Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Lymphokines – e.g. – interferons – interlukins – etc.
Reexamination Certificate
1999-08-31
2003-06-24
Mertz, Prema (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Lymphokines, e.g., interferons, interlukins, etc.
C536S023500, C435S069520, C435S071100, C435S071200, C435S325000, C435S320100, C435S471000, C435S252300, C435S254110, C424S085200
Reexamination Certificate
active
06583270
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns a novel human cytokine. In particular, isolated nucleic acid molecules are provided encoding interleukin-19 (IL-19). IL-19 polypeptides are also provided, as are vectors, host cells and recombinant methods for producing the same. The invention further concerns therapeutic methods for modulating cytokine production.
2. Related Art
Interleukin-10 (IL-10) is a pleiotropic cytokine that has been implicated as an important regulator of the functions of lymphoid and myeloid cells. IL-10 blocks activation of cytokine synthesis and several accessory functions of macrophages, thus acting as a potent suppressor of the effector functions of macrophages, T cells and NK cells. IL-10 has also been implicated in the regulation of differentiation of B cells, mast cells and thymocytes.
IL-10 was identified independently in two different lines of experiments. One of these identified a B-cell-derived mediator which co-stimulated active thymocytes (Suda et al.,
Cell Immunol.
129:228 (1990)). The other identification determined that IL-10 is involved in the cross-regulation between two often mutually exclusive effector arms of immunity carried out by T helper (CD4
+
) subpopulations, Th1 (involved in cell-mediated immune responses) and Th2 (involved in antibody-mediated immune responses). In this role, IL-10 is expressed by Th2 cells and functions to suppress cytokine production by Th1 cells, an activity termed cytokine synthesis inhibitory factor (CSIF) activity.
cDNA clones encoding murine IL-10 (mIL-10) were isolated based on the expression of CSIF activity (Moore et al., Science 248:1230-34 (1990)). cDNA clones encoding human IL-10 (hIL-10) were subsequently identified by cross-hybridization with the mouse cDNA (Vieira et al.,
Proc. Natl. Acad. Sci USA
88:1172-1176 (1991)). mIL-10 is expressed by mouse CD4
+
Th2 cells, at least one CD8
+
clone, B lymphomas, T cells, activated mast cell lines, activated macrophages, keratinocytes, and Ly-1 B (B-1) cells (Fiorentino, D. F. et al.,
J. Exp. Med.
170:2081 (1989); (Moore et al.,
Science
248:1230-34 (1990); 87-93 (1992); Lin et al.,
Ann. N.Y. Acad. Sci.
651 O'Garra et al.
Int. Immunol.
2: 821-832 (1990); MacNeil et al.,
J. Immunol.
145: 4167-4173 (1990); Fiorentino et al.,
J. Immunol.
147:3815-3822 (1991); Hisatsune et al,
Lymphokine Cytokine Res.
11:651-683 (1992)). hIL-10 is expressed by human CD4
+
T cells and Th0, Th1, and Th2 T cell clones, by CD8
+
T cells and clones (Yssel et al.,
J. Immunol.
), monocytes/macrophages, keratinocytes, activated B cells, B lymphomas, and Burkitt lymphoma lines infected with a transforming EBV strain, but not with a non-transforming strain (Vieira, P. et al.,
Proc. Natl. Acad. Sci. USA
88:1172-76 (1991); de Waal-Malefyt, R. et al.,
J. Exp. Med.
174:1209-20 (1991); de Waal-Malefyt, R. et al.,
J. Exp. Med.
174:915-24 (1991); Salgame, P. et al,
Science
254:279-82 (1991); Yamamura, M. et al.,
Science
254:277-79 (1991); Ralph, P. et al.,
J. Immunol.
148:808-14 (1992); Benjamin, D. et al.,
Blood
80:1289-98 (1992)). Thus, IL-10 is not strictly a Th2-specific cytokine, and its pattern of expression resembles IL-6 more than IL-4 or IL-5 (Wang, S. C. et al.,
Transplant. Proc.
23:2920-22 (1991)). Like IL-6 but unlike most other T cell derived cytokines, IL-10 expression is not inhibited by cyclosporin or FK-506 (Wang, S. C. et al.,
Transplant Proc.
23:2920 (1991)).
In an attempt to determine the in vivo role of IL-10, normal mice were treated from birth to adulthood with IL-10-neutralizing antibodies (Wang, S. C. et al.,
Transplant Proc.
23:2920 (1991); Ishida, H. et al.,
J. Exp. Med.
175:1213 (1992)) The resulting phenotypic changes included an increased level of circulating IFN-&ggr;, TNF-&agr; and IL-6, reduced serum IgM and IgA, a marked depletion of peritoneal B cells, and an inability to develop in vivo antibody responses to two bacterial antigens known be combatted with antibody produced by peritoneal B cells (Hayakawa, K. et al.,
Annu. Rev. Immunol.
6:197 (1988)). The reduction in peritoneal B cells was determined to be a consequence of IFN-&ggr; elevation (Ishida, H. et al.,
J. Exp. Med.
175:1213 (1992)).
Other experiments have shown that IL-10 suppresses in vitro production of inflammatory monokines such as TNF-&agr; and IL-1. This data corresponds to in vivo studies which show that IL-10 antagonists elevate the same inflammatory monokines. These results predict a strong anti-inflammatory role for IL-10. In addition, IL-10 antagonists may be useful to enhance Th1 immunity, which could be beneficial in infectious diseases of viral origin, or diseases involving intracellular pathogens.
The diverse biological activities of IL-10 have led to predictions that both IL-10 and its antagonists will have a wide range of clinical applications. It is clear that there is a continuing need in the art for isolating novel cytokines capable of mediating such diverse biological processes.
SUMMARY OF THE INVENTION
The present invention provides isolated nucleic acid molecules comprising a polynucleotide encoding a human IL-19 polypeptide having the amino acid sequence in
FIG. 1
[SEQ ID NO: 2] or the amino acid sequence encoded by the cDNA clone deposited as ATCC Deposit Number 97662 on Jul. 17, 1996. The nucleotide sequence determined by sequencing the deposited IL-19 cDNA clone, which is shown in
FIG. 1
[SEQ ID NO: 1], contains an open reading frame encoding a polypeptide of about 177 amino acid residues including an initiation codon at nucleotide positions 44-46, a leader sequence of about 24 amino acid residues and a deduced molecular weight of about 20.4 kDa. The 153 amino acid sequence of the predicted mature IL-19 protein is shown in
FIG. 1
(last 153 residues) and in SEQ ID NO:2 (from amino acid residue 1 to residue 153).
The present invention also relates to recombinant vectors which include the isolated nucleic acid molecules of the present invention and to host cells containing the recombinant vectors, as well as to methods of making such vectors and host cells and for using them for production of IL-19 polypeptides or peptides by recombinant techniques.
The invention further provides an isolated IL-19 polypeptide having an amino acid sequence encoded by a polynucleotide described herein.
IL-19, which is secreted, and which has significant homology to IL-10, is believed by the present inventors to be expressed only, or at least primarily, in activated monocytes (FIG.
4
). Thus, detecting IL-19 gene expression in cells of the immune system is useful for identifing activated monocytes. Further, for a number of disorders, it is believed by the inventors that significantly higher or lower levels of IL-19 gene expression can be detected in bodily fluids (e.g., serum, plasma, urine, synovial fluid or spinal fluid) taken from an individual having such a disorder, relative to a “standard” IL-19 gene expression level, i.e., the IL-19 expression level in bodily fluids from an individual not having the disorder. Thus, the invention provides a diagnostic method useful during diagnosis of a disorder related to an abnormal level of IL-19 gene expression, which involves (a) assaying IL-19 gene expression level in cells or body fluid of that individual; (b) comparing that IL-19 gene expression level with a standard IL-19 gene expression level, whereby an increase or decrease in the assayed IL-19 gene expression level compared to the standard expression level is indicative of a disorder. An additional aspect of the invention is related to a method for treating an individual in need of an increased level of IL-19 activity in the body, which involves administering to such an individual a composition comprising an IL-19 polypeptide of the invention. A still further aspect of the invention is related to a method of treating an individual in need of a decreased level of IL-19 activity in the body, which involves administering to such an individual a composit
Kenny Joseph J.
Rosen Craig A.
Human Genome Sciences Inc.
Mertz Prema
Sterne Kessler Goldstein & Fox P.L.L.C.
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