Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-12-21
2001-09-25
Jones, W. Gary (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S004000, C435S005000, C435S006120, C435S091100, C435S091200, C435S069100, C435S007100, C514S001000
Reexamination Certificate
active
06294339
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to diagnostic methods based upon a particular genotype in the Tumor Necrosis Factor (TNF&agr;) gene, more specifically, a guanine (G) to adenine (A) transition at the −238 site in one of the TNF&agr; genes giving a GA (or adenine adenine genotype, AA) genotype rather than the GG genotype at this locus. More specifically, this invention relates to a method for diagnosis of increased risk of death in patients with community-acquired pneumonia (CAP) and diagnosing pre-disposition or susceptibility to increased risk of death in patients who develop CAP, by screening for the presence of this A allele risk polymorphism. The invention also relates to compositions for screening for the polymorphism and improved treatment choices for patients having the polymorphism of the present invention. The invention also relates to screening assays and therapeutic and prophylactic methods.
BACKGROUND OF THE INVENTION
Pneumonia is a common clinical entity, particularly among the elderly. A thorough understanding of the epidemiology and microbiology of community-acquired pneumonia (CAP) is essential for appropriate diagnosis and management. Although the microbiology of CAP has remained relatively stable over the last decade, there is new information on the incidence of atypical pathogens, particularly in patients not admitted to hospital, and new information on the incidence of pathogens in cases of severe CAP and in CAP in the elderly. Recent studies have provided new data on risk factors for mortality in CAP, which can assist the clinician in decisions about the need for hospital admission. The emergence of antimicrobial resistance in
Streptococcus pneumonia,
the organism responsible for most cases of CAP, has greatly affected the approach to therapy, especially in those patients who are treated empirically. Guidelines for the therapy of CAP have been published by the
American Thoracic Society,
the
British Thoracic Society,
and, most recently, the
Infectious Diseases Society of America
and others. These guidelines differ in their emphasis on empirical versus pathogenic-specific management.
CAP remains a significant health problem and patients continue to die despite receiving appropriate antibiotic therapy. Modification of the host immune response, both anti- and pro-inflammatory approaches, has yet to live up to the promise of improved outcome. Despite this, there is significant reason for optimism. Some immunomodulatory therapies clearly have efficacy in some patients. As the understanding of the immune response to pneumonia improves the ability to tailor specific therapies for individual patients will also improve, hopefully avoiding the deleterious effects that have so far prevented the development of an effective immune based therapy. The possibility of delivering cytokines directly to the lung, is a particularly promising way of achieving the desired pulmonary effect without systemic side effects. Corticosteroids are currently unique in that they have a proven role in the therapy of pneumonia due to
P. carinii.
The development of pathogen specific therapies, such as INF for
L. pneumophila,
based on an improved understanding of host-pathogen interactions, are awaited.
The past 20 years has seen an explosion in our knowledge of human immunology and we are only now beginning to explore the therapeutic possibilities this has made available. The next 10 years promises to finally provide a significant advance in the therapy of pneumonia, the first substantial gain since penicillin.
In light of the prevalence of CAP and the evolution of resistance in the most common bacterial CAP pathogen, physicians advise obtaining specimens for culture of CAP pathogens and analyzing patterns of susceptibility, especially of
S. pneumonia,
in their communities, using antibiotics appropriately and prudently, according to prevailing susceptibilities when empirical treatment is called for, and immunizing susceptible patients with pneumococcal and influenza vaccines. This is because the mortality of patients with severe CAP approaches or may exceed 20%, compared to less than 1% for patients with non-severe CAP (Fine et al.
New Engl. J. Med.
1997.336:243-238,
British Thoracic Society, Q. J. Med.
1987.239:192-220, Niederman et al.
Am. Rev. Resp. Dis.
1993.148:1418-1426). In such cases an ability to improve accuracy of diagnosis of, or predisposition or susceptibility to, severe CAP would be of distinct advantage and may lead to improved outcomes and lower medical costs for such patients.
TNF&agr; acts on many healthy cells in addition to cancer cells and has been widely described in the literature. See e.g., Alfonso et al.
Immunogenetics
1994.39:150-154. It is important in regulating immune and inflammatory responses and plays a large role in septic shock. It is released by a variety of cells including red and white blood cells, cells that line blood vessels, nervous system cells, muscle cells, bone cells, and some tumor cells. Although it was first observed to kill certain tumor cells (sarcoma cells), TNF has been found to help some tumors grow. In addition, TNF can be very toxic to normal cells. Early experiments found that administering TNF caused fever and loss of appetite. TNF also has been shown to affect the metabolism of many cell types, causing them to need more oxygen. It has been found to play a role in many autoimmune diseases, such as rheumatoid arthritis and myasthenia gravis. Certain viral and bacterial infections can cause healthy cells to produce elevated levels of TNF.
Tumor necrosis factor alpha (TNF&agr;) is a critical component of the host immune response to infection. However TNF&agr; also plays a major role in the clinical manifestations of septic shock, a frequently fatal complication of CAP. A number of polymorphisms in or near the TNF&agr; gene on chromosome 6 have been described. The TNF&agr; −238 polymorphism is a guanine (G) to adenine (A) transition, with the A allele associated with greater TNF&agr; production in-vitro, although this has not been a uniform finding. Carriage of the TNF&agr;-238 A allele has been associated with an increased risk of severe malarial anemia, chronic hepatitis B and C infection, alcoholic steatohepatitis, and psoriasis.
Carriage of the A allele of the TNF&agr;-238 polymorphism is believed to be associated with a greater risk of mortality, and greater risk of septic shock, in patients with CAP. It is a surprising feature of the present invention to be able to identify patients having an increased risk of death from CAP by the method of the present invention thereby identifying more effective treatment options such as pneumococcal and influenza vaccination of such at risk patients.
BRIEF SUMMARY OF THE INVENTION
It is a particular object of the invention to provide a method of identifying predisposition or susceptibility to increased risk of death in patients with CAP. Thus, the invention also relates to compositions for screening for the TNF&agr; A allele, i.e., GA or AA genotype at the −238 site, and improved treatment choices for patients identified at being at risk for an increased risk of death when they have CAP. Subjects with a TNF&agr; AA genotype at the −238 site are believed to be at a similar or greater risk of death than patients with the GA genotype. The invention also relates to screening assays using the TNF&agr; A allele described herein and therapeutic and prophylactic methods discovered using such screening assays.
Other preferred embodiments of the present invention will be apparent to one of ordinary skill in light of the following description of the invention and of the claims.
DETAILED DESCRIPTION OF THE INVENTION
In a first aspect, the invention provides a method of diagnosing a disease condition associated with the A allele (GA or AA genotype) at the −238 site of TNF&agr;. The first aspect of the invention further provides a method of identifying an animal, including a human, predisposed or susceptible to a risk associated with a particular
Waterer Grant William
Wunderink Richard Glenn
Jones W. Gary
Licata & Tyrrell P.C.
Taylor Janell E.
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