COMPOSITION FOR DIAGNOSIS OF DISEASES

Abstract

The present invention relates to a composition for diagnosis of pancreatic diseases, more specifically, to a composition which can diagnose pancreatic cancer, a kit for diagnosis comprising the same, and a method of providing information for diagnosis using the composition.

The present invention can accurately predict or identify the risk of pancreatic cancer, and moreover, can diagnose pancreatic cancer by effectively distinguishing pancreatic cancer from different types of cancer. In addition, in the present invention, it is possible to diagnose pancreatic cancer simply and rapidly through a non-invasive method by using monocytes obtained from blood, serum or plasma obtained from an individual.

Claims

1. A composition for diagnosing a pancreatic disease comprising an agent for measuring an expression level of at least one protein selected from the group consisting of an interleukin 10 receptor (IL-10R), an interleukin 22 receptor (IL-22R), interleukin 22 (IL-22), interleukin 29 (IL-29), and interferon lambda receptor 1 isoform 1 (IFNLR1 isoform 1), or mRNA of a gene encoding the protein.

2. The composition according to claim 1, wherein the composition is to a mononuclear cell isolated from a target subject.

3. The composition according to claim 1, wherein the composition comprises an agent for measuring an expression level of the interleukin 10 receptor or mRNA of the gene encoding the interleukin 10 receptor.

4. The composition according to claim 3, wherein the composition further comprises an agent for measuring an expression level of the interleukin 22 receptor or mRNA of the gene encoding the interleukin 22 receptor.

5. The composition according to claim 3, wherein the composition further comprises an agent for measuring an expression level of at least one protein selected from the group consisting of interleukin 22 (IL-22), interleukin 29 (IL-29), and interferon lambda receptor 1 isoform 1 (IFNLR1 isoform 1), or mRNA of the gene encoding the protein.

6. The composition according to claim 1, wherein the agent for measuring the expression level of the protein comprises at least one selected from the group consisting of antibodies, oligopeptides, ligands, PNAs (peptide nucleic acids) and aptamers that specifically bind to the protein.

7. The composition according to claim 1, wherein the agent for measuring the expression level of the mRNA comprises at least one selected from the group consisting of primers, probes and antisense nucleotides that specifically bind to the mRNA.

8. The composition according to claim 1, wherein the pancreatic disease is a pancreatic cancer.

9. A kit for diagnosing a pancreatic disease comprising the composition for diagnosis according to any one of claims 1 to 8.

10. The kit according to claim 9, wherein the kit is an RT-PCR kit, a DNA chip kit, an ELISA kit, a protein chip kit, a rapid kit, or a multiple reaction-monitoring (MRM) kit.

11. A method of providing information for diagnosis of a pancreatic disease comprising measuring an expression level of at least one protein selected from the group consisting of an interleukin 10 receptor (IL-10R), an interleukin 22 receptor (IL-22R), interleukin 22 (IL-22), interleukin 29 (IL-29), or interferon lambda receptor 1 isoform 1 (IFNLR1 isoform 1), or mRNA of a gene encoding the protein in a biopsy specimen isolated from a target subject.

12. The method according to claim 11, wherein the biopsy specimen is at least one selected from the group consisting of blood, serum and plasma isolated from the subject.

13. The method according to claim 12, wherein the biopsy specimen comprises at least one of a mononuclear cell or exosome isolated from the subject.

14. The method according to claim 11, comprising measuring an expression level of the interleukin 10 receptor, or mRNA of a gene encoding the interleukin 10 receptor from the biopsy specimen.

15. The method according to claim 14, further comprising measuring an expression level of the interleukin 22 receptor, or mRNA of a gene encoding the interleukin 22 receptor from the biopsy specimen.

16. The method according to claim 14, further comprising measuring an expression level of at least one protein selected from the group consisting of interleukin 22, interleukin 29 and interferon lambda receptor 1 isoform 1, or mRNA of a gene encoding the protein from the biopsy specimen.

17. The method according to claim 11, wherein likelihood of the onset of the pancreatic disease is determined to be high, when the expression level of the protein or the mRNA measured from the biopsy specimen isolated from the target subject is higher than an expression level of a normal control group.

18. The method according to claim 14, wherein likelihood of the onset of the pancreatic disease is determined to be high, when the expression level of the interleukin 10 receptor or the mRNA of the gene encoding the interleukin 10 receptor measured from the biopsy specimen isolated from the target subject is 2 times or more the expression level of the normal control group.

19. The method according to claim 15, wherein likelihood of the onset of the pancreatic disease is determined to be high, when the expression level of the interleukin 22 receptor or the mRNA of the gene encoding the interleukin 22 receptor measured from the biopsy specimen isolated from the target subject is higher than an expression level of a normal control group.

20. The method according to claim 19, wherein likelihood of the onset of the pancreatic disease is determined to be high, when the expression level of the interleukin 22 receptor or the mRNA of the gene encoding the interleukin 22 receptor measured from the biopsy specimen isolated from the target subject is 1.5 times or more the expression level of the normal control group.

21. The method according to claim 11, wherein the pancreatic disease is a pancreatic cancer.

22. A method of screening a therapeutic drug for a disease comprising: (a) measuring an expression level of at least one protein selected from the group consisting of an interleukin receptor, an interleukin 22 receptor, interleukin 22, interleukin 29 and interferon lambda receptor 1 isoform 1 or mRNA of a gene encoding the protein in a biopsy specimen isolated from a patient with the disease; (b) administering a candidate drug to the patient; and (c) measuring the expression level of at least one protein selected from the group consisting of an interleukin 10 receptor, an interleukin 22 receptor, interleukin 22, interleukin 29 and interferon lambda receptor 1 isoform 1, or the mRNA of the gene encoding the protein in the biopsy specimen isolated from the patient, after the administration of the candidate drug.

Description

DESCRIPTION OF DRAWINGS

[0103] Reference will now be made in detail to the preferred embodiments of the present invention, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts.

[0104] FIG. 1 shows the proportion (%) of the number of mononuclear cells expressing IL-22 relative to the total number of mononuclear cells in blood collected from the normal control group, pancreatic cancer patients, pancreatitis patients, lung cancer patients and colorectal cancer patients using FACS analysis in Example 1.

[0105] FIG. 2 shows the proportion (%) of the number of mononuclear cells expressing IL-22R relative to the total number of mononuclear cells in blood collected from the normal control group, pancreatic cancer patients, pancreatitis patients, lung cancer patients and colorectal cancer patients using FACS analysis in Example 1.

[0106] FIG. 3 shows the proportion (%) of the number of mononuclear cells expressing IL-10R relative to the total number of mononuclear cells in blood collected from the normal control group, pancreatic cancer patients, pancreatitis patients, lung cancer patients and colorectal cancer patients using FACS analysis in Example 1.

[0107] FIG. 4 is a graph showing comparison of mRNA expression levels of IL-10RB in mononuclear cells in the blood collected from the normal control group, pancreatic cancer patients, cholangiocarcinoma patients and gallbladder cancer patients in Example 2.

[0108] FIG. 5 is a graph showing comparison of mRNA expression levels of IL-10RA in mononuclear cells in the blood collected from the normal control group, pancreatic cancer patients, cholangiocarcinoma patients and gallbladder cancer patients in Example 2.

[0109] FIG. 6 is a graph showing comparison of mRNA expression levels of IL-22 in mononuclear cells in the blood collected from the normal control group, pancreatic cancer patients, cholangiocarcinoma patients and gallbladder cancer patients in Example 3.

[0110] FIG. 7 is a graph showing comparison of mRNA expression levels of IL-29 in mononuclear cells in the blood collected from the normal control group, pancreatic cancer patients, cholangiocarcinoma patients and gallbladder cancer patients in Example 3.

[0111] FIG. 8 is a graph showing comparison of mRNA expression levels of IFNLR1 isoform 1 in mononuclear cells in the blood collected from the normal control group, pancreatic cancer patients, cholangiocarcinoma patients and gallbladder cancer patients in Example 4.

[0112] FIG. 9 is a graph showing comparison of mRNA expression levels of IFNLR1 isoform 3 in mononuclear cells in the blood collected from the normal control group, pancreatic cancer patients, cholangiocarcinoma patients and gallbladder cancer patients in Example 4.

[0113] FIG. 10 shows the proportion (%) of the number of mononuclear cells expressing IL-22 relative to the total number of mononuclear cells in blood collected from pancreatic cancer patients before and after surgery in Example 5.

[0114] FIG. 11 shows the proportion (%) of the number of mononuclear cells expressing IL-22R relative to the total number of mononuclear cells in blood collected from pancreatic cancer patients before and after surgery in Example 5.

[0115] FIG. 12 shows the proportion (%) of the number of mononuclear cells expressing IL-10R relative to the total number of mononuclear cells in blood collected from pancreatic cancer patients before and after surgery in Example 5.

[0116] FIG. 13 is a graph showing the results of analysis through paired T test after measuring the proportion of the number of mononuclear cells expressing IL-10R relative to the total number of mononuclear cells in blood collected from pancreatic cancer patients before surgery and 3 months after surgery in Example 6.

[0117] FIG. 14 is a graph showing comparison of mRNA expression levels of IL-10RB in exosomes collected from the normal control group, pancreatic cancer patients, cholangiocarcinoma patients and gallbladder cancer patients in Example 7.

[0118] FIG. 15 is a graph showing comparison of mRNA expression levels of IL-22RA in exosomes collected from the normal control group, pancreatic cancer patients, cholangiocarcinoma patients and gallbladder cancer patients in Example 7.

[0119] FIG. 16 is a graph showing comparison of mRNA expression levels of IFNLR1 isoform 1 in exosomes collected from the normal control group, pancreatic cancer patients, cholangiocarcinoma patients and gallbladder cancer patients in Example 7.

BEST MODE FOR INVENTION

[0120] According to an embodiment of the present invention, the present invention is directed to a composition for diagnosing a disease containing an agent for measuring an expression level of at least one protein selected from the group consisting of an interleukin 10 receptor (IL-10R), an interleukin 22 receptor (IL-22R), interleukin 22 (IL-22), interleukin 29 (IL-29), and interferon lambda receptor 1 isoform 1 (IFNLR1 isoform 1), or mRNA of a gene encoding the protein.

[0121] According to another embodiment of the present invention, the present invention is directed to a kit for diagnosing a disease containing the composition for diagnosis according to the present invention.

[0122] According to yet another embodiment of the present invention, the present invention is directed to a method of providing information for diagnosis of a disease including measuring an expression level of at least one protein selected from the group consisting of an interleukin 10 receptor (IL-10R), an interleukin 22 receptor (IL-22R), interleukin 22 (IL-22), interleukin 29 (IL-29), or interferon lambda receptor 1 isoform 1 (IFNLR1 isoform 1), or mRNA of a gene encoding the protein in a biopsy specimen isolated from a target subject.

[0123] According to yet another embodiment of the present invention, the present invention is directed to a method of screening a therapeutic drug for a disease comprising (a) measuring an expression level of at least one protein selected from the group consisting of an interleukin 10 receptor, an interleukin 22 receptor, interleukin 22, interleukin 29 and interferon lambda receptor 1 isoform 1 or mRNA of the gene encoding the protein in a biopsy specimen isolated from a patient with the disease, (b) administering a candidate drug to the patient, and (c) measuring the expression level of at least one protein selected from the group consisting of an interleukin 10 receptor, an interleukin 22 receptor, interleukin 22, interleukin 29 and interferon lambda receptor 1 isoform 1, or the mRNA of the gene encoding the protein in the biopsy specimen isolated from the patient, after the administration of the candidate drug.

MODE FOR INVENTION

[0124] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are provided only for illustration of the present invention and should not be construed as limiting the scope of the present invention.

Preparation Example 1

[0125] Histopaq 1077 was purchased from Sigma-Aldrich Corporation, and Brefeldin A was purchased from BioLegend Inc. As antibodies, Alexa 647 anti-IL-22 and PE anti-mouse IL-10R were purchased from BioLegend Inc., and PerCP mouse IL-22R was purchased from R & D. PBS (phosphate buffered solution) containing 0.5% bovine serum albumin (BSA) was used as a FACS buffer. A cell fixation buffer and a perm/wash buffer were also purchased from BioLegend Inc.

Example 1

[0126] 1. Isolation of Peripheral Blood Mononuclear Cells (PBMCs)

[0127] Blood samples were collected from 3 pancreatic cancer patients, 3 pancreatitis patients, 3 normal control group subjects, 3 lung cancer patients and 3 colorectal cancer patients and stored at room temperature. Since the separation of mononuclear cells is difficult when blood viscosity is high, blood samples were prepared through 1:1 dilution in 1PBS. Ficoll (Histopaque 1077, Sigma) was prepared in the same volume as blood in a 15 ml conical tube. Blood samples were added onto Ficoll such that the blood samples were not mixed. The resulting blood samples were centrifuged at 400 g for 30 minutes with minimum acceleration and deceleration. During this process, a white-cell (mononuclear cell) layer was separately collected, and PBS was added thereto to conduct washing with centrifugation at 400 g for 3 minutes. The washed cells were collected, resuspended in 50 l FACS buffer, and then cultured on ice for 1 hour with a PE anti-mouse IL-10R antibody and a PerCP mouse IL-22R antibody. The cells were then washed twice with FACS buffer and resuspended in 500 l FACS buffer.

[0128] 2. Treatment with Brefeldin A

[0129] The collected cells were counted, seeded at 110.sup.6 cells/ml in RPMI 1640 medium containing 2% penicillin and streptomycin, treated with 1Brefeldin A and cultured for 6 hours.

[0130] 3. Fixing, Perming and Staining

[0131] The cultured cells were collected, washed twice with FACS buffer (0.5% BSA in PBS), and fixed with 500 l of fixed buffer on ice for 30 minutes. Then, the cells were washed twice with FACS buffer, resuspended in 1 ml of perm buffer and then centrifuged twice for 20 minutes. Then, the cells were collected again, resuspended in 50 l of perm buffer and then cultured on ice for 1 hour with Alexa 647 anti-IL-22 antibody. The cells were washed twice with FACS and resuspended in 500 l of FACS buffer.

[0132] 4. FACS Analysis

[0133] The number of cells expressing IL-10R, IL-22R or IL-22 relative to the total number of mononuclear cells was expressed in % using a FACSCalibur (BD Biosciences, San Jose, Calif.). The results are shown in the following Table 1 and FIGS. 1 to 3. In the following Table 1, data are expressed as meanSD, and statistical analysis was performed using the Kruskal-Wallis test using Dunn's post hoc analysis.

TABLE-US-00001 TABLE 1 Mean SD (%) Normal Pancreatic Lung Item control group Pancreatitis cancer cancer Colorectal cancer IL-22 2.44 0.02 4.06 3.49 2.25 1.31 0.51 0.43 0.21 0.01 IL-22R 2.16 0.49 40.30 8.00 14.20 14.88 0.60 0.55 0.37 0.13 IL-10R 2.59 0.75 38.40 7.80 23.20 8.65 7.13 4.93 2.01 0.89

[0134] As shown in Table 1 and FIGS. 1 to 3, the expression levels of IL-22 in pancreatitis patients and pancreatic cancer patients correspond to about 1.7 times and 0.9 times relative to the expression level of IL-22 in the normal control group respectively, but the expression level of IL-10R, to which IL-22 binds, was about 14.8 times increased in the pancreatitis patients than in the normal control group, and was about 9.0 times increased in the pancreatic cancer patients than in the normal control group. However, the expression level of IL-10R was about 2.75 times increased in lung cancer patients than in the normal control group, and the expression level of IL-10R was about 0.78 times decreased in the colorectal cancer patients than in the normal control group.

[0135] In addition, it was found that, regarding the expression level of IL-22R, the pancreatitis patients had an increase of about 18.66 times compared to the normal control group, and the pancreatic cancer patients had an increase of about 6.57 times compared to the normal control group. However, the lung cancer patients had a decrease of about 0.28 times compared to the normal control group and the colorectal cancer patients had a notable decrease of about 0.17 times compared to the normal control group.

[0136] Further, regarding the expression level of IL-22R relative to IL-22, the expression level of IL-22R relative to the expression level of IL-22 in pancreatitis patients was about 9.93 times, and the expression level of IL-22R relative to the expression level of IL-22 in pancreatic cancer was about 6.31 times. This indicates that, although IL-22 binds to IL-22R, the expression level of IL-22R was significantly increased compared to IL-22. However, the expression level of IL-22R relative to the expression level of IL-22 in lung cancer patients was about 1.18 times, and the expression level of IL-22R relative to the expression level of IL-22 in colorectal cancer patients was about 1.76 times. This indicates that the expression level of IL-22 is similar to that of IL-22R.

[0137] These results demonstrate that the expression level of IL-10R in pancreatitis or pancreatic cancer patients is clearly differentiated from that of the normal control group or patients of other diseases, and pancreatitis and pancreatic cancer also have distinct expression behaviors.

[0138] Therefore, with the method according to the present invention, pancreatitis and pancreatic cancer can be detected and diagnosed with high accuracy, and the diagnosis can be carried out while distinguishing between pancreatitis and pancreatic cancer.

Example 2

[0139] Blood samples were collected from 4 normal control group subjects, 4 pancreatic cancer patients, 2 cholangiocarcinoma patients and 2 gallbladder cancer patients, and peripheral blood mononuclear cells (PBMCs) were separated from the blood samples in the same manner as in Example 1, and the ratio of mRNA expression levels of IL-10R beta subunits (IL-10RB) and IL-22R alpha subunits (IL-22RA) in the PBMCs compared to the normal control group was measured, and the results are shown in FIGS. 4 and 5.

[0140] As shown in FIGS. 4 and 5, IL-10RB mRNA expression level increased about 3 times and IL-22RA mRNA expression level increased about 6 times, respectively, in PBMCs isolated from pancreatic cancer patients compared to the normal control group, but the expression level of IL-10RB mRNA in cholangiocarcinoma and gallbladder cancer patients increased about 1 to 2 times, and the expression level of IL-22RA mRNA decreased in cholangiocarcinoma patients.

[0141] These results indicate that the mRNA expression levels of IL-10RB and IL-22RA detected in PBMCs were significantly increased in pancreatic cancer compared to other types of cancer.

Example 3

[0142] Blood samples were collected from 4 normal control group subjects, 4 pancreatic cancer patients, 2 cholangiocarcinoma patients and 2 gallbladder cancer patients, and peripheral blood mononuclear cells (PBMCs) were separated from the blood samples in the same manner as in Example 1, and the ratio of mRNA expression levels of IL-22 and IL-29 in the PBMCs compared to the normal control group was measured, and the results are shown in FIGS. 6 and 7.

[0143] As shown in FIGS. 6 and 7, the expression levels of IL-22 mRNA and IL-29 mRNA were increased about 4 times or more in PBMCs isolated from pancreatic cancer patients compared to the normal control group, but the expression levels of the two markers in cholangiocarcinoma patients were decreased, and the expression levels thereof in gallbladder cancer patients were increased only about 2 to 3 times.

[0144] These results indicate that the mRNA expression levels of IL-22 and IL-29 detected in PBMCs were significantly increased in pancreatic cancer compared to other types of cancer.

Example 4

[0145] Blood samples were collected from 4 normal control group subjects, 4 pancreatic cancer patients, 2 cholangiocarcinoma patients and 2 gallbladder cancer patients, peripheral blood mononuclear cells (PBMCs) were then separated from the blood samples in the same manner as in Example 1, and the ratio of mRNA expression levels of interferon receptor 1 isoform 1 (IFNLR1 isoform 1) and interferon receptor 1 isoform 3 (IFNLR1 isoform 3), which bind to IL-29, in the PBMCs compared to the normal control group was measured, and the results are shown in FIGS. 8 and 9.

[0146] As shown in FIGS. 8 and 9, the mRNA expression level of interferon receptor 1 isoform 1, which binds to IL-29, increased about 3 times or more in PBMCs isolated from pancreatic cancer patients compared to the normal control group, but increased about 1 to 2 times in cholangiocarcinoma and gallbladder cancer patients.

[0147] These results indicate that the mRNA expression level of interferon receptor 1 isoform 1 detected in PBMCs was significantly increased in pancreatic cancer compared to other types of cancer.

Example 5

[0148] Blood samples were collected from pancreatic cancer patients who underwent pancreatic cancer resection (pancreatotomy) before and after the surgery, PBMCs were then isolated from the blood samples in the same manner as in Example 1, and the number of cells expressing IL-10R, IL-22R or IL-22 relative to the total number of mononuclear cells was expressed in % using a FACSCalibur (BD Biosciences, San Jose, Calif.). The results are shown in the following Table 2 and FIGS. 10 to 12.

TABLE-US-00002 TABLE 2 Mean SD (%) Item Before surgery After surgery IL-22 2.56 3.45 1.30 1.53 IL-22R 6.98 9.75 4.65 5.78 IL-10R 13.89 9.74 7.41 5.85

[0149] As can be seen from Table 2 and FIGS. 10 to 12, when the total mass of pancreatic cancer tissue is reduced due to pancreatotomy of pancreatic cancer patients, the expression levels of IL-10R, IL-22 and IL-22R in mononuclear cells are remarkably decreased, and in particular, the expression level of IL-10R is significantly decreased.

Example 6

[0150] Blood samples were collected from pancreatic cancer patients who underwent pancreatic cancer resection (pancreatotomy) before surgery and 3 months after surgery, PBMCs were then isolated from the blood samples in the same manner as in Example 1, and the number of cells expressing IL-10R (marker C) relative to the total number of mononuclear cells was measured using a FACSCalibur (BD Biosciences, San Jose, Calif.) and then analyzed using a paired T test. The results are shown in FIG. 13.

[0151] As shown in FIG. 13, the proportion of mononuclear cells expressing IL-10R was significantly decreased after the cancer tissue was removed from pancreatic cancer patients using pancreatotomy compared to before surgery.

Example 7

[0152] Blood samples were collected from 4 normal control group subjects, 4 pancreatic cancer patients, 2 cholangiocarcinoma patients and 2 gallbladder cancer patients, exosomes circulating in the plasma were separated from the blood samples, and the ratio of mRNA expression levels of IL-10R beta subunit (IL-10RB), IL-22R alpha 1 (IL-22RA) and interferon receptor 1 isoform 1 (IFNLR1 isoform 1) in the exosomes compared to the normal control group was measured, and the results are shown in FIGS. 14 to 16.

[0153] As can be seen from FIGS. 14 to 16, the expression levels of IL-10RB mRNA, IL-22RA mRNA and interferon receptor 1 isoform 1 mRNA were about 4 times, about 1.5 times and about 2.5 times increased, respectively, in the exosomes isolated from pancreatic cancer patients than in the normal control group. However, in the exosomes isolated from cholangiocarcinoma patients, the expression level of IL-10RB mRNA was about 1.5 times increased than that of the normal control group, and the expression level of interferon receptor 1 isoform 1 mRNA was only about 1.5 times increased than that of the normal control group, particularly, the expression level of IL-22RA mRNA was decreased compared to the normal control group. In the case of gallbladder cancer patients, the expression level of IL-10RB mRNA was equivalent to that of the normal control group in the exosomes isolated therefrom, and the mRNA expression levels of IL-22RA and interferon receptor 1 isoform 1 were about 1.5 times higher at most compared to the normal control group.

[0154] The results showed that the expression levels of IL-10RB, IL-22RA and interferon receptor 1 isoform 1 mRNA expressed in exosomes isolated from plasma in pancreatic cancer patients were significantly increased compared to the normal control group and other cancer patients.

INDUSTRIAL APPLICABILITY

[0155] The present invention relates to a composition for diagnosis of a variety of diseases such as pancreatic cancer, a kit for diagnosis containing the same, and a method of providing information for diagnosis using the composition.

TABLE-US-00003 [SequenceListingFreeText] SEQIDNO:1(IL-10RB): mawslgswlggcllysalgmvpppenvrmnsynfknilqwespafakgnl tftaqylsyrifqdkcmnttltecdfsslskygdhtlryraefadehsdw ynitfcpvddtiigppgmqvevladslhmrflapkieneyetwtmknvyn swtynvqywkngtdekfqitpqydfevlrnlepwttycyqvrgflpdrnk agewsepvceqtthdetvpswmvavilmasvfmvclallgcfallwcvyk ktkyafsprnslpqhlkeflghphhntllffsfplsdendvfdklsviae dsesgkqnpgdscslgtppgqgpqs SEQIDNO:2(IL-22RA): mrtlltiltvgslaahapedpsdllqhvkfqssnfeniltwdsgpegtpd tvysieyktygerdwvakkgcqritrkscnltvetgnltelyyarvtavs aggrsatkmtdrfsslqhttlkppdvtciskvrsiqmivhptptpiragd ghrltledifhdlfyhlelqvnrtyqmhlggkqreyeffgltpdteflgt imicvptwakesapymcrvktlpdrtwtysfsgaflfsmgflvavlcyls yryvtkppappnslnvqrvltfqplrfiqehvlipvfdlsgpsslaqpvq ysqirvsgprepagapqrhslseitylgqpdisilqpsnvpppqilspls yapnaapevgppsyapqvtpeaqfpfyapqaiskvqpssyapqatpdswp psygvcmegsgkdsptgtlsspkhlrpkgqlqkeppagscmlgglslqev tslameesqeakslhqplgictdrtsdpnvlhsgeegtpqylkgqlplls svqieghpmslplqppsrpcspsdqgpspwglleslvcpkdeakspapet sdleqpteldslfrglaltvqwes SEQIDNO:3(IL-22): maalqksvssflmgtlatscllllallvqggaaapisshcrldksnfqqp yitnrtfmlakeasladnntdvrligeklfhgvsmsercylmkqvlnftl eevlfpqsdrfqpymqevvpflarlsnrlstchiegddlhiqrnvqklkd tvkklgesgeikaigeldllfmslrnaci SEQIDNO:4(IL-29): maaawtvvlvtlvlglavagpvptskptttgkgchigrfkslspqelasf kkardaleeslklknwscsspvfpgndlrllqvrerpvaleaelaltlkv leaaagpaledvldqplhtlhhilsqlqaciqpqptagprprgrlhhwlh rlqeapkkesagcleasvtfnlfrlltrdlkyvadgnlclrtsthpest SEQIDNO:5(IFNLR1isoform1): magperwgplllcllqaapgrprlappqnvtllsqnfsvyltwlpglgnp qdvtyfvayqssptrrrwreveecagtkellcsmmclkkqdlynkfkgrv rtvspsskspwveseyldylfevepappvlvltqteeilsanatyqlppc mppldlkyevafwkegagnktlfpvtphgqpvqitlqpaasehhclsart iytfsvpkyskfskptcfllevpeanwaflvlpsllilllviaaggviwk tlmgnpwfqrakmpraldfsghthpvatfqpsrpesvndlflcpqkeltr gvrptprvrapatqqtrwkkdlaedeeeedeedtedgvsfqpyieppsfl gqehqapghseaggvdsgrpraplvpsegssawdssdrswastvdsswdr agssgylaekgpgqgpggdghqeslpppefskdsgfleelpednlsswat wgtlppepnlvpggppvslqtltfcwesspeeeeeareseiedsdagswg aestqrtedrgrtlghymar