, Science 264:703-707 (1994).
Another property of this family of ligands which is potentially clinically useful is the ability to selectively induce apoptosis (programmed cell death) in a variety of cancer cells, but not in most normal cells. The two known members of the TNF family which induce apoptosis in the widest variety of cell lines are TRAIL (TNF related apoptosis inducing ligand) and Fas ligand. See, for example, T. Suda et al., Cell 75:1169-1178 (1993); Wiley et al., Immunity 3:673-682, (1995). This property is unique to the TNF family of ligands.
Members of the TNF family of ligands can be identified by a region of amino acid conservation, which is approximately restricted to the N-terminal 150 amino acids. This region forms a b-pleated sheet structure, which trimerizes and interacts with the cognate receptors.
Specifically, with the exception of lymphotoxin-alpha, members of the TNF family of ligands are type II membrane spanning proteins whole extracellular C-terminal domains combine to form these trimeric complexes. These ligand trimers, either presented on cell surfaces or shed to produce soluble molecules, initiate a variety of biological activities by cross-linking congnate members of the parallel family of TNF receptors (Smith, C. A. et al., Cell 76:959-962). These activities include T-cell co-stimulation (Goodwin, R. G. et al., Eur. J. Immunol, 23:2631-2641; Smith, C. A. et al., Cell 73:1349-1360; and Goodwin, R. G. et al., Cell 73:447-456.), apoptosis (Daniel, P. T. et al., J. Immunol. 152:5624-5632 and Wiley, S. R. et al., Immunity. 3:673-682), B-cell proliferation and isotype switching (Allen, R. C. et al., Science 259:990-993 and Alderson, M. R. et al., J. Exp. Med. 181:71-77), and development of peripheral lymph nodes (De Tongi, P. et al., Science 264:703-707).
Further, within the aforementioned N-terminal domain there are isolated regions of homology which correspond to the strands of the b-pleated sheet. Therefore, the total amino acid sequence identity between TNF family members is not high, but can be recognized by those skilled in the art.
Given the crucial roles of members of this family of molecules in immune regulation, investigation into the existence and identity of other members of the TNF family is desirable. The identification and characterization of these molecules provide means to identify and treat a variety of immune disorders.