Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Using tissue cell culture to make a protein or polypeptide
Reexamination Certificate
1997-01-17
2001-08-14
Gambel, Phillip (Department: 1644)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Using tissue cell culture to make a protein or polypeptide
C435S326000, C435S334000, C435S343000, C435S343100, C435S343200, C435S346000, C530S387100, C530S388100, C530S388700, C530S388200, C530S388220, C530S388730, C530S388750
Reexamination Certificate
active
06274347
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to human leukocyte-associated cell surface proteins, particularly to leukocyte adhesion molecule-1 (LAM+1) and methods for its detection.
BACKGROUND OF THE INVENTION
The ability of leukocytes to leave the circulation and to migrate into tissues is a critical feature of the immune response. Normally, the infiltrating leukocytes phagocytize invading organisms or dead or damaged cells. However, in pathologic inflammation, infiltrating leukocytes can cause serious and sometimes deadly damage. Leukocyte-mediated inflammation is implicated in a number of human clinical manifestations, including the adult respiratory distress syndrome, multi-organ failure and reperfusion injury.
Several different receptor adhesion molecules participate in the process of adhesion and transmigration of leukocytes through vascular endothelium at sites of inflammation (Springer, Nature 346:425-434 (1990)). One of the several molecules involved in the initial attachment of leukocytes to endothelium is the leukocyte adhesion molecule-1 (LAM-1, L-selectin) (Kishimoto et al., Proc. Natl. Acad. Sci. USA 87:2244-2248 (1990); Ley et al., Blood 77:2553-2555 (1991); Spertini et al., J. Immunol. 147:2565-2573 (1991)). LAM-1 is a member of the selectin family of adhesion molecules (Bowen et al., J. Cell Biol. 109:421-427 (1989); Siegelman et al., Proc. Natl. Acad. Sci. USA 86:5562-5566 (1989); Tedder et al., J. Exp. Med. 170:123-133 (1989)) that includes, the mouse L-selectin, MEL-14 (Gallatin et al., Nature 304:30-34 (1983); Lasky et al., Cell 56:1045-1055 (1989); Siegelman et al., Science 243:1165-1172 (1989)), Endothelial-Leukocyte Adhesion Molecule-1 (ELAM-1, E-selectin) (Bevilacqua et al., Proc. Natl. Acad. Sci. USA 84:9238-9243 (1987); Bevilacqua et al., Science 243:1160-1164 (1989); Luscinskas et al., J. Immunol. 1422257 (1989); Luscinskas et al., J. Immunol. 146:1617-1625 (1991)), and CD62 (PADGEM, GMP-140, P-selectin) (Geng et al., Nature 343:757-760 (1990); Johnston et al., Cell 56:1033-1044 (1989); Larsen et al., Cell 59:305-312 (1989); Larsen et al., Cell 63:467-474 (1990)). All selectins are derived from evolutionarily related genes (Collins et al., J. Biol. Chem. 266:2466-2478 (1991); Johnston et al., J. Biol. Chem. 34:21381-21385 (1990); Ord et al., J. Biol. Chem. 265:7760-7767 (1990); Watson et al., J. Exp. Med. 172:263-272 (1990)), and are characterized by an NH
2
,-terminal, Ca
+
-dependent lectin domain, an epidermal growth factor (EGF)-like domain followed by multiple short consensus repeat (SCR) domains, a transmembrane region, and a cytoplasmic tail.
LAM-1 is expressed on the surface of most leukocytes, including lymphocytes, neutrophils, monocytes, eosinophils, hematopoietic progenitor cells and immature thymocytes (Griffin et al., J. Immunol. 145:576-584 (1990); Tedder et al., J. Immunol. 144:532-540 (1990)). LAM-1 is a highly glycosylated protein of 95-105,000 M
r
on neutrophils and 74,000 M
r
on lymphocytes (Griffin et al., J. Immunol. 145:576-584 (1990); Tedder et al., Eur. J. Immunol. 20:1351-1355 (1990)). Human LAM-1 and mouse MEL-14 mediate the binding of lymphocytes to high endothelial venues (HEV) of peripheral lymph nodes through interactions with a constitutively expressed ligand (Imai et al., J. Cell Biol. 113:1213-1221 (1991); Kishimoto et al., Proc. Natl. Acad. Sci. USA 87:2244-2248 (1990); Spertini et al., Leukemia 5:300-308 (1991); Stamper Jr. et al., J. Exp. Med. 144:828-833 (1976); Tedder et al., J. Immunol. 144:532-540 (1990)), and are also involved in lymphocyte, neutrophil and monocyte attachment at sites of inflammation (Hallmann et al., Biochem. Biophys. Res. Commun. 174:236-243 (1991); Jutila et al., J. Immunol. 143:3318-3324 (1989); Lewinsohn et al., J. Immunol. 138:4313-4321 (1987); Smith et al., J. Clin. Invest. 87:609-618 (1991); Spertini et al., J. Immunol. 147:2565-2573 (1991); Watson et al., Nature 349:164-167 (1991)). In vitro, endothelial cell surface expression of the LAM-1 ligand(s) is induced only after exposure of the endothelial cells to inflammatory cytokines, and the endothelial ligand shares many functional features with the LAM-1 ligand(s) expressed by HEV (Smith et al., J. Clin. Invest. 87:609-618 (1991); Spertini et al., J. Immunol. 147:2565-2573 (1991)). Sulfated carbohydrates and mAb that bind to the lectin domain of LAM-1 inhibit LAM-1-specific adhesion (Imai et al., J. Cell Biol. 113:1213-1221 (1991); Kansas et al., J. Cell Biol. 114:351-358 (1991); Spertini et al., J. Immunol. 147:2565-2573 (1991); Stoolman et al., Blood 70:1842-1850 (1987); Yednock et al., J. Cell Biol. 104:725-731 (1987); Yednock et al., J. Cell. Biol. 104:713-723 (1987)). The lectin domain of LAM-1. seems to act as the ligand binding unit to determine specificity, while the EGF-like and SCR domains appear to regulate the affinity of this interaction (Kansas et al., J. Cell Biol. 114:351-358 (1991); Siegelman et al., Cell 61:611-622 (1990); Spertini et al., J. Immunol. 147:942-949 (1991); Watson et al., J. Cell Biol. 115:235 (1991)).
It has been proposed that the treatment of a patient suffering from pathologic inflammation with an antagonist to adhesion receptor function can result in the reduction of leukocyte migration to a level manageable by the target endothelial cells and the subsequent dramatic recovery of the patient. Local administration of therapeutic agents can block competitively the adhesive interactions between leukocytes and the endothelium adjacent to an inflamed region. Therapeutic agents can also be administered on a systemic level for the treatment of a patient suffering from disseminated inflammation (Harlan and Liu, eds.,
Adhesion: Its Role in Inflammatory Disease,
W. H. Freeman (in press)).
A unique feature of the L-selectins is that both human LAM-1 and mouse MEL-14 are shed from the cell surface following cellular activation in vitro (Griffin et al., J. Immunol. 145:576-584 (1990); Jung et al., J. Immunol. 144:3130-3136 (1990); Kishimoto et al., Science 245:1238-1241 (1989); Kishimoto et al., Proc. Natl. Acad. Sci. USA 87:2244-2248 (1990); Spertini et al., Leukemia 5:300-308 (1991)). It has been proposed for the mouse that shedding of MEL-14 from leukocytes might be necessary to enable the leukocytes to transmigrate through endothelium into sites of inflammation in vivo (Jutila et al., J. Immunol. 143:3318-3324 (1989); Kishimoto et al., Science 245:1238-1241 (1989)). This would provide a rapid means for the regulation of leukocyte adhesion and de-adhesion to endothelium. Although the subsequent fate and possible function of the shed LAM-1 (sLAM-1) molecule is not known, the presence of a soluble factor present in rat thoracic duct lymph capable of inhibiting lymphocyte binding to HEV has been demonstrated (Chin et al., J. Immunol. 125:1764-1769 (1980)). Furthermore, this factor was shown to be antigenically related to a structure(s) present on lymphocytes (Chin et al., J. Immunol. 125:1764-1769 (1980); Chin et al., J. Immunol. 125:1770-1774 (1980); Chin et al., J. Immunol. 131:1368-1374 (1983)).
A number of surface molecules present on cells of various lineages are now known to be shed and thereby released into the extracellular milieu (Tedder, Am. J. Respir. Cell Mol. Biol. 5:305-306 (1991)). These include many of the growth factor receptors, the receptors for interleukin-1, interleukin-2 (CD25), transferrin (CD72), insulin, growth hormone, tumor necrosis factor (Porteu et al., J. Exp. Med. 172:599-607 (1990)), colony-stimulation factor-1 (Downing et al., Mol. Cell. Biol. 9:2890-2896 (1989)) and nerve growth factor (DiStefano et al., Proc. Natl. Acad. Sci. USA 85:270-274 (1988)) as well as CD8, and CD14. These proteins are quite diverse in structure and amino acid sequence and have no unifying functional characteristics that are currently appreciated. In most cases, proteases cleave the receptor near the membrane, releasing a nearly intact extracellular domain (DiStefano et al., Proc. Natl. Acad. Sci. USA 85:270-274 (1988); Downing et al., Mol. Cell. Biol. 9:2890-2896 (1989); Kishimoto et a
Schleiffenbaum Boris
Spertini Olivier
Tedder Thomas F.
Dana-Farber Cancer Institute Inc.
Fish & Neave
Gambel Phillip
Gunnison, Esq. Jane T.
Haley, Jr., Esq. James F.
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