JP2005537236A - Probiotic treatment - Google Patents

Abstract

Production of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) or neurotrophin 4 (NT4) in the treatment and / or prevention of various diseases, particularly inflammatory diseases Use of a selectively upregulating bacterial strain or an active derivative, fragment or variant thereof. The bacterial strain may be Lactobacillus, in particular Lactobacillus reuteri.

Description

  The present invention particularly relates to immunomodulation and therapeutic effects of bacterial species.

The defense mechanism that protects the human gastrointestinal tract from colonization by enterobacteria is very complex and involves both immune and non-immune aspects (VJ McCracken and HR Gaskins, 'Probiotics a critical review ". ', Horizon Scientific Press, UK, 1999, p.278.). Innate defense mechanisms include antibacterial compounds such as low gastric pH, bile salts, peristalsis, mucin layer and lysozyme (DC Savage, 'Microbiological of the Gut', Academic Press, London, 1997, p. 278.). The immune mechanism includes special lymphoid aggregates that are distributed throughout the small intestine and colon, called Peyer's patches, ie the underlying M cells (MF Kagneoff. Gastroenterol, 1993, 105, 1275). Luminal antigens presented at these sites will stimulate appropriate T and B cell subsets, with the establishment of cytokine networks and secretion of antibodies into the gastrointestinal tract (MR Neutra and J -P Kraehenbuhl, 'Essentials of mucosal immunology', Academic Press, San Diego, 1996, p. 29., M. E. Lamm. Ann. Rev. Microbiol. 1997, 51, 311). Furthermore, antigen presentation can occur by epithelial cells to intraepithelial lymphocytes and underlying lamina propria immune cells (S. Raychaudhuri et al. Nat Biotechnol., 1998, 16, 1025). Thus, the host substantially obtains gastrointestinal immune defense. However, since the gastrointestinal mucosa is the largest surface with which the host contacts the external environment, there should be a special control mechanism to control the immune response to 100 tonnes of food processed by the gastrointestinal tract over the life span ( F. Shanahan, 'Physiology of the gastrointestinal tract', Raven Press, 1994, p. 643.). Furthermore, more than 500 kinds of bacteria form colonies in the intestine, and the number in the colon is 10 ₁₁ to 10 ₁₂ / g. These control mechanisms must therefore be able to distinguish non-pathogenic adherent bacteria from invasive pathogens that cause severe damage to the host. In fact, the intestinal flora contributes to host defense by competing with newly ingested potentially pathogenic microorganisms.

  The microbial flora on the mucosal surface is numerous and complex. Hundreds of bacterial species are present and account for about 90% of the cells found in the human body, with the remaining cells being human. Most of these bacterial species do not cause disease and may actually provide significant health benefits to the host (eg, Bifidobacteria and Lactobacillus). These bacterial species are called symbiotic flora. There is a mechanism by which the symbiotic system on the mucosal surface can recognize the symbiotic non-pathological flora as distinct from pathogenic organisms.

  Bacteria present in the human gastrointestinal tract can promote inflammation. It has been suggested that an unusual immune response to the ingested microbial flora is associated with certain disease states, such as inflammatory bowel disease (Brandzeag P. et al. Springer Semin. Immunopathol., 1997, 18). 555). Antigens associated with normal flora lead to immune tolerance and immunodeficiency, making this tolerance a major mechanism of mucosal inflammation (Stallmach A. et al, Immunol. Today, 1998, 19, 438). Evidence for this collapse of tolerance includes an increase in antibody levels against the gut flora in IBD patients.

  Methods that inhibit the production of unfavorable molecules, such as in vivo pro-inflammatory molecules, are considered to have great therapeutic potential.

  According to the present invention, inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, tumors (especially of the digestive tract and immune system), diarrhea diseases, antibiotic-related diarrhea, childhood diarrhea, appendicitis, autoimmunity Disease, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, peritoneal disease, diabetes, organ transplantation, bacterial infection, viral infection, fungal infection, periodontal disease, urological disease, sexually transmitted disease, HIV infection, HIV replication, HIV related Diarrhea, surgery-related trauma, surgery-induced metastatic disease, sepsis, weight loss, loss of appetite, fever control, cachexia, wound healing, ulcers, intestinal barrier function, allergy, asthma, respiratory disorder, circulatory system disorder , Coronary heart disease, anemia, blood coagulation disorder, kidney disease, central nervous system disorder, liver disease, ischemia, nutritional disorder, osteoporosis, endocrine disorder, epidermal disorder, psoriasis and / or acne and Alternatively, in prevention, bacteria that selectively upregulate nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) or neurotrophin 4 (NT4), or their active Use of a derivative, fragment or variant is provided.

  Preferably, the bacterial species is derived from a human symbiotic flora that stimulates nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) or neurotrophin 4 (NT4).

  In one embodiment of the invention, the bacterial species is Lactobacillus. Preferably, the Lactobacillus is Lactobacillus reuteri.

  The bacteria may be live or non-live. This also includes components or variants of bacterial species.

  According to the present invention, a bacterial strain that selectively upregulates the production of NGF, BDNF, NT3 or NT4 in the treatment and / or prevention of various diseases such as inflammatory diseases, or an active derivative, fragment or mutation thereof Body use is provided.

  Furthermore, according to the present invention, inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, tumors (especially of the digestive tract and immune system), diarrheal diseases, antibiotic-related diarrhea, childhood diarrhea, appendicitis, self Immune disease, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, peritoneal disease, diabetes, organ transplantation, bacterial infection, viral infection, fungal infection, periodontal disease, urological disease, sexually transmitted disease, HIV infection, HIV replication, HIV Related diarrhea, surgery-related trauma, surgery-induced metastatic disease, sepsis, weight loss, loss of appetite, fever control, cachexia, wound healing, ulcers, intestinal barrier function, allergy, asthma, respiratory disorder, circulatory system Treatment of disorders, coronary heart disease, anemia, blood clotting disorders, renal diseases, central nervous system disorders, liver diseases, ischemia, nutritional disorders, osteoporosis, endocrine disorders, epidermis disorders, psoriasis and / or acne NGF in beauty / or prevention, BDNF, NT3 or NT4 or an active derivative thereof, the use of fragments or variants.

  The present invention also provides the use of NGF, BDNF, NT3 or NT4, or active derivatives, fragments or variants thereof in the treatment and / or prevention of various diseases such as inflammatory diseases.

  Furthermore, according to the present invention, inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, tumors (especially of the digestive tract and immune system), diarrheal diseases, antibiotic-related diarrhea, childhood diarrhea, appendicitis, self Immune disease, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, peritoneal disease, diabetes, organ transplantation, bacterial infection, viral infection, fungal infection, periodontal disease, urological disease, sexually transmitted disease, HIV infection, HIV replication, HIV Related diarrhea, surgery-related trauma, surgery-induced metastatic disease, sepsis, weight loss, loss of appetite, fever control, cachexia, wound healing, ulcers, intestinal barrier function, allergy, asthma, respiratory disorder, circulatory system Treatment of disorders, coronary heart disease, anemia, blood clotting disorders, renal diseases, central nervous system disorders, liver diseases, ischemia, nutritional disorders, osteoporosis, endocrine disorders, epidermis disorders, psoriasis and / or acne In beauty / or prevention, NGF, BDNF, NT3 or NT4, and selectively upregulate bacterial strains IL10 or an active, derivatives, the use of fragments or variants.

  Also, according to the present invention, a method for screening the therapeutic potential of bacterial species for use in disease-specific therapy comprising the process of stimulating epithelial cells with different bacterial species to induce various cytokine profiles Is provided.

  Further in accordance with the present invention is a disease-specific therapy comprising the process of stimulating epithelial cells with different bacterial species to selectively upregulate NGF, BDNF, NT3 or NT4 and induce various cytokine profiles. Methods are provided for screening the therapeutic potential of bacterial species for use.

  In addition, according to the present invention, a preparation comprising a bacterial species that induces NGF, BDNF, NT3 or NT4, or an active derivative, fragment or variant thereof is provided.

  Furthermore, the present invention provides a formulation comprising a bacterial species that induces NGF, BDNF, NT3 or NT4, and / or IL10, or an active derivative, fragment or variant thereof.

  Also according to the present invention, a bacterial species that induces NGF, BDNF, NT3 or NT4, or an active derivative, fragment or variant thereof for use in the prevention and / or treatment of various diseases such as inflammatory diseases A formulation consisting of is provided.

  The present invention also provides a preparation comprising NGF, BDNF, NT3 or NT4, or an active derivative, fragment or variant thereof for use in the prevention / treatment of various diseases such as inflammatory diseases. The

  Furthermore, according to the present invention, inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, tumors (especially of the digestive tract and immune system), diarrheal diseases, antibiotic-related diarrhea, childhood diarrhea, appendicitis, self Immune disease, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, peritoneal disease, diabetes, organ transplantation, bacterial infection, viral infection, fungal infection, periodontal disease, urological disease, sexually transmitted disease, HIV infection, HIV replication, HIV Related diarrhea, surgery-related trauma, surgery-induced metastatic disease, sepsis, weight loss, loss of appetite, fever control, cachexia, wound healing, ulcers, intestinal barrier function, allergy, asthma, respiratory disorder, circulatory system Treatment of disorders, coronary heart disease, anemia, blood clotting disorders, renal diseases, central nervous system disorders, liver diseases, ischemia, nutritional disorders, osteoporosis, endocrine disorders, epidermis disorders, psoriasis and / or acne In beauty / or prevention, NGF, BDNF, NT3 or selectively upregulate bacterial species production NT4, or an active derivative thereof, is a vaccine consisting of a fragment or variant is provided.

  In addition, according to the present invention, a bacterial species that selectively upregulates the production of NGF, BDNF, NT3 or NT4 in the treatment and / or prevention of various diseases such as inflammatory diseases, or an active derivative or fragment thereof Alternatively, a vaccine comprising a variant is provided.

  Also according to the present invention, inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, tumors (especially of the gastrointestinal tract and immune system), diarrhea diseases, antibiotic-related diarrhea, childhood diarrhea, appendicitis, Autoimmune disease, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, peritoneal disease, diabetes, organ transplantation, bacterial infection, viral infection, fungal infection, periodontal disease, urological disease, sexually transmitted disease, HIV infection, HIV replication, HIV-related diarrhea, surgery-related trauma, surgery-induced metastatic disease, sepsis, weight loss, loss of appetite, fever control, cachexia, wound healing, ulcers, intestinal barrier function, allergy, asthma, respiratory failure, circulation Systemic disorder, coronary heart disease, anemia, blood coagulation system disorder, kidney disease, central nervous system disorder, liver disease, ischemia, nutritional disorder, osteoporosis, endocrine disorder, epidermal disorder, psoriasis and / or acne treatment NGF, BDNF, NT3 or NT4 or an active derivative thereof, and a vaccine consisting of a fragment or variant is provided in and / or prophylaxis.

  Throughout this specification, the term derivative is taken to include the active form of a bacterial species having modifications that do not substantially cause the activity of the bacterial species. The term variant is taken to include species with amino acid mutations that do not substantially cause the activity of the species. The term fragment is taken to include subunits encoded by nucleic acid sequences present in all or part of the mother cell bacterial species.

One of the mechanisms by which probiotic organisms can protect against mucosal inflammation is direct or indirect through interaction with mucosal epithelial cells, thereby up-regulating and preventing anti-epithelial cells. It expresses inflammatory molecules. These include cytokines such as IL-10, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophins such as neurotrophin 3 (NT3) or neurotrophin 4 (NT4), And products of arachidic acid such as PGE ₂ are included.

  The present invention is directed to bacterial species, bacterial species having immunomodulatory and therapeutic effects by stimulation of their NGF activity. In addition, the bacterial species are considered to have immunomodulation and therapeutic effects by stimulation of their BDNF, NT3 or NT4 activity.

  In the present invention, it has been found that certain species of symbiotic microorganisms such as Bifidobacteria and Lactobacillus induce NGF synthesis, resulting in an immunomodulatory effect in vivo.

  After exposure to symbiotic microorganisms, epithelial cells induced NGF production, which inhibited the development of proinflammatory cytokines. NGF and cytokines appear to be upregulated in opposite directions.

  In the present invention, it has surprisingly been found that when epithelial cells are stimulated with Lactobacillus reuteri, NGF is selectively induced, thereby attenuating the production of TNF-induced IL-8 cytokines.

  Lactobacillus is commercially available. Lactobacillus reuteri species RF14249 and RF20013 have been deposited with deposit numbers F275 (DSM2006), JCM112, ATCC23272, and NCD02589.

  Nerve growth factor (NGF), which Professor Rita Levi-Montalcini won the Nobel Prize for his discovery, is the first neurotrophin or nerve growth factor discovered. This is essential for nerve growth in many components of the peripheral nervous system, autoimmune nervous system, particularly the sympathetic and central nervous systems. It is synthesized and secreted by many cells in addition to that of the nervous system. These include structural cells such as glia and fibroblasts, cells of the immune system such as T lymphocytes (especially TH2), and cells associated with inflammatory processes such as eosinophils, mast cells and dendritic cells. Is included. This has multiple trait functions in addition to many effects on the nervous system. This is synthesized in a relatively large shape, whereas its active ingredient is a 2.5S molecule with a molecular weight of about 26K. Its position on the chromosome is 1p13. This promotes neuronal survival and growth, but has an effect on many different lineages, including the promotion of basic hematopoietic colony growth of basic stained cells and eosinophils, IgG4 B cells And the promotion of synthesis and prevention of apoptosis in neutrophils, eosinophils and mast cells (Bienenstock et al., 2000). This also indicates that it has wound healing properties (Matsuda et al., 1998) and is thought to protect against a mucosal inflammation model of hapten-induced colitis (Reinshagen et al., 2000). Very recently, T cells transfected with the gene for NGF have been shown to protect the central nervous system against damage in an autoimmune model of slipping disease, autoimmune encephalomyelitis (Flugel) et al., 2001).

  NGF is an important neurotrophin and is essential for many different physiological functions. Induction of NGF results in improved immune control and promotes wound healing. Thus, methods that induce NGF production with attenuation of various cytokines have great therapeutic potential.

  Another important neurotrophin that is essential for many different physiological functions is brain-derived neurotrophic factor (PDNF) neurotrophin 3 (NT3) or neurotrophin 4 (NT4). These neurotrophins are closely related to NGF, and it is believed that these neurotrophins are induced by bacterial species in the same way that NGF was induced.

  The present invention has potential value as a therapy in the prevention and / or treatment of immune control of dysregulation such as undesirable inflammatory reactions (eg inflammatory bowel disease).

  However, stimulation of epithelial cells by various bacterial species is believed to result in epithelial cells having various cytokine profiles. Therefore, these various immunotherapeutic properties can be applied to a wide range of disease states.

  Other Bifidobacteria and Lactobacillus are potentially L. Has the same effect as Reuteri. Such Bifidobacteria and Lactobacillus are generally isolated from the microbial flora in the human digestive tract. The immune system in the gastrointestinal tract cannot have a significant response to members of this flora, because the resulting inflammatory activity can also destroy host cells and tissue functions. Thus, there is some mechanism by which the immune system can recognize symbiotic non-pathological members of the gut flora as distinct from pathological organisms. This ensures that damage to the host tissue is limited and the protective barrier is still maintained.

  The bacterial species may be a genetically altered variant or a naturally occurring variant thereof.

  Preferably, the bacterial species takes the form of living cells. Alternatively, the bacterial species can take the form of non-viable cells.

  The present invention also relates to the potential of bacterial species in customizing epithelial cell phenotype and function. In this way, customization of disease specific treatment can be achieved utilizing selection of bacterial species.

  The effect on cytokine production is unique to each probiotic species tested. Thus, specific probiotic species can be selected to normalize cytokine imbalances that are exclusive, especially for specific types of diseases. Customization of disease specific treatments can be achieved using selection of probiotic species.

  Recognition of bacterial species by epithelial cells gives rise to significant patterns of cytokine production and immune responses. Cytokines produced by epithelial cells are secreted into the extracellular environment. These cytokines convey useful information to neighboring cells that do not necessarily need to be in physical contact with epithelial cells. This “bystander” effect results in many different types of cells that are affected by cytokine networks established by epithelial cells stimulated with bacteria.

Immunity education The gut flora is important for the development and proper functioning of the small intestinal immune system. In the absence of intestinal flora, the small intestinal immune system is underdeveloped, as demonstrated in animal models that do not contain any bacteria, and certain functional parameters such as macrophage phagocytic ability and immunoglobulin production disappear (Clabbe et al ,, 1968, Westmann et al., 1996). It has become clearer that the gut microbiota is important in stimulating a non-injury immune response. Increasing the frequency and severity of allergic diseases in Western Europe, coupled with the reduced number and range of infection exposures encountered by hosts, is associated with improved health. This lack of immune stimulation causes the host to become non-pathogenic but react to antigenic substances, resulting in allergy or autoimmunity. By consciously consuming a series of non-pathogenic immunoregulatory bacteria, necessary and appropriate educational stimuli can be given to the host to properly develop and control immune function.

  The human immune system plays an important role in the pathogenesis and pathology of a very wide range of human diseases. Low and high immune responsiveness is part or most of the disease state. A family of organisms called cytokines is particularly important for the control of the immune process. When these delicate cytokine networks get confused, they become increasingly relevant to many diseases. These diseases include inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, tumors (especially those of the digestive tract and immune system), diarrheal diseases, antibiotic-related diarrhea, childhood diarrhea, appendicitis, self Immune disease, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, peritoneal disease, diabetes, organ transplantation, bacterial infection, viral infection, fungal infection, periodontal disease, urological disease, sexually transmitted disease, HIV infection, HIV replication, HIV Related diarrhea, surgery-related trauma, surgery-induced metastatic disease, sepsis, weight loss, loss of appetite, fever control, cachexia, wound healing, ulcers, intestinal barrier function, allergy, asthma, respiratory disorder, circulatory system Includes disorders, coronary heart disease, anemia, blood clotting disorders, kidney disease, central nervous system disorders, liver disease, ischemia, nutritional disorders, osteoporosis, endocrine disorders, epidermal disorders, psoriasis and acne , But it is not limited to these.

  Because most cytokines have both pro-inflammatory and anti-inflammatory activities, cytokine release patterns or networks are associated with various types of immune responses. The presence of T cells with different patterns of cytokine secretion can differentiate inflammatory or immune responses into at least three categories, cell-mediated, humoral responses, or Th3 / Tr1 regulatory responses. Th2 cells secrete IL-4, IL-5, IL-9, IL-10 and IL-13, whereas Th1 responses are classified by IFNα, TNFβ and IL-2 production leading to cell-mediated responses, As a result, a body fluid reaction occurs. The Th3 / Tr1 response is characterized by T cell secretion of the regulatory cytokines IL-10 and TGF. Differentiating T cells into either network depends on the cytokine environment in which the original antigen priming occurs (Seder et al., 1992). Furthermore, the polarization of T cell subpopulations is affected by a number of other cell types including dendritic cells and epithelial cells (Mosmann & Sad, 1996). This reaction also increases IL-6 and IL-10 production and inhibits the production of TNFα and IL-1β, thereby affecting the immune complex into the inflammatory site affecting the Th1 / Th2 equilibrium. Some type of stimulation, such as deposition, dominates. In order to successfully eliminate pathogens, it is necessary to establish a correct cytokine network. For example, the intracellular bacterium Listeria monocytogenes elicits a Th1 response, whereas the extracellular parasite, Nippostronylus brasiliensis, requires a Th2 response. Each of these T cell subsets produces cytokines that are autocrine growth factors of the subset and promotes the differentiation of inactive T cells into the subset (Trichineri et al., 1996). These two subsets also produce cytokines that cross-regulate their growth and activity. IFNγ amplifies Th1 development and inhibits Th2 T cell proliferation, whereas IL-10 blocks Th1 activation. Tr1 cells are markedly repressed by cytokine-independent mechanisms such as direct cell-to-cell contact and antigen-specific T cell responses mediated by IL-10 and TGFβ secretion (Groux et al., 1997). Has an effect.

  The cytokine network involved in the immune response is usually contingent on a complex number of regulatory pathways that result in limiting cell damage and eradicating infectious organisms. However, uncontrolled release of these cytokines can result in damage. Incorrect Th1 / Th2 responses contribute to the pathology of certain diseases. For example, the healing form of wrinkles (tubercloid lesions) is associated with a Th1 response, while uncontrolled wrinkles (lepromal lesions) are associated with a Th2 response. Chronic inflammatory reactions can lead to host death. For example, rats infected with the protozoan parasite Trypanosoma become cachexia, develop anemia, and eventually die. The production of pro-inflammatory cytokines is associated with the pathology of many diseases. In Langerhans cell histiocytosis, cytokines may be involved in some of the tissue damage seen in the disease (Kannourakis & Abbas, 1994). Rheumatoid arthritis is a chronic inflammatory disease of the synovial joint that results in cartilage destruction and bone erosion (Kouskoff et al., 1996). High levels of pro-inflammatory cytokines have been detected in patients with rheumatoid arthritis, and this level may be related to disease activity, converted energy metabolism and food intake (Rubenoff et al., 1994). ). In septic patients, cardiovascular shock and organ dysregulation can be initiated by the production of proinflammatory cytokines stimulated by infectious organisms, particularly in patients with cerebral malaria (Kwiatkowski et al., 1990). Certain alleles of polymorphic sites associated with TNFα production have been shown to predict patients with cerebral malaria (Kwiatowski et al, 1990) and severe sepsis that will be very bad. Also, the genetic predisposition to increased TNFα production may be related to the development of autoimmune diseases such as diabetes and systemic lupus erythematosus. Inhibition of pro-inflammatory cytokine production reduces damage caused by many disease states. IL-1RA reduces the severity of diseases such as shock, lethal infection, inflammatory bowel disease, experimental arthritis, and proliferation of human leukemia cells (see Dinarello, 1992). Inhibition of TNFα in septic shock prevents shock syndrome and tissue wounds despite persistent bacteremia in animal models. Loss of TNF receptor type I in knockout mice protects against endotoxic shock. Anti-cytokines strategies for humans with sepsis have had pessimistic consequences that may be due to complex problems such as delayed administration of these factors after the first inflammatory attack. However, studies on neutralizing TNFα antibodies in rheumatoid arthritis and Crohn's disease have had great success in significantly reducing the observed disease activity (Moreland et al., 1997, Stack et al.,). 1997). Inhibition of transcription factors such as NF-κB responsible for intracellular signaling in inflammatory responses has succeeded in reducing tissue damage in animals with chronic enteritis (Neurath et al., 1996). . Furthermore, the transfer of T cells secreting IL-10 suppressed colitis in the mouse model (Asserman et al., 1999). Furthermore, consumption of certain bacterial species has led to attenuation of gastrointestinal inflammatory activity (O'Mahony et al., 2001, Rembacken et al., 1999). Thus, while an inflammatory response is essential for host tissue defense and repair, an uncontrolled response can lead to severe tissue and organ damage and can lead to host death.

  TGFβ is a family of closely related molecules called TGFβ1-β5. All are released from the cell in a biologically inactive form due to its relationship with the latent protein and are considered a critical regulatory step. Three receptors have been identified for TGFβ. Only two of these receptors convert intracellular signals, suggesting a decoy function for the third receptor. Like the MIP family, TGFβ also functions as a chemotactic factor for both monocytes and neutrophils. However, this cytokine has the opposite effect, as both pro-inflammatory and anti-inflammatory effects have been described. TGFβ is released by platelet aggregation following conduit damage, resulting in recruitment of inflammatory cells to the tissue. Activated monocytes and neutrophils synthesize TGFβ and further increase cellular recruitment. Monocyte integrin expression is also enhanced by TGFβ, as is the induction of collagenase type IV, which aids migration through the basement membrane to the site of inflammation (Wahl et al., 1993). TGFβ increases FcγRIII (CD16) expression, which recognizes antibody-bound cells and thereby increases phagocytic activity. The production of inflammatory cytokines by monocytes can be stimulated by TGFβ as well. However, the expression of IL-1 receptor antagonist (IL-1RA) is similarly increased, suggesting that this cascade may be partially self-regulating. TGFβ is also important as a negative regulator. This antagonizes the effects of many inflammatory cytokines and inhibits the proliferation of thymocyte B cells and hematopoietic stem cells. The behavior of many types of cells can be inhibited by TGFβ, including natural killer (NK) cells, cytotoxic T lymphocytes and lymphokine active killer (LAK) cells. TGFβ also has a suppressive effect on the release of reactive oxygen and nitrogen intermediates by tissue microphages (Ding et al., 1990). The immunoinhibitory effect of TGFβ can be most clearly observed in its impact on diseases such as experimental arthritis, multiple sclerosis and transplant rejection. Through stimulation of matrix protein production, TGFβ is important for wound healing, which is also demonstrated by chemotactic activity on fibroblasts. Therefore, TGFβ has important functions in eliminating inflammatory responses and promoting healing within inflammatory lesions.

IL-10 is produced by T cells, B cells, monocytes and macrophages (De Waal Malefyt et al., 1991). This cytokine promotes B cell proliferation and differentiation into antibody secreting cells (Go et al., 1990). IL-10 exhibits anti-inflammatory activity in most cases. It upregulates IL-1RA expression by monocytes and suppresses most of monocyte inflammatory activity. IL-10 inhibits monocyte production of cytokines, reactive oxygen and nitrogen intermediates, MHC class II expression, parasite killing and IL-10 production by feedback mechanisms (De Waal Malefyt et al., 1991). . This cytokine _also, PGE 2 -cAMP dependent pathway (Mertz et al., 1994) have been shown to block monocyte production of intestinal collagenase and type IV collagenase by interfering with, therefore, chronic inflammation It can also be an important regulator of connective tissue destruction found in sex diseases.

  Interleukin-8 (IL-8) is one of the cytokines including the macrophage inflammatory protein family (MIP). The MIP-1 and MIP-2 families represent a group of proteins that are chemotactic factors for leukocytes and fibroblasts. This protein family is also called intecrins because cells other than macrophages can synthesize them. These cells include T and B cells, epithelial cells, fibroblasts, endothelial cells, keratinocytes, smooth muscle cells, synovial cells, neutrophils, chondrocytes, hepatocytes , Platelets and tumor cells. MIP-1α, -1β, connective tissue activating protein (CTAP), platelet factor IV (PF4) and IL-8 stimulate neutrophil chemotaxis. Monocyte chemotactic protein (MCP-1) and RANTES are chemotactic for monocytes, whereas PF4 and CTAP are chemotactic for fibroblasts. Stimulation of epithelial cells by certain pathogenic bacteria or pro-inflammatory cytokines such as TNF results in the release of IL-8, which recruits neutrophils and lymphocytes to the damaged or inflamed site. Roles other than chemotaxis have also been described for some of these family members. MCP-1 stimulates monocyte cell growth inhibitory activity and superoxide anion release. CTAP and PF4 increase fibroblast proliferation, IL-8 increases vascular permeability, while MIP-1α and -1β are pyrogenic. IL-8 is closely involved in the inflammatory response within the gastrointestinal tract. Stimulation of IL-8 (and other proinflammatory cytokines) contributes to the development of gastrointestinal disorders.

TNFα is a pro-inflammatory cytokine and mediates many of the local and systemic effects seen in inflammatory responses. This cytokine is essentially a product derived from monocytes or macrophages, but includes lymphocytes, neutrophils, NK cells, mast cells, astrocytes, epithelial cells (Neal et al., 1995), endothelial cells and smooth muscle cells. Other cell types can synthesize TNFα as well. TNFα is synthesized as a prohormone and mature 17.5 kDa species can be observed by processing. Purified TNFα has been observed as dimers, trimers and pentamers, and it is postulated that this trimer form is the active form in vivo. Three receptors have been identified for TNFα. Soluble receptors appear to function as TNFα inhibitors, while two membrane-bound forms have been identified with molecular weights of 60-80 kDa, respectively (Schall et al., 1990). Local TNFα production at the site of inflammation can be induced by endotoxin, and the glucocorticoid dexamethasone inhibits cytokine production. Many cell types are stimulated as a result of TNFα production. Significant antiviral effects can be observed in TNFα treated cell lines, and the IFNs synergize with TNFα to enhance this effect (Wong & Goeddel, 1986). Endothelial cells are stimulated by TNFα resulting in the expression of procoagulant activity, adhesion molecules, IL-1, hematopoietic growth factor, platelet activating factor (PAF) and arachidonic acid metabolites. TNFα stimulates neutrophil adhesion, phagocytosis, degranulation, reactive oxygen intermediate production, and may also affect cell migration (Livingston et al., 1989). All GM-CSF, TGFβ, IL- 1, IL-6, PGE 2 and TNFα also leukocyte synthesis itself be stimulated by TNFα administration (Cicco et al., 1990) . Programmed cell death (apoptosis) can be slowed in monocytes (Mangan et al., 1991), while effects on fibroblasts include enhanced chemotaxis and IL-6, PGF ₂ and Includes promotion of collagenase synthesis. While local TNFα production promotes wound healing and immune responses, deregulated systemic release of TNFα is extremely toxic and effects such as cachexia, fever and acute protein production have been observed (Dinarello et al.,). 1988).

Inflammation is a term that refers to the local accumulation of bodily fluids, plasma proteins and leukocytes at the site of physical injury, infection or where an immune response is ongoing. Control of the inflammatory response is exerted at several levels (see Henderson B., and Wilson M. 1998. In ″ Bacteria-Cytokine interactions in health and disease. Portland Press, 79-130). , Cytokines, hormones (eg hydrocortisone), prostaglandins, reactive intermediates and leukotrienes, which are low molecular weight bioactive proteins that control development, tissue repair and hematopoiesis On the other hand, it is involved in the production and control of immune and inflammatory responses, which also provide a means of communication between leukocytes themselves and with other cell types. Most cytokines are multifaceted and express multiple biologically overlapping activities: Cytokine cascades and networks control the inflammatory response rather than the effects of specific cytokines on specific cell types ( Arai KI, et al., Annu Rev Biochem 1990; 59: 783-836) Reduction of the inflammatory response results in a decrease in the concentration of the relevant activation signal and other inflammatory mediators, leading to a stoppage of the inflammatory response TNFα is a central pro-inflammatory cytokine because it initiates biological effects that cause a cascade of cytokines and an inflammatory condition, so substances that inhibit TNFα such as, for example, infliximab are now inflammation Used to treat sexual diseases .

  Pro-inflammatory cytokines are thought to play a major role in the pathology of many inflammatory diseases, including inflammatory bowel disease (IBD). Current therapies for treating IBD aim to reduce the levels of these pro-inflammatory cytokines, including IL-8 and TNFα. Such therapies can also play an important role in the treatment of systemic inflammatory diseases such as rheumatoid arthritis.

  The strains of the invention have potential applications in the treatment of a range of inflammatory diseases, especially if used in combination with other anti-inflammatory therapies such as non-steroidal anti-inflammatory drugs (NSAIDs) or infliximab You can also.

  It is not known whether complete bacterial cells are required to carry out an immunomodulatory effect or whether individual active ingredients of bacterial species can be used alone. Pro-inflammatory components of certain cell types have been identified. The pro-inflammatory effect of gram-negative bacteria is mediated by a number of cellular structures including lipopolysaccharide (LPS). Only LPS induces a proinflammatory network. It is believed that components of probiotic bacteria have anti-inflammatory activity due to whole cell effects. When these components are isolated, pharmaceutical grade manipulation is expected. Thus, the term bacterial species as used herein refers to its active ingredient.

  A common use of bacterial species is in the form of living cells. However, it can also be extended to non-viable cells such as dead sterilized flora and components containing beneficial factors expressed by bacterial species. This can include microorganisms that have been killed by exposure to altered pH or application of pressure. In the case of non-viable cells, preparation of the formulation is easier, the cells can be easily incorporated into the drug, and the storage conditions are not limited. Lactobacillus casei YIT9018 provides an example of effective use of heat-killed cells, such as methods for the treatment and / or prevention of tumor growth as described in US Pat. No. 4,347,405. .

Introducing prebiotics probiotic organisms such is done by ingesting microbes in a suitable carrier. It would be beneficial to provide a medium that promotes the growth of these probiotic strains in the large intestine. Adding one or more oligosaccharides, polysaccharides, or other prebiotics enhances the growth of lactic acid bacteria in the gastrointestinal tract (Gibson, GR. Br. J. Nutr. 1998; 80 (4): S209-12). Prebiotics are any food ingredient that has no life that is specifically fermented in the colon by native bacteria such as Bifidobacteria and Lactobacillus that are considered to be of positive value. . Types of prebiotics include those containing fructose, xylose, soya, galactose, glucose and mannose. Co-administration of a probiotic strain and one or more prebiotic compounds increases the in vivo growth of the administered probiotic and provides a more significant health benefit and is referred to as Symbiotech Yes.

It will be appreciated that the other active ingredients probiotic strains can be administered prophylactically or as a therapeutic method as such or in conjunction with the other probiotic and / or prebiotic substances mentioned above. Furthermore, the fungi can be used as part of a preventive or therapeutic strategy with other active substances such as those used for the treatment of inflammation or other disorders, especially those involving immunity. Such combinations can be administered as a single formulation or as separate formulations, simultaneously or at different times, using the same or different routes of administration.

  The invention can be more clearly understood from the following examples.

Example 1. NGF stimulation of epithelial cells Human colon epithelial cell lines T-84 and HT-29 were mixed incubated with 0, 10, 100 or 1000 ng / ml NGF. The levels of IL-6, IL-8, IL-10, TGFβ and NGF mRNA were quantified using RT-PCR. NGF increased IL-10 levels in a dose-dependent manner. The highest induction of IL-10 was observed within 1 hour of stimulation. None of the other cytokines were induced by NGF stimulation.

Example 2 IL-10 stimulation of epithelial cells Human colon epithelial cell lines T-84 and HT-29 were mixed incubated with 0, 1, 10 or 100 ng / ml IL-10. The levels of IL-6, IL-8, IL-10, TGFβ and NGF mRNA were quantified using RT-PCR. IL-10 selectively increased the level of NGF in a dose-dependent manner (FIG. 2). The highest induction of NGF was observed after 1 hour of stimulation (Figure 3). None of the other cytokines were induced by IL-10 stimulation.

Example 3 FIG. Lactobacillus selectively upregulates NGF.
Human colonic epithelial cell lines T-84 and HT-29 were mixed and incubated with Lactobacillus reuteri for 2 hours. The levels of IL-6, IL-8, IL-10 and NGF mRNA were quantified using RT-PCR. L. Reuteri selectively increased the level of NGF (FIG. 4). None of the other cytokines were induced by bacterial stimulation.

Example 4 Lactobacillus inhibits TNFα-induced IL-8.
Human colon epithelial cell lines T-84 and HT-29 were mixed and incubated with Lactobacillus reuteri for 2 hours followed by 30 minutes with 10 ng / ml TNFα. IL-8 mRNA levels were quantified using RT-PCR. Furthermore, after measuring the level of intracellular IL-8, the mixture was incubated with Brefeldin A for 3 hours. Cells were then lysed and IL-8 levels were measured by ELISA. L. Reuteri reduced TNF-induced IL-8 production at both mRNA and protein levels (FIGS. 5 and 6). Heat inactivated bacterial cells did not maintain this immunomodulatory effect (FIG. 5).

  The present invention is not limited to the above-described embodiments, and can be variously changed in detail.

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Bar graph showing the induction of IL-10 by NGF in a dose dependent manner. Bar graph showing induction of NGF by IL-10 in a dose dependent manner. Bar graph showing time induction of NGF by IL-10. The bar graph which shows the stimulating effect with respect to NGF production of a Lactobacillus species. The bar graph which shows the inhibitory effect on the TNF (alpha) induction IL-8 mRNA level of a Lactobacillus species. The bar graph which shows the inhibitory effect to the TNF (alpha) induction IL-8 protein level of the Lactobacillus sp.

Claims (19)

  Inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, tumors (especially of the digestive tract and immune system), diarrhea disease, antibiotic-related diarrhea, childhood diarrhea, appendicitis, autoimmune disease, multiple sclerosis , Alzheimer's disease, rheumatoid arthritis, peritoneal disease, diabetes, organ transplantation, bacterial infection, viral infection, fungal infection, periodontal disease, urological disease, sexually transmitted disease, HIV infection, HIV replication, HIV-related diarrhea, surgery-related trauma , Surgery-induced metastatic disease, sepsis, weight loss, loss of appetite, fever control, cachexia, wound healing, ulcers, intestinal barrier function, allergy, asthma, respiratory disorder, cardiovascular disease, coronary heart disease, anemia For the treatment and / or prevention of blood clotting disorders, kidney diseases, central nervous system disorders, liver diseases, ischemia, nutritional disorders, osteoporosis, endocrine disorders, epidermis disorders, psoriasis and / or acne Bacteria that selectively upregulate nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) or neurotrophin 4 (NT4), or active derivatives thereof, Use of fragments or mutants.   The bacterial species is derived from a human symbiotic flora that stimulates nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) or neurotrophin 4 (NT4) Use according to claim 1.   Use according to claim 1, characterized in that the bacterial species is Lactobacillus.   Use according to claim 3, characterized in that the Lactobacillus is Lactobacillus reuteri.   The use according to any one of claims 1 to 4, wherein the bacterium is non-viable or a component or variant thereof.   Use of a bacterial strain or an active derivative, fragment or variant thereof that selectively upregulates the production of NGF in the treatment and / or prevention of various diseases such as inflammatory diseases.   Inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, tumors (especially of the digestive tract and immune system), diarrheal diseases, antibiotic-related diarrhea, childhood diarrhea, appendicitis, autoimmune diseases, multiple sclerosis , Alzheimer's disease, rheumatoid arthritis, peritoneal disease, diabetes, organ transplantation, bacterial infection, viral infection, fungal infection, periodontal disease, urological disease, sexually transmitted disease, HIV infection, HIV replication, HIV-related diarrhea, surgery-related trauma , Surgery-induced metastatic disease, sepsis, weight loss, loss of appetite, fever control, cachexia, wound healing, ulcers, intestinal barrier function, allergy, asthma, respiratory disorder, cardiovascular disease, coronary heart disease, anemia For the treatment and / or prevention of blood coagulation system disorders, kidney diseases, central nervous system disorders, liver diseases, ischemia, nutritional disorders, osteoporosis, endocrine disorders, epidermis disorders, psoriasis and / or acne That nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) or neurotrophin 4 (NT4), or an active derivative thereof, using a fragment or variant.   Use of nerve growth factor (NGF) or an active derivative, fragment or variant thereof in the treatment and / or prevention of various diseases such as inflammatory diseases.   Inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, tumors (especially of the digestive tract and immune system), diarrheal diseases, antibiotic-related diarrhea, childhood diarrhea, appendicitis, autoimmune diseases, multiple sclerosis , Alzheimer's disease, rheumatoid arthritis, peritoneal disease, diabetes, organ transplantation, bacterial infection, viral infection, fungal infection, periodontal disease, urological disease, sexually transmitted disease, HIV infection, HIV replication, HIV-related diarrhea, surgery-related trauma , Surgery-induced metastatic disease, sepsis, weight loss, loss of appetite, fever control, cachexia, wound healing, ulcers, intestinal barrier function, allergy, asthma, respiratory disorder, cardiovascular disease, coronary heart disease, anemia For the treatment and / or prevention of blood coagulation system disorders, kidney diseases, central nervous system disorders, liver diseases, ischemia, nutritional disorders, osteoporosis, endocrine disorders, epidermis disorders, psoriasis and / or acne Te, NGF, BDNF, NT3 or NT4, and selectively upregulate bacterial strains IL10 or an active derivatives, the use of a fragment or variant.   A method for screening the therapeutic potential of bacterial species for use in disease-specific therapy comprising the process of stimulating epithelial cells with different bacterial species to induce various cytokine profiles.   Epithelial cells are stimulated with different bacterial species to selectively upregulate NGF, BDNF, NT3 or NT4 and induce various cytokine profiles for use in disease-specific therapies. A method for screening therapeutic potential.   A method substantially as herein described in connection with an embodiment.   A preparation comprising a bacterial species that induces NGF, BDNF, NT3 or NT4, or an active derivative, fragment or variant thereof.   A formulation comprising a bacterial species that induces NGF, BDNF, NT3 or NT4, and / or IL10, or an active derivative, fragment or variant thereof.   A preparation comprising a bacterial species that induces NGF, BDNF, NT3 or NT4, or an active derivative, fragment or variant thereof for use in the prevention and / or treatment of various diseases such as inflammatory diseases.   A preparation comprising NGF, BDNF, NT3 or NT4, or an active derivative, fragment or variant thereof for use in the prevention / treatment of various diseases such as inflammatory diseases.   Inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, tumors (especially of the digestive tract and immune system), diarrheal diseases, antibiotic-related diarrhea, childhood diarrhea, appendicitis, autoimmune diseases, multiple sclerosis , Alzheimer's disease, rheumatoid arthritis, peritoneal disease, diabetes, organ transplantation, bacterial infection, viral infection, fungal infection, periodontal disease, urological disease, sexually transmitted disease, HIV infection, HIV replication, HIV-related diarrhea, surgery-related trauma , Surgery-induced metastatic disease, sepsis, weight loss, loss of appetite, fever control, cachexia, wound healing, ulcers, intestinal barrier function, allergy, asthma, respiratory disorder, cardiovascular disease, coronary heart disease, anemia For the treatment and / or prevention of blood coagulation system disorders, kidney diseases, central nervous system disorders, liver diseases, ischemia, nutritional disorders, osteoporosis, endocrine disorders, epidermis disorders, psoriasis and / or acne Te, NGF, BDNF, NT3 or bacterial species that selectively upregulate production of NT4, or an active derivative thereof, a vaccine consisting of a fragment or variant thereof.   A vaccine comprising a bacterial species that selectively upregulates the production of NGF, BDNF, NT3 or NT4, or an active derivative, fragment or variant thereof in the treatment and / or prevention of various diseases such as inflammatory diseases.   Inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, tumors (especially of the digestive tract and immune system), diarrheal diseases, antibiotic-related diarrhea, childhood diarrhea, appendicitis, autoimmune diseases, multiple sclerosis , Alzheimer's disease, rheumatoid arthritis, peritoneal disease, diabetes, organ transplantation, bacterial infection, viral infection, fungal infection, periodontal disease, urological disease, sexually transmitted disease, HIV infection, HIV replication, HIV-related diarrhea, surgery-related trauma , Surgery-induced metastatic disease, sepsis, weight loss, loss of appetite, fever control, cachexia, wound healing, ulcers, intestinal barrier function, allergy, asthma, respiratory disorder, cardiovascular disease, coronary heart disease, anemia For the treatment and / or prevention of blood coagulation system disorders, kidney diseases, central nervous system disorders, liver diseases, ischemia, nutritional disorders, osteoporosis, endocrine disorders, epidermis disorders, psoriasis and / or acne NGF Te, BDNF, NT3 or NT4 or an active derivative thereof, a vaccine consisting of a fragment or variant thereof.

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