Natural killer cell enhancing factor C

Details Natural killer cell enhancing factor C Natural killer cell enhancing factor C

1999-09-29

2001-09-25

Mertz, Prema (Department: 1646)

Drug, bio-affecting and body treating compositions

Lymphokine

C530S351000, C514S002600, C514S008100, C514S012200, C514S885000, C536S023100, C536S023500, C435S069500, C435S071200, C435S252300, C435S254110, C435S325000, C435S471000, C435S320100

Reexamination Certificate

active

06294164

ABSTRACT:

This invention relates to newly identified polynucleotides, polypeptides encoded by such polynucleotides, the use of such polynucleotides and polypeptides, as well as the production of such polynucleotides and polypeptides. More particularly, the polypeptide of the present invention has been putatively identified as a natural killer cell enhancing factor C, sometimes hereinafter referred to as “NKEF C.” The invention also relates to inhibiting the action of such polypeptides.
Natural killer (NK) cells are a subset of lymphocytes capable of lysing a variety of tumor cells without prior activation. Lymphokine-activated killer (LAK) cells are mainly NK cells activated by interleukin-2, and are capable of lysing wider ranges of tumor cells with higher cytotoxic activity. NK cells are proposed to function as natural surveillance to deter cancer development in the body (Whiteside, T. and Herberman, R. B.,
Clin. Immunol. Immunopathol
., 58:1-23 (1989) and Trinchieri, G.,
Adv. Immunol
., 47:187-376 (1989)). LAK cells, in combination with IL-2, have been used in experimental models and in clinical studies to successfully treat some metastatic tumors (Rosenberg, S. A., et al.,
N. Engl. J. Med
., 316:889-897 (1987)). NK cells are also important controlling viral infection and the regulation of hematopoiesis (Trinchieri (1989), Kiessling, R., et al.,
Eur. J. Immunol
., 7:655-663 (1977), Kiessling, R. and Wigzell, H.,
Curr. Top. Microbiol. Immunol
., 92:107-123 (1981)). Given the important roles of NK/LAK cells in maintaining the host well-being, it is not surprising that their activities are stringently controlled in vivo.
NK/LAK activity is influenced by various cellular and humoral components in the blood (Golub, S. H., et al., R. E. Schmidt (ed.):
Natural Killer Cells: Biology and Clinical Application
, pp. 203-207, S. Karger, A G Basel (1990)), for instance, the regulation by red blood cells (RBC), which enhance NK cytotoxicity against different target cells (Shau, H., et al., E. Lotzova (ed.):
Natural Killer Cells: Their Definition, Functions, Lineage and Regulation
: pp. 235-349, S. Karger, A G Basel (1993)) and which also upregulate LAK development (Yannelli, J. R., et al.,
Cancer Res
., 48:5696-5700 (1988)).
Oxdidative stress is an important yet incompletely understood phenomenon, cells use reactive oxygen species (ROS) to carry out essential functions. Under proper control, ROS initiates conception, cell differentiation and proliferation. If not properly controlled, ROS causes serious damage to cellular components which may lead to apoptotic cell death. ROS are known to cause large-scale cell death, senile changes, inflammation and tissue injuries in the body.
Two NKEF genes (NKEF-A and B) from a K562 erythroleukemia cell cDNA library have recently been cloned (Shau, H., et al.,
Immunogenetics
, 40:129-134 (1994)). They have been identified as members of a new class of highly conserved antioxidant proteins. They share extensive homology with each other (88% identical at the amino acid level, 71% identical in nucleotide sequence). It is not clear whether the dimeric NKEF is a homo- or hetero-dimer of the A or B peptides in vivo. NKEF A and NKEF B are differentially expressed in different tissues. NKEF A and NKEF B have similar antioxidant activity, but NKEF A has higher NK enhancing activity than NKEFB. Transfecting NKEF DNA into different cells resulted in cell-type-dependent enhanced cell proliferation or growth inhibition.
This large family of proposed antioxidant genes are highly conserved from bacteria to mammals while mammals have been found to carry more than one NKEF-related gene, bacteria and yeast have been found to carry only one copy (Sauri, H., et al.). Members of this family have been described as thiol-specific antioxidants. These genes (NKEF-A and B) encode recombinant proteins which possess antioxidant function in the protection of protein and DNA from oxidative damage. NKEF is a 44 kD protein isolated from red blood cell cytosol that increases NK cell cytotoxicity to tumor target cells (Shau, H., et al.,
Cell. Immunol
., 147, 1-11 (1993)). NKEF is a diner protein composed of two approximately 22 kD monomers linked by disulphide bonds.
Two of the other NKEF-related proteins are human thiol-specific antioxidant protein (HPRP) isolated from a hippocampus cDNA library, and the proliferation-associated gene (PAG), found to be hyperexpressed in transformed cells. HPRP is 95% identical to NKEF B by nucleotide sequences, and 93% identical by amino acid sequence. Alignment with NKEF-related proteins in other species suggested that NKEF B and HPRP are the same. PAG shares 98% identity with NKEF A by nucleotide sequence, and 97% at the amino acid level, and may be identical to NKEFA.
In mice, the two homologous genes are MSP23 and MER5. MER5 is 61% identical to NKEF A in amino acid sequence and 64% identical to NKEFB. Even more striking is MSP23, which is 93% identical to NKEF A and 76% identical to NKEFB. MSP23 is induced by oxidative stress in mouse macrophage. MER5 is hyperexpressed in murine erythroleukemic cells, and is necessary for differentiation in those cells. NKEF and NKEF-related proteins show no sequence homology to other known antioxidants, such as catalase, superoxide dismutase, or glutathione peroxidase, nor do they exhibit the enzymatic activity of those antioxidants.
This family of antioxidant genes has been found to selectively suppress activation of NF-&kgr;B. Nuclear factor &kgr;B (NF-&kgr;B) is a transcriptional activator important for the expression of human immunodeficiency virus type I (HIV-I) upon T-cell activating stimuli (Englund, G. et al.,
Virology
, 181:150-157 (1991), Nabel, G., and Baltimore, D.,
Nature
(London), 326:711-713 (1987)). Most of the target genes of NF-&kgr;B in T-cells and other types encode proteins involved in immune, inflammatory and acute phase responses.
The polypeptide of the present invention has been putatively identified as a natural killer enhancing factor C due to its amino acid sequence homology with human natural killer enhancing factor. This identification has been made as a result of amino acid sequence homology.
In accordance with one aspect of the present invention, there is provided a novel mature polypeptide, as well as biologically active and diagnostically or therapeutically useful fragments, analogs and derivatives thereof. The polypeptide of the present invention is of human origin.
In accordance with another aspect of the present invention, there are provided isolated nucleic acid molecules encoding a polypeptide of the present invention, including mRNAs, DNAs, cDNAs, genomic DNAs as well as analogs and biologically active and diagnostically or therapeutically useful fragments thereof.
In accordance with yet a further aspect of the present invention, there is provided a process for producing such polypeptide by recombinant techniques comprising culturing recombinant prokaryotic and/or eukaryotic host cells, containing a nucleic acid sequence encoding a polypeptide of the present invention, under conditions promoting expression of said protein and subsequent recovery of said protein.
In accordance with yet a further aspect of the present invention, there is provided a process for utilizing such polypeptide, or polynucleotide encoding such polypeptide for therapeutic purposes, for example, to inhibit the growth of leukemia cells, to treat viral infection, to augment the effects of natural killer protein to treat neoplasias such as tumors and cancers, to prevent inflammation, and to prevent damage from superoxide radicals in the body, for example, tissue injury and aging.
In accordance with yet a further aspect of the present invention, there are also provided nucleic acid probes comprising nucleic acid molecules of sufficient length to specifically hybridize to a nucleic acid sequence of the present invention.
In accordance with yet a further aspect of the present invention, there are provided antibodies against such polypeptides.
In accordance with another aspect of the present invention, the

Affiliated with

Also associated with

Rating

Natural killer cell enhancing factor C does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Natural killer cell enhancing factor C, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Natural killer cell enhancing factor C will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2526863