WO2006067427A2 - Method of diagnosis - Google Patents
Method of diagnosis Download PDFInfo
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- WO2006067427A2 WO2006067427A2 PCT/GB2005/004955 GB2005004955W WO2006067427A2 WO 2006067427 A2 WO2006067427 A2 WO 2006067427A2 GB 2005004955 W GB2005004955 W GB 2005004955W WO 2006067427 A2 WO2006067427 A2 WO 2006067427A2
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- WO
- WIPO (PCT)
- Prior art keywords
- level
- patient
- egf
- analytes
- transplant
- Prior art date
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6854—Immunoglobulins
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
- G01N2333/4701—Details
- G01N2333/4737—C-reactive protein
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/475—Assays involving growth factors
- G01N2333/485—Epidermal growth factor [EGF] (urogastrone)
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/52—Assays involving cytokines
- G01N2333/54—Interleukins [IL]
- G01N2333/5412—IL-6
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/52—Assays involving cytokines
- G01N2333/54—Interleukins [IL]
- G01N2333/55—IL-2
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/12—Pulmonary diseases
- G01N2800/122—Chronic or obstructive airway disorders, e.g. asthma COPD
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/24—Immunology or allergic disorders
- G01N2800/245—Transplantation related diseases, e.g. graft versus host disease
Definitions
- the present invention relates to the diagnosis of chronic obstructive pulmonary syndrome (COPD) and transplantation reaction.
- COPD chronic obstructive pulmonary syndrome
- COPD chronic pulmonary disease
- the disease is characterised by wheezing, breathing difficulties and chronic cough, and may become complicated by bronchitis, pneumonia and lung cancer.
- An organ or tissue transplant may be rejected by a patient because of an adverse transplantation reaction. Such a reaction is observed after an allogeneic (i.e. mismatched) transplant is made, causing destruction, detachment or rejection of the transplanted organ or tissue.
- Cytokines are low molecular weight proteins or glycoproteins that were initially characterised as communication molecules of the immune system. They can be secreted by a number of different cell types and play a key role in the regulation of the immune system and the co-ordination of the host response to injury and infection. Cytokines produce their actions by binding to specific high-affinity cell surface receptors. The range of actions displayed by individual cytokines can be broad and diverse and is dependent on the receptor. Receptors can be soluble and can bind to the cytokine, in turn inhibiting the binding of the cytokine to the cell surface receptor, blocking its biological. Cytokines operate within a complex network and may act synergistically or antagonistically. They can influence the production of other cytokines from other cell types. Initially, it was thought that the cytokines were restricted to the immune system but it has since been demonstrated that they are also involved in signalling in the central nervous and endocrine systems.
- Cytokines can be measured by either immunoassay or bioassay.
- Bioassays measure the functional activity of cytokines and require that some measure of biological activity be recorded.
- Immunoassays are based on an antibody that recognises a small portion of the cytokine and therefore most are very specific for the cytokine being measured. It is possible for biologically inactive cytokines and proteolytically degraded cytokines to be measured.
- the present invention is based on the discovery of a number of markers of COPD and kidney transplant rejection, including cytokines such as IL-6, IL-8 and EGF. 55
- a first aspect of the invention is a method of diagnosis of chronic obstructive pulmonary disease in a patient, which comprises:
- Another aspect of the invention is a method of diagnosis of transplantation reaction in a patient, which comprises:
- the transplant may be an organ or tissue transplant, for example a kidney transplant.
- a method of diagnosis of COPD preferably comprises determining the levels of IL-6, IL-8 and EGF.
- Diagnosis of transplantation reaction preferably involves determining the levels of a plurality of analytes, preferably including IL-2, IL-6, IL-8 and IL-10.
- diagnosis preferably further comprises determining the levels of one or more of urea, creatinine, uric acid and glucose. It will be appreciated that the benchmark levels may vary somewhat between patients and depend on such factors as the age, general health, weight, sex and diet or the patient in question.
- the levels of the or each analyte may be determined using any suitable method known in the art.
- a preferred system for the detection of cytokines is the "Evidence” immunoassay analyser (Randox Laboratories Ltd).
- the Evidence system is a fully automated immunoassay analyser based on a protein biochip array and allows for the simultaneous quantification of a plurality of analytes. Systems such as the Roche Hitachi 7600 DDP analyser may be used to assess other biochemical parameters.
- the analysis is preferably performed using a sample, e.g. a serum sample, taken from the patient.
- the levels of a variety of analytes in serum were assessed in a group of 26 elderly patients suffering from COPD grade Il (i.e. in the stable period of the disease).
- the following cytokines were assessed using the Evidence analyser system: IL-6, IL-8, EGF, IgD 1 IgM and CRP.
- a group of 31 age-matched, healthy persons was used as a control.
- FK506 is a macrocyclic lactone immunosuppressant, and is used for the prevention of allograft rejection in organ transplantation.
- Serum levels of IL-6, IL-8 and IL-10 increased significantly in recovered kidney transplant patients (p ⁇ 0.01), whereas serum EGF levels decreased markedly (p ⁇ 0.01). Unusual serum biochemistry parameters were also found in recovered kidney transplanted patients, especially for serum LDH 1 which was increased in the patient group.
- Example 3 assessment of post-operative kidney transplant patients The clinical significance of serum cytokines in kidney transplant patients was evaluated by monitoring the variation of cytokines and biochemistry parameters post- transplant operation.
- Serum cytokines (IL-2, IL-6, IL-8, IL-10. MCP-1, EGF and VEGF) were measured using protein biochips from Randox Laboratories Ltd., on the Evidence automated immunoassay analyser. Serum biochemistry parameters were measured using the Roche Hitachi 7600DDP analyser and reagents. All parameters were monitored in 10 patients over 90 days post-transplant.
- IL-6 and IL-8 peaked at 7 days after the kidney transplant operation, whereas levels of IL-2 and IL-10 peaked at 14 days. After 14 days, IL-2 and IL-10 decreased gradually, but IL-6 and IL-8 remained higher than the controls. It was found that VEGF, EGF and MCP-1 in kidney failure patients increased gradually after transplantation, but EGF was still lower than controls at 90 days post-transplant. Urea, creatinine, uric acid and glucose were restored to normal levels by two months post- transplant.
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- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Food Science & Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Microbiology (AREA)
- Cell Biology (AREA)
- Biotechnology (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
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- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
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Abstract
Methods of diagnosing chronic obstructive pulmonary disease or a transplantation reaction in a patient are provided. Diagnosing chronic obstructive pulmonary disease in a patient comprises (a) determining the level of each of one or more analytes in the patient, wherein the one or more analytes are selected from IL-6, IL-8, EGF, CRP, IgD and IgM; and (b) establishing the significance of the or each level. Diagnosing transplantation reaction in a patient comprises (a) determining the level of each of one or more analytes in the patient, wherein the one or more analytes are selected from IL-2, IL-6, IL-8, IL-10, VEGF, EGF, MCP-1 and LDH; and (b) establishing the significance of the or each level.
Description
METHOD OF DIAGNOSIS
Field of the Invention
The present invention relates to the diagnosis of chronic obstructive pulmonary syndrome (COPD) and transplantation reaction. Background to the Invention
COPD is a progressive disease that most commonly results from smoking. The disease is characterised by wheezing, breathing difficulties and chronic cough, and may become complicated by bronchitis, pneumonia and lung cancer. An organ or tissue transplant may be rejected by a patient because of an adverse transplantation reaction. Such a reaction is observed after an allogeneic (i.e. mismatched) transplant is made, causing destruction, detachment or rejection of the transplanted organ or tissue.
Cytokines are low molecular weight proteins or glycoproteins that were initially characterised as communication molecules of the immune system. They can be secreted by a number of different cell types and play a key role in the regulation of the immune system and the co-ordination of the host response to injury and infection. Cytokines produce their actions by binding to specific high-affinity cell surface receptors. The range of actions displayed by individual cytokines can be broad and diverse and is dependent on the receptor. Receptors can be soluble and can bind to the cytokine, in turn inhibiting the binding of the cytokine to the cell surface receptor, blocking its biological. Cytokines operate within a complex network and may act synergistically or antagonistically. They can influence the production of other cytokines from other cell types. Initially, it was thought that the cytokines were restricted to the immune system but it has since been demonstrated that they are also involved in signalling in the central nervous and endocrine systems.
Cytokines can be measured by either immunoassay or bioassay. Bioassays measure the functional activity of cytokines and require that some measure of biological activity be recorded. Immunoassays are based on an antibody that recognises a small portion of the cytokine and therefore most are very specific for the cytokine being measured. It is possible for biologically inactive cytokines and proteolytically degraded cytokines to be measured. Summary of the Invention
The present invention is based on the discovery of a number of markers of COPD and kidney transplant rejection, including cytokines such as IL-6, IL-8 and EGF.
55
2
A first aspect of the invention is a method of diagnosis of chronic obstructive pulmonary disease in a patient, which comprises:
(a) determining the level of each of one or more analytes in the patient, wherein the one or more analytes are selected from IL-6, IL-8, EGF, CRP, IgD and IgM; and
(b) establishing the significance of the or each level.
Another aspect of the invention is a method of diagnosis of transplantation reaction in a patient, which comprises:
(a) determining the level of each of one or more analytes in the patient, wherein the one or more analytes are selected from IL-2, IL-6, IL-8, IL-10,
VEGF, EGF, MCP-1 and LDH; and
(b) establishing the significance of the or each level. The transplant may be an organ or tissue transplant, for example a kidney transplant.
Other aspects of the invention concern the use of compounds which promote or inhibit the production of the above analytes, in the manufacture of medicaments for the therapy of COPD and transplantation reaction. Description of Preferred Embodiments
Elevated levels of IL-6 and IL-8, or reduced levels of EGF are believed to be indicative of COPD. A method of diagnosis of COPD preferably comprises determining the levels of IL-6, IL-8 and EGF. Diagnosis of transplantation reaction preferably involves determining the levels of a plurality of analytes, preferably including IL-2, IL-6, IL-8 and IL-10. In the case of transplant patients, diagnosis preferably further comprises determining the levels of one or more of urea, creatinine, uric acid and glucose. It will be appreciated that the benchmark levels may vary somewhat between patients and depend on such factors as the age, general health, weight, sex and diet or the patient in question.
The levels of the or each analyte may be determined using any suitable method known in the art. A preferred system for the detection of cytokines is the "Evidence" immunoassay analyser (Randox Laboratories Ltd). The Evidence system is a fully automated immunoassay analyser based on a protein biochip array and allows for the simultaneous quantification of a plurality of analytes. Systems such as the Roche Hitachi 7600 DDP analyser may be used to assess other biochemical parameters. The analysis is preferably performed using a sample, e.g. a serum sample, taken from the patient.
The invention will now be illustrated by way of example only.
Example 1: diagnosis of COPD
The levels of a variety of analytes in serum were assessed in a group of 26 elderly patients suffering from COPD grade Il (i.e. in the stable period of the disease). The following cytokines were assessed using the Evidence analyser system: IL-6, IL-8, EGF, IgD1 IgM and CRP. A group of 31 age-matched, healthy persons was used as a control.
As Table 1 shows, the levels of IL-6, IL-8, IgD, IgM and CRP were markedly higher in patients suffering from COPD. The patients also had noticeably lower levels of EGF relative to the control.
Table 1
Example 2: assessment of recovered kidney transplant patients
FK506 is a macrocyclic lactone immunosuppressant, and is used for the prevention of allograft rejection in organ transplantation. The immune function and biochemical metabolism of recovered kidney transplant patients, treated with FK506, was assessed by measuring serum cytokines and biochemistry parameters.
A group of 130 kidney transplant patients treated with FK506 (1-6 months after operation) and 80 age-matched healthy volunteers were observed. Overnight fasting blood samples were taken in the morning and the serum separated within 30 minutes. Serum cytokines (IL-2, IL-6, IL-8, IL-10, MCP-1 , EGF and VEGF) were measured using protein biochips from Randox Laboratories Ltd., on the Evidence automated immunoassay analyser. Serum biochemistry parameters were measured using the Roche Hitachi 7600DDP analyser and reagents.
Serum levels of IL-6, IL-8 and IL-10 increased significantly in recovered kidney transplant patients (p<0.01), whereas serum EGF levels decreased markedly (p<0.01).
Unusual serum biochemistry parameters were also found in recovered kidney transplanted patients, especially for serum LDH1 which was increased in the patient group.
Example 3: assessment of post-operative kidney transplant patients The clinical significance of serum cytokines in kidney transplant patients was evaluated by monitoring the variation of cytokines and biochemistry parameters post- transplant operation.
Serum cytokines (IL-2, IL-6, IL-8, IL-10. MCP-1, EGF and VEGF) were measured using protein biochips from Randox Laboratories Ltd., on the Evidence automated immunoassay analyser. Serum biochemistry parameters were measured using the Roche Hitachi 7600DDP analyser and reagents. All parameters were monitored in 10 patients over 90 days post-transplant.
The levels of IL-6 and IL-8 peaked at 7 days after the kidney transplant operation, whereas levels of IL-2 and IL-10 peaked at 14 days. After 14 days, IL-2 and IL-10 decreased gradually, but IL-6 and IL-8 remained higher than the controls. It was found that VEGF, EGF and MCP-1 in kidney failure patients increased gradually after transplantation, but EGF was still lower than controls at 90 days post-transplant. Urea, creatinine, uric acid and glucose were restored to normal levels by two months post- transplant.
Claims
1. A method of diagnosis of chronic obstructive pulmonary disease in a patient, which comprises: (a) determining the level of each of one or more analytes in the patient, wherein the one or more analytes are selected from IL-6, IL-8, EGF, CRP, IgD and IgM; and (b) establishing the significance of the or each level.
2. A method according to claim 1 , which comprises determining the levels of IL-6, IL-8 and EGF.
3. A method according to claim 1 or claim 2, wherein step (b) comprises comparing the or each level with those of a control, wherein the control is a person who is not suffering from a chronic obstructive pulmonary disease.
4. A method of diagnosis of transplantation reaction in a patient, which comprises: (a) determining the level of each of one or more analytes in the patient, wherein the one or more analytes are selected from IL-2, IL-6, IL-8, IL-10,
VEGF, EGF, MCP-1 and LDH; and
(b) establishing the significance of the or each level.
5. A method according to claim 4, which comprises determining the levels of IL-2, IL-6, IL-8, IL-10 and EGF.
6. A method according to claim 4 or claim 5, wherein step (b) comprises comparing the or each level with those of a control, wherein the control is a person who is not suffering from transplantation reaction.
7. A method according to any preceding claim, wherein the or each level is determined using a sample taken from the patient.
8. A method according to claim 7, wherein the sample is a serum sample.
9. A method according to any of claims 4 to 8, which further comprises determining the level of each of one or more of urea, creatinine, uric acid and glucose in the patient.
10. A method according to any of claims 4 to 8, wherein the transplant is an organ or tissue transplant.
11. A method according to claim 10, wherein the transplant is a kidney transplant.
12. Use of a compound which inhibits the production of IL-6, IL-8, IgD, IgM or CRP, or which promotes the production of EGF; for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease.
13. Use of a compound which inhibits the production of IL-2, IL-6, IL-8 or IL-10, or which promotes the production of VEGF, EGF or MCP-1 ; for the manufacture of a medicament for the therapy of transplantation reaction, wherein the transplant is a kidney transplant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05820425A EP1828778A2 (en) | 2004-12-20 | 2005-12-20 | Method of diagnosis |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0427827.1 | 2004-12-20 | ||
| GB0427827A GB0427827D0 (en) | 2004-12-20 | 2004-12-20 | Method of diagnosis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2006067427A2 true WO2006067427A2 (en) | 2006-06-29 |
| WO2006067427A3 WO2006067427A3 (en) | 2006-09-14 |
Family
ID=34090351
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB2005/004955 WO2006067427A2 (en) | 2004-12-20 | 2005-12-20 | Method of diagnosis |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1828778A2 (en) |
| GB (1) | GB0427827D0 (en) |
| WO (1) | WO2006067427A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2325657C1 (en) * | 2007-03-30 | 2008-05-27 | Государственное учреждение "УФИМСКИЙ НАУЧНО-ИССЛЕДОВАТЕЛЬСКИЙ ИНСТИТУТ ГЛАЗНЫХ БОЛЕЗНЕЙ" Академии наук Республики Башкортостан (УфНИИ ГБ АН РБ) | Method of unfavourable lingering course forecast of rheumatoid uveitis |
| RU2479846C2 (en) * | 2007-06-22 | 2013-04-20 | Саппоро Медикал Юниверсити | Method for detecting or treating graft versus host reaction |
| US8812249B2 (en) | 2009-06-25 | 2014-08-19 | University Hospital Of North Staffordshire Nhs Trust | Analyzer apparatus and methods for lung disease |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2002254234A1 (en) * | 2001-03-14 | 2002-09-24 | Centocor, Inc. | Chronic obstructive pulmonary disease-related immunglobulin derived proteins, compositions, methods and uses |
| WO2005041877A2 (en) * | 2003-10-29 | 2005-05-12 | Children's Medical Center Corporation | Method of inhibiting rejection following organ transplantation |
-
2004
- 2004-12-20 GB GB0427827A patent/GB0427827D0/en not_active Ceased
-
2005
- 2005-12-20 EP EP05820425A patent/EP1828778A2/en not_active Withdrawn
- 2005-12-20 WO PCT/GB2005/004955 patent/WO2006067427A2/en active Application Filing
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2325657C1 (en) * | 2007-03-30 | 2008-05-27 | Государственное учреждение "УФИМСКИЙ НАУЧНО-ИССЛЕДОВАТЕЛЬСКИЙ ИНСТИТУТ ГЛАЗНЫХ БОЛЕЗНЕЙ" Академии наук Республики Башкортостан (УфНИИ ГБ АН РБ) | Method of unfavourable lingering course forecast of rheumatoid uveitis |
| RU2479846C2 (en) * | 2007-06-22 | 2013-04-20 | Саппоро Медикал Юниверсити | Method for detecting or treating graft versus host reaction |
| US8812249B2 (en) | 2009-06-25 | 2014-08-19 | University Hospital Of North Staffordshire Nhs Trust | Analyzer apparatus and methods for lung disease |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2006067427A3 (en) | 2006-09-14 |
| EP1828778A2 (en) | 2007-09-05 |
| GB0427827D0 (en) | 2005-01-19 |
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