Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...
Patent
1997-01-06
2000-10-24
Navarro, Albert
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
435 71, 435 72, 435 724, 435 772, 435 79, 435 792, 436501, 436536, 5303871, 5303881, C12Q 100, G01N 3353, G01N 33567, G01N 33542
Patent
active
061365262
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD AND BACKGROUND
The present invention relates to the use of human neutrophil lipocalin (HNL) as a diagnostic marker, in particular for diagnosis in connection with inflammation that may have a bacterial origin. The determination of the HNL level in a sample from a patient assists in discriminating between bacterial and viral infection.
The main function of human neutrophils is to sense, approach, and destroy invading micro-organisms, in particular pyogenic bacteria. Invading micro-organisms cause degranulation and exocytosis of various granule proteins from neutrophils (Henson, J. Immunol. 107 (1971) 1535-46). The determination of the granule proteins released from neutrophils has long been used as indicators of neutrophil activation in infections and inflammation (Schmekel et al., Inflam. 14 (1990) 447-54; and Lash et al., Blood 61(1983) 885-8). C-reactive protein (CRP) is an acute phase reactant produced in the liver and its measurement has been used in the early diagnosis of bacterial infections.
The results presented herein indicate a sequence identity between HNL and human neutrophil 24 kD N-formyl-peptide binding protein, 25 kD .alpha.-2-microglobulin-related protein (Triebel et al., FEBS Lett. 314 (1992) 386-) and neutrophil gelatinase-associated lipocalin (NGAL) (Kjeldsen et al., J. Biol. Chem. 268 (1993) 10425-). The preliminary isolation of HNL has been published (Venge et al., J. Leukocyte Biol. Supplement 1 (1990) 28). During the priority year the complete purification/characterization and assay of human neutrophil lipocalin have been published (Xu et al., Scand. J. Lab. Invest. 54 (1994) 365-76 and Xu et al., J. Immunol. Meth. 171 (1994) 245-52).
OBJECTIVES OF THE INVENTION
There exists a need for new diagnostic markers for bacterial infections and markers that distinguish bacterial infections from viral infections. There also exists a need for markers and methods providing improved specificities for this type of diagnoses.
The present invention provides means that comply with these needs.
THE INVENTION
We have now surprisingly found that HNL derives specifically from neutrophils from which it is released in increased amounts when neutrophils are activated, for instance in connection with inflammation. Inflammatory conditions will be reflected in elevated levels while a lowered neutrophil activity will be reflected in subnormal levels.
In its broadest aspect the invention is thus the use of HNL as a diagnostic marker for neutrophil activity in a liquid sample containing neutrophils.
The method employed comprises the steps: individual that is to be diagnosed, and then normal concentration range) for apparently healthy individuals (normal individuals).
If the level found deviates from the normal level this is an indication that the individual suffers from some abnormal condition. A raised level will be indicative of inflammation that mostly is caused by an infection that in turn with high likelihood is of bacterial origin preferably with exclusion of viral infections. A raised level may also be found in samples where the neutrophils have been in contact with exogeneous surfaces so as to release HNL (e.g. plastics or glass surfaces, catheters and extracorporeal arrangements). Subnormal levels may be found in connection with bone marrow transplantation and leukemia or other cases where the number of neutrophils are reduced. It follows that monitoring changes in HNL in samples from a bone marrow transplanted patient will also monitor the success of the transplantation (a progressive increase from subnormal to normal levels will be indicative of the function of the transplant).
It is important to be able to differentiate between bacterial and viral infections in order to determine the correct treatment, for instance during asthmatic exacerbations.
The sample is derived from a human individual and contains neutrophils and/or HNL. Due to the systemic presence of neutrophils potential samples are broncho alveolar lavage fluid, blood (including serum and plasma samples), urine, cer
REFERENCES:
patent: 4659678 (1987-04-01), Forrest et al.
patent: 5200319 (1993-04-01), Arnaout et al.
Blood, vol. 83, No. 3, 1994, Lars Kjeldsen et al, "Identification of Neutrophil Gelatinase-Associated Lipocalin as a Novel Matrix Protein of Specific Granules in Human Neutrophils," pp. 799-807, see p. 806, left paragraph.
The Journal of Biological Chemistry, vol. 268, No. 14, May 1993, Lars Kjeldsen et al, "Isolation and Primary Structure of NGAL, a Novel Protein Associated with Human Neutrophil Gelatinase," see p. 10425-10432.
National Library of Medicine (NLM), File Medline, Medline accession No. 94169380, Kjeldsen, L. et al: "Isolation and Characterization of Gelatinase Granules from Human Neutrophils," and Blood 1994, Mar. 15; 83(6):1649-9.
Blood, vol. 82, No. 10, Nov. 1993, Lars Kjeldsen et al, "Structural and Functional Heterogeneity Among Peroxidase-Negative Granules in Human Neutrophils: Identification of a Distinct Gealtinase-Containing Granule Subset by Combined Immunocytochemistry and Subcelluloar. . . " pp. 3183-3191.
Venge et al (J. of Leuk. Bio. Supp 1 1990 p. 28).
Allen et al (Biochimica et Biophysica Acta 991 1989 pp 123-133).
Triebel et al (FEBS letters vol. 314 (3) Dec. 1992 pp 386-388).
Sevier et al (Clinical Chem. vol. 27(11) 1981 pp 1797-1806).
Kouppi et al (Scandinavian J. of Inf. Dis. vol. 25(4) 1993 pp 435-440).
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