Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1998-05-22
2001-05-22
Saunders, David (Department: 1644)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007200, C435S007240, C435S007320, C435S007340
Reexamination Certificate
active
06235487
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to methods to diagnose inflammatory conditions triggered by the presence of certain bacteria. Particularly, the invention is directed to an assay for the detection of a patient's immune response against certain bacteria. The presence of this immune response is useful in diagnosing certain inflammatory diseases such as Crohn's disease.
BACKGROUND OF THE INVENTION
Crohn's disease is an inflammatory disease of the gastrointestinal tract, most often affecting the ileum and colon, but which may affect any part of the digestive tract from the mouth to the anus. The disease manifestations usually are isolated to the digestive tract, but other manifestations such as inflammation of skin structures, the eyes, and the joints have been well described. The disease is known to have spontaneous exacerbations and remissions.
The cause of Crohn's disease is not known. One of the oldest theories is that Crohn's disease is caused by infection by or immune response against certain bacterial species. That theory is based on the similarity of the microscopic appearance of diseased tissue in Crohn's disease to the microscopic appearance of diseased tissue in mycobacterial disease such as tuberculosis. Further studies have not conclusively shown that mycobacterial species are causal in Crohn's disease. It is generally thought that Crohn's disease is an autoimmune disease, but that there may be an important role for some bacteria, though what that role might be is unknown.
The type of inflammatory response in Crohn's disease is a granulomatous response. It is known that the bacterial products from the cell walls of bacteria can cause a granulomatous response in susceptible animals such as certain strains of rat. Other facts known about Crohn's disease are that it runs in families, is rare in infants, patients with Crohn's disease eat more sugar, patients treated with a sucrose free diet have less complications of Crohn's disease, patients with exacerbations of their Crohn's symptoms often have resolution of the symptoms when placed on formula diets (all of which are sucrose free), Crohn's seems to have lesions in the gut in areas of stasis, many patients with Crohn's disease do well when treated with oral antibiotics, and diversion of the intestinal stream by surgical intervention leads to resolution of disease in the excluded segment, only to see recurrence when the intestine is reattached.
S. mutans
is a mouth-associated organism that produces an enzyme known as glucosyltransferase. Glucosyltransferase polymerizes sucrose to create a polymer that aids in adhering
S. mutans
to teeth and in protecting the organism from the host.
S. mutans
sheds bacterial components into the digestive tract. Some components that are shed are the end products of
S. mutans
metabolic pathways; others due to normal cell constituent turnover and death.
Some reports in the medical literature have looked at the presence of
S. mutans
in patients with Crohn's disease. Meurman, J. K. et. aL,
Oral Surg. Oral Med Oral Pathol
77:465-468 (1994) reported that patients with active Crohn's disease had higher counts of
S. mutans
than patients with inactive disease. Their study did not make any measures of immune response. They hypothesized that increased
S. mutans
counts were secondary to the fact that their patients had also increased their sucrose intake because sucrose “is more digestible and causes less gastrointestinal symptoms than a fat-containing diet” in Crohn's disease patients.
Sundh, B. et. al,
Oral Surg. Oral Med. Oral Pathol
76:564-569 (1993) also studied patients with Crohn's disease, and reported average
S. mutans
counts as well as general measures of immunity in patients and controls. Salivary IgA antibody levels were measured, but they did not test whether the antibody would recognize
S. mutans
, and only IgA antibodies were measured. Their report of the average number of
S. mutans
in patients is not a comparable statistic to the number of patients with high or low counts as reported by Meurman. Their study did not make any measures of specific immune response against
S. mutans.
Berghouse et. al.
Gut
25:1071-1077 (1984) reported that not all sucrose ingested by patients with an ileostomy could be accounted for when the output of the ileal output was measured for sucrose. The assay tested for sucrose monomers and small molecular weight sucrose polymers. The study did not show a difference in sucrose concentration between Crohn's disease patients and otherwise normal ileostomy patients.
Clinicians diagnose Crohn's disease by history, physical examination, x-ray studies with or without barium contrast material within the digestive tract, and colonoscopy or upper endoscopy. In early Crohn's disease, however, there may be little in the way of narrowing of the terminal ileum visible on x-ray studies.
There are general tests that reflect inflammation, such as erythrocyte sedimentation rate, C reactive protein, and orosomucoids, but there are no specific tests for Crohn's disease. A blood test for Crohn's disease would be of considerable utility, allowing confirmation of the diagnosis in the frequent case of trying to diagnose early Crohn's disease, where the absence of specific findings on x-ray and endoscopic studies may lead to the diagnosis of irritable bowel syndrome or nonspecific colitis. Depending on the characteristics of the test, a number of useful results such as prediction of clinical course, need for surgery, establishing risk of Crohn's disease in family members, or other important results may be obtained. A test that could be performed on surgical specimens removed from patients which would confirm the diagnosis of Crohn's disease would also be useful because often the characteristic histologic findings for Crohn's disease are absent in surgical specimens.
SUMMARY OF THE INVENTION
Recognizing the need for a simple assay for Crohn's disease, the inventor investigated the relationship between Crohn's disease and immunological reactivity in such patients. These studies have resulted in the development of a simple assay for Crohn's disease that detects the patient's immunological response to
S. mutans
antigens.
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Klasen L.S. (Jun. 1994) Clin Immunology and Immunopathology 71(3) 303-308.*
Sundh et al (Nov. 1993) Oral Surg Oral Med Oral Pathol 76:564-569.*
Meurman et al (May 1994) Oral Surg Oral Med Oral Pathol 77:465-468.*
Merrian Webster's Collegiate Dictionary, Tenth Edition Merrian-Webster Inc. SpringField, Mass USA p. 319, 1996.*
Berghouse, L. et al., “Comparison between the bacterial and oligosaccharide content of ileostomy effluent in subjects taking diets rich in refined or unrefined carbohydrate,”Gut 25: 1071-1077 (Oct. 1984).
Cromartie, W.J. et al., “Arthritis in Rats After Systemic Injection of Streptococcal Cells or Cell Walls,”J. Exp. Med. 146:1585-1602 (Dec. 1977).
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DeCloux Amy
Saunders David
Sterne Kessler Goldstein & Fox P.L.L.C.
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