Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-12-07
2003-06-10
Eyler, Yvonne (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S016700, C530S307000, C530S308000, C530S329000
Reexamination Certificate
active
06576611
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to reducing or preventing impairment of respiratory tract mucosal immunity and risk of pneumonia associated with a lack of enteral feeding, such as with the use of total parenteral nutrition (TPN) or, more generally, with a lack of immunological stimulation of the gastrointestinal tract through oral or gastrointestinal feeding. In particular, the present invention relates to methods of reducing or preventing impairment of respiratory tract mucosal immunity. The present invention also relates to compositions useful in such methods.
2. Description of the Related Art
Infectious complications are the most common cause of death following trauma in patients without head injuries (Baker et al.,
Am J Surg.,
140:144-150 (1980)), and a frequent cause of morbidity and mortality in malnourished patients, patients sustaining surgical complications, and patients requiring prolonged intensive care unit (ICU) stays. Despite intravenous (IV) nutrition, multiple antibiotics, and aggressive ICU care, mortality from sepsis (i.e., the presence of pathogenic organisms or their toxins in the blood or tissues) averages 30%, with a range of 20-60% depending upon the patient population studied (Bone et al.,
Crit. Care Med.,
17:389-393 (1989); Bone et al.,
N. Eng. J. Med.,
317:653-658 (1987); Ziegler et al.,
N. Eng. J. Med.,
324:429-436 (1991); Hinshaw et al.,
N. Eng. J. Med.,
317:659-665 (1987); and Kreger et al.,
Am. J. Med.,
68:344-34 (1980)). Septic morbidity, especially pneumonia, is significantly reduced in critically injured patients when enteral feeding rather than parenteral feeding or no feeding at all is provided (Kudsk et al.,
Ann. Surg.,
224:531-543 (1996). This suggests that enteral feeding provides benefits to host defenses (Kudsk et al.,
Ann. Surg.,
215:503-513 (1992); Moore et al.,
J. Trauma,
26:874-881 (1986); Moore et al.,
J. Trauma,
29:916-923 (1989); and Moore et al.,
Ann. Surg.,
216:172-183 (1992)).
The mechanisms responsible for improved recovery with the use of enteral feeding are poorly understood, but it is hypothesized that lack of enteral feeding leads to a breakdown in the gastrointestinal barrier, thus allowing molecules and perhaps bacteria to gain entry into the body resulting in inflammation and distant infection (Deitch,
J. Trauma,
30:S184-S189 (1990); Deitch,
Surgery,
107:411-416 (1990); Ziegler et al.,
Arch. Surg.,
123:1313-1319 (1988); Deitch et al.,
Ann. Surg.,
205:681 (1987); and Deitch,
Perspect. Crit. Care,
1:1-31 (1988)). Most investigators have studied barrier integrity by focusing on changes in gut morphology and permeability to bacteria and macromolecules (Bushman et al.,
Gastroenterology,
104:A612 (1993)).
Nutritional models which preserve IgA (i.e., immunoglobulin A) within the mucin layer also appear to preserve normal gastrointestinal (GI) colonization and reduce bacterial translocation (Deitch et al.,
JPEN,
17:332-336 (1993); and Haskel et al.,
Ann. Surg.,
217:634-643 (1993)). Although systemic responses to injury increase gut permeability in some patients, data demonstrating that this increased permeability causes infectious complications, such as pneumonia, are not convincing (Deitch,
Surgery,
107:411-416 (1990); Ziegler et al.,
Arch. Surg.,
123:1313-1319 (1988); and Langkamp-Henken et al.,
Crit. Care Med.,
23:660-664 (1995)).
Components in mucosal defense and barrier integrity up-regulated by bombesin include lactoferrin, peroxidases, lysozymes, the mucin, and high molecular weight glycoprotein. IgA is one of the primary immunologic defenses against many mucosal infections. Moreover, a critical component in mucosal defense and barrier integrity is the availability of secretory IgA (sIgA) in the mucin layer coating the mucosa (Svanborg et al. in Ogra et al., eds.,
Handbook of Mucosal Immunology,
71-78; and Killian et al. in Ogra et al., eds.,
Handbook of Mucosal Immunology,
127-140). sIgA binds or agglutinates bacteria, viruses, and potentially other toxic molecules, eliminating the key to invasive mucosal infection, i.e., adherence of infectious agents to human mucosal cells (Svanborg in Ogra et al., eds.,
Handbook of Mucosal Immunology,
71-78). Levels of IgA are dependent upon adequate numbers of functioning immunocompetent cells in the lamina propria and a cytokine milieu appropriate to the production of IgA (Kiyono et al. in Ogra et al., eds.,
Handbook of Mucosal Immunology,
263-274; and Lebman et al. in Ogra et al., eds.,
Handbook of Mucosal Immunology,
243-250). As IgA is released from plasma cells within the lamina propria, it is transported through mucosal epithelia cells by secretory components. In the mucin layer, sIgA binds and agglutinates potential noxious agents without inducing inflammation. sIgA also appears to improve the functional capabilities of other immune cells such as, neutrophils, to mount defenses against infectious agents.
Once initial activation of precursor IgA-producing cells occurs within the Peyer's patches, the antigen-sensitized cells undergo mitotic changes and the resulting B lymphoblasts migrate to regional lymph nodes and eventually to the systemic circulation via the thoracic duct (Tomasi, Jr.,
Rev. Infect. Dis.,
5:S784-S792 (1983)). Experiments using whole bacteria, bacterial products, live or killed viruses, or modified viral antigens have shown that the antigen-sensitized precursor cells home not only to the GI tract but also to the respiratory tract, and mammary, parotid, and lacrimal glands where they produce IgA for transport through the epithelial cells into external secretions if the appropriate T cell signals and antigenic stimulation exist (Kiyono et al. in Ogra et al., eds.,
Handbook of Mucosal Immunology,
263-274; Mestecky et al. in Ogra et al., eds.,
Handbook of Mucosal Immunology,
357-372; Mestecky, J.,
J. Clin. Immunol.,
7:265-276 (1987); and McGhee et al.,
Vaccine,
10:75-88 (1992)).
These observations have led to the concept of a common mucosal immune system and explain the extra-intestinal effects of enteral or parenteral feeding on respiratory tract immunity. The concept of a common mucosal immune system may be the link between intestinal changes and extra-intestinal susceptibility to infection, in particular the respiratory tract.
The human body devotes significant resources to maintain mucosal immunity, including 50% of its functioning immune cells to produce secretory IgA to help control its endogenous microbial GI flora (Brandtzaeg in Ogra et al., eds.,
Handbook of Mucosal Immunology,
3-8; Tomasi in Ogra et al., eds.,
Handbook of Mucosal Immunology,
251-262). The mucosal immune circuit initially begins with antigenic uptake via M cells, which are the cells overlying the intestinal lymphatic follicle of the Peyer's patches (PP). B cells (i.e., B lymphocytes), sensitized by antigen processed within the Peyer's patches, then migrate to the mesenteric lymph nodes where, under the appropriate cytokine milieu, they proliferate and migrate via the thoracic duct into the vascular tree. Once in the vascular system, these sensitized cells home to the lamina propria of the intestine, producing IgA which plays an important role in gut barrier function (Ottaway,
Gastro. Clin. North Am.,
20:511-529 (1991); and Salmi et al.,
Gastroenterol. Clin. North Am,
20:495-505 (1991)).
Specialized enteral nutritional support has been used to reduce malnutrition and the incidence of infectious complications in critically ill persons. Certain patients, however, are often unable to tolerate enteral feedings and must be fed parenterally. Lack of enteral feeding or a lack of immunological stimulation of the GI tract, such as may occur with intravenous TPN, for example, can lead to atrophy of the small intestinal gut-associated lymphoid tissue (GALT); decreases in intestinal and respiratory tract IgA levels; as well as increases in mucosal permeability, bacterial overgrowth, and bacterial translocation. Lack of enteral feeding or a lack of immunological s
Eyler Yvonne
Hamud Fozia
Licata & Tyrrell P.C.
Wisconsin Alumni Research Foundation
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