EP1511502A2 - Therapies probiotiques utilisant lactobacillus reuteri - Google Patents

Therapies probiotiques utilisant lactobacillus reuteri

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Publication number
EP1511502A2
EP1511502A2 EP03760112A EP03760112A EP1511502A2 EP 1511502 A2 EP1511502 A2 EP 1511502A2 EP 03760112 A EP03760112 A EP 03760112A EP 03760112 A EP03760112 A EP 03760112A EP 1511502 A2 EP1511502 A2 EP 1511502A2
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EP
European Patent Office
Prior art keywords
disease
disorders
ngf
inflammatory
bdnf
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP03760112A
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German (de)
English (en)
Inventor
John Bienenstock
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University College Cork
Original Assignee
Alimentary Health Ltd
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Publication date
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Publication of EP1511502A2 publication Critical patent/EP1511502A2/fr
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    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
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    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
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    • A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells

Definitions

  • the invention relates to the immunoregulatory and therapeutic effects of a bacterial strain in particular immunoregulatory and therapeutic effects of a bacterial strain.
  • Innate defence mechanisms include the low pH of the stomach, bile salts, peristalsis, mucin layers and anti-microbial compounds such as lysozyme (D.C. Savage, 'Microbial Ecology of the Gut', Academic Press, London, 1997, p.278.).
  • Immunological mechanisms include specialized lymphoid aggregates, underlying M cells, called peyers patches, which are distributed throughout the small intestine and colon (M.F. Kagnoff. Gastroenterol. 1993, 105, 1275).
  • Luminal antigens presented at these sites result in stimulation of appropriate T and B cell subsets with establishment of cytokine networks and secretion of antibodies into the gastrointestinal tract (M.R. ⁇ eutra and J-P Kraehenbuhl, 'Essentials of mucosal immunology', Academic Press,
  • microflora on mucosal surfaces are vast in number and complexity. Many hundreds of bacterial strains exist and account for approximately 90% of the cells found in the human body, the remainder of the cells being human. The vast majority of these bacterial strains do not cause disease and may actually provide the host with significant health benefits (e.g. bifidobacteria and lactobacilli) . These bacterial strains are termed commensal organisms. Mechanism (s) exist whereby the immune system at mucosal surfaces can recognise commensal non-pathogenic flora as being different to pathogenic organisms.
  • Bacteria present in the human gastrointestinal tract can promote inflammation. Aberrant immune responses to the indigenous microflora have been implicated in certain disease states, such as inflammatory bowel disease (Brandzeag P. et al. Springer Semin. Immunopathol, 1997, 18, 555). Antigens associated with the normal flora usually lead to immunological tolerance and failure to achieve this tolerance is a major mechanism of mucosal inflammation (Stallmach A. et al., Immunol. Today, 1998, 19, 438). Evidence for this breakdown in tolerance includes an increase in antibody levels directed against the gut flora in patients with inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • a bacterial strain or an active derivative, fragment or mutant thereof which selectively upregulates the production of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) or neurotrophin 4 (NT4) in the treatment and/or prophylaxis of inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, cancer (particularly of the gastrointestinal and immune systems), diarrhoeal disease, antibiotic associated diarrhoea, paediatric diarrhoea, appendicitis, autoimmune disorders, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, coeliac disease, diabetes mellitus, organ transplantation, bacterial infections, viral infections, fungal infections, periodontal disease, urogenital disease, sexually transmitted disease, HIV infection, HIV replication, HIV associated diarrhoea, surgical associated trauma, surgical-induced metastatic disease, sepsis, weight loss, anorexia, fever
  • NGF nerve growth factor
  • the bacterial strain is derived from the human commensal flora which stimulate the production of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) or neurotrophin 4 (NT4).
  • NGF nerve growth factor
  • BDNF brain derived neurotrophic factor
  • NT3 neurotrophin 3
  • NT4 neurotrophin 4
  • the bacterial strain is a Lactobacillus.
  • the Lactobacillus is Lactobacillus reuteri.
  • the bacteria may be viable or non viable. Also included are components or mutants of the strain. ALIM23/C
  • the invention provides use of a bacterial strain or an active derivative, fragment or mutant thereof which selectively upregulates the production of NGF, BDNF, NT3 or NT4 in the treatment and/or prophylaxis of various diseases such as inflammatory diseases.
  • the invention further provides use of NGF, BDNF, NT3 or NT4 or an active derivative, fragment or mutant thereof in the treatment and/or prophylaxis of inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, cancer (particularly of the gastrointestinal and immune systems), diarrhoeal disease, antibiotic associated diarrhoea, paediatric diarrhoea, appendicitis, autoimmune disorders, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, coeliac disease, diabetes mellitus, organ transplantation, bacterial infections, viral infections, fungal infections, periodontal disease, urogenital disease, sexually transmitted disease, HIV infection, HIV replication, HIV associated diarrhoea, surgical associated trauma, surgical-induced metastatic disease, sepsis, weight loss, anorexia, fever control, cachexia, wound healing, ulcers, gut barrier function, allergy, asthma, respiratory disorders, circulatory disorders, coronary heart disease, anaemia, disorders
  • the invention also provides use of NGF, BDNF, NT3 or NT4 or an active derivative, fragment or mutant thereof in the treatment and/or prophylaxis of various diseases such as inflammatory diseases.
  • the invention further provides use of a bacterial strain or an active derivative, fragment or mutant thereof which selectively upregulates the production of NGF, BDNF, NT3 or NT4 and IL-10 in the treatment and/or prophylaxis of inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, cancer (particularly of the gastrointestinal and immune systems), ALIM23/C - 5 - diarrhoeal disease, antibiotic associated diarrhoea, paediatric diarrhoea, appendicitis, autoimmune disorders, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, coeliac disease, diabetes mellitus, organ transplantation, bacterial infections, viral infections, fungal infections, periodontal disease, urogenital disease, sexually transmitted disease, HIV infection, HIV replication, HIV associated diarrhoea, surgical associated trauma, surgical-induced metastatic disease, sepsis, weight loss, anorexia, fever control, cachexia, wound healing
  • the invention also provides a method for screening the therapeutic potential of bacterial strains for use in disease specific therapies comprising stimulating epithelial cells with different bacterial species to induce different cytokine profiles.
  • the invention further provides a method for screening the therapeutic potential of bacterial strains for use in disease specific therapies comprising stimulating epithelial cells with different bacterial species to selectively upregulate NGF, BDNF, NT3 or NT4 and induce different cytokine profiles.
  • the invention also provides a formulation comprising a bacterial strain or an active derivative, fragment or mutant thereof which induces NGF, BDNF, NT3 or NT4.
  • the invention further provides a formulation comprising a bacterial strain or an active derivative, fragment or mutant thereof which induces NGF, BDNF, NT3 or NT4 and/or IL-10.
  • the invention also provides a formulation comprising a bacterial strain or an active derivative, fragment or mutant thereof which induces NGF, BDNF, NT3 or NT4 for ALIM23/C
  • the invention also provides a formulation comprising NGF, BDNF, NT3 or NT4 or an active derivative, fragment or mutant thereof for use in the prevention and/or treatment of various diseases such as inflammatory diseases.
  • the invention further provides a vaccine comprising a bacterial strain or an active derivative, fragment or mutant thereof which selectively upregulates the production of NGF, BDNF, NT3 or NT4 in the treatment and/or prophylaxis of inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, cancer (particularly of the gastrointestinal and immune systems), diarrhoeal disease, antibiotic associated diarrhoea, paediatric diarrhoea, appendicitis, autoimmune disorders, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, coeliac disease, diabetes mellitus, organ transplantation, bacterial infections, viral infections, fungal infections, periodontal disease, urogenital disease, sexually transmitted disease, HIV infection, HIV replication, HIV associated diarrhoea, surgical associated trauma, surgical-induced metastatic disease, sepsis, weight loss, anorexia, fever control, cachexia, wound healing, ulcers, gut barrier function, allergy, asthma
  • the invention also provides a vaccine comprising a bacterial strain or an active derivative, fragment or mutant thereof which selectively upregulates the production of NGF, BDNF, NT3 or NT4 in the treatment and/or prophylaxis of various diseases such as inflammatory diseases.
  • a vaccine comprising a bacterial strain or an active derivative, fragment or mutant thereof which selectively upregulates the production of NGF, BDNF, NT3 or NT4 in the treatment and/or prophylaxis of various diseases such as inflammatory diseases.
  • the invention also provides a vaccine comprising NGF, BDNF, NT3 or NT4 or an active derivative, fragment or mutant thereof in the treatment and/or prophylaxis of inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, cancer (particularly of the gastrointestinal and immune systems), diarrhoeal disease, antibiotic associated diarrhoea, paediatric diarrhoea, appendicitis, autoimmune disorders, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, coeliac disease, diabetes mellitus, organ transplantation, bacterial infections, viral infections, fungal infections, periodontal disease, urogenital disease, sexually transmitted disease, HIV infection, HIV replication, HIV associated diarrhoea, surgical associated trauma, surgical-induced metastatic disease, sepsis, weight loss, anorexia, fever control, cachexia, wound healing, ulcers, gut barrier function, allergy, asthma, respiratory disorders, circulatory disorders, coronary heart disease, ana
  • the term derivative is taken to include active forms of the bacterial strain with modifications which do not substantially effect the activity of the strain.
  • mutant is taken to include strains with amino acid variations which do not substantially effect the activity of the strain.
  • fragment is taken to include sub-units encoded by a nucleic acid sequence present in all or part of the parent bacterial strain.
  • Fig. 1 is a bar graph showing the induction of IL-10 by NGF in a dose dependant manner
  • Fig. 2 is a bar graph showing the induction of NGF by IL-10 in a dose dependant manner
  • Fig. 3 is a bar graph showing the temporal induction of NGF by IL-10
  • Fig. 4 is a bar graph showing the stimulatory effect of a lactobacillus species on NGF production
  • Fig. 5 is a bar graph showing the inhibitory effect of a lactobacillus strain on TNF ⁇ induced IL-8 mRNA levels.
  • Fig. 6 is a bar graph showing the inhibitory effect of a lactobacillus strain on TNF ⁇ induced IL-8 protein levels.
  • One of the mechanisms whereby probiotic organisms may protect against mucosal inflammation may be directly or indirectly through interaction with the mucosal epithelium thereby causing the epithelium to upregulate and express molecules which are anti-inflammatory.
  • cytokines such as IL-10
  • neurotrophins such as nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) or neurotrophin 4 (NT4) and products of arachidonic acid such as PGE 2 .
  • the present invention is directed toward bacterial strains, which have immunoregulatory and therapeutic effects due to their stimulation of NGF activity. It is also envisaged that the bacterial strains, would have immuno-regulatory and therapeutic effects due to their stimulation of BDNF, NT3 or NT4 activity.
  • ALIM23/C ALIM23/C
  • NGF NGF-induced NGF production which resulted in inhibition of pro-inflammatory cytokine generation.
  • NGF and the cytokines appear to reciprocally upregulate each other.
  • Lactobacillus is commercially available. Lactobacillus reuteri strain type RF 14249 and RF 20013 is deposited under the designation F275 (DSM20016), JCM112, ATCC23272, NCD02589.
  • Nerve growth factor for which discovery Professor Rita Levi-Montalcini received the Nobel Prize, was the first neurotrophin, or nerve growth factor to be discovered. It is essential for the growth of nerves in the peripheral nervous system, the autonomic nervous system, especially the sympathetic, and many components of the central nervous system. It is synthesised and secreted by a large number of cells in addition to those of the nervous system: these include structural cells such as the glia, and fibroblasts, cells of the immune system such as T-lymphocytes (especially TH2) and cells involved in the inflammatory process such as eosinophils, mast cells and dendritic cells. It has pleiotropic functions in addition to its multiple effects in the nervous system.
  • the active component is a 2.5S molecule with a molecular weight of about 26K. It's chromosomal location is lpl3. It promotes the survival and growth of neurons but in addition has many effects in many different systems which include promotion of human hemopoietic colony growth of basophils and eosinophils, the promotion of synthesis by B-cells of ALIM23/C
  • IgG4 IgG4 and the prevention of apoptosis in neutrophils, eosinophils and mast cells (Bienenstock et al., 2000). It has also been shown to have wound healing properties (Matsuda et al., 1998) and appears to protect against a mucosal inflammatory model of hapten-induced colitis (Reinshagen et al., 2000). Most 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 demyelinating disease, autoimmune encephalomyelitis (Flugel et al., 2001).
  • NGF is an important neurotrophin and is essential for many different physiological functions.
  • the induction of NGF results in improved immunological control and promotes wound healing.
  • a method of inducing NGF production with the attenuation of different cytokines has therefore large therapeutic potential.
  • BDNF brain derived neurotrophic factor
  • NT3 neurotrophin 3
  • neurotrophin 3 NT3
  • NT4 neurotrophin 4
  • the invention has potential therapeutic value in the prophylaxis and/or treatment of dysregulated immunological control, such as undesirable inflammatory reactions (e.g. inflammatory bowel disease).
  • dysregulated immunological control such as undesirable inflammatory reactions (e.g. inflammatory bowel disease).
  • Bifidobacteria and Lactobacilli strains potentially have the same effect as L. reuteri.
  • Such Bifidobacteria and Lactobacilli are typically isolated from the ALIM23/C
  • the strain may be a genetically modified mutant or it may be a naturally occurring variant thereof.
  • the strain is in the form of viable cells.
  • the strain may be in the form of non-viable cells.
  • the invention also relates to the potential of bacterial strains in customising epithelial cell phenotype and function. In this way customisation of disease specific therapies may be accomplished using a selection of bacterial strains.
  • cytokine production is specific for each of the probiotic strains examined.
  • specific probiotic strains may be selected for normalising an exclusive cytokine imbalance particular for a specific disease type.
  • Customisation of disease specific therapies can be accomplished using a selection of probiotic strains.
  • cytokine production and immune responses Recognition of bacterial species by epithelial cells results in distinct patterns of cytokine production and immune responses.
  • the cytokines produced by epithelial cells are secreted into the extracellular milieu. These cytokines deliver an informative signal to neighbouring cells, which do not necessarily have to be in physical contact with the epithelial cell. This "bystander" effect results in many different cell types being influenced by the cytokine network established by bacterial stimulated epithelial cells.
  • ALIM23/C ALIM23/C
  • the enteric flora is important to the development and proper function of the intestinal immune system. In the absence of an enteric flora, the intestinal immune system is underdeveloped, as demonstrated in germ free animal models, and certain functional parameters are diminished, such as macrophage phagocytic ability and immunoglobulin production (Crabbe et al, 1968, Wostmann et al, 1996). The importance of the gut flora in stimulating non-damaging immune responses is becoming more evident. The increase in incidence and severity of allergies in the western world has been linked with an increase in hygiene and sanitation, concomitant with a decrease in the number and range of infectious challenges encountered by the host.
  • This lack of immune stimulation may allow the host to react to non-pathogenic, but antigenic, agents resulting in allergy or autoimmunity. Deliberate consumption of a series of non-pathogenic immunomodulatory bacteria would provide the host with the necessary and appropriate educational stimuli for proper development and control of immune function.
  • the human immune system plays a significant role in the aetiology and pathology of a vast range of human diseases. Hyper and hypo-immune responsiveness results in, or is a component of, the majority of disease states.
  • One family of biological entities, termed cytokines, are particularly important to the control of immune processes. Pertubances of these delicate cytokine networks are being increasingly associated with many diseases.
  • diseases include but are not limited to inflammatory disorders, immunodeficiency, inflammatory bowel disease, irritable bowel syndrome, cancer (particularly those of the gastrointestinal and immune systems), diarrhoeal disease, antibiotic associated diarrhoea, paediatric diarrhoea, appendicitis, autoimmune disorders, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, coeliac disease, diabetes mellitus, organ transplantation, bacterial infections, viral infections, fungal infections, periodontal disease, urogenital ALIM23/C
  • - 13 - disease sexually transmitted disease, HIV infection, HIV replication, HIV associated diarrhoea, surgical associated trauma, surgical-induced metastatic disease, sepsis, weight loss, anorexia, fever control, cachexia, wound healing, ulcers, gut barrier function, allergy, asthma, respiratory disorders, circulatory disorders, coronary heart disease, anaemia, disorders of the blood coagulation system, renal disease, disorders of the central nervous system, hepatic disease, ischaemia, nutritional disorders, osteoporosis, endocrine disorders, epidermal disorders, psoriasis and acne vulgaris.
  • T cells which differ in their pattern of cytokine secretion, allows differentiation of inflammatory or immune responses into at least three categories, cell mediated or humoral responses or Th3/Trl regulatory responses.
  • Thl responses are categorised by IFN ⁇ , TNF ⁇ and IL-2 production leading to a cell-mediated response while Th2 cells secrete IL-4, IL-5, IL-9, IL-10 and IL-13 resulting in a humoral response.
  • Th3/Trl responses are characterised by T cell secretion of the regulatory cytokines IL-10 and TGF .
  • T cells into either network depends on the cytokine milieu in which the original antigen priming occurs (Seder et al., 1992).
  • the polarisation of T cell subpopulations are influenced by a number of other cell types including dendritic cells and epithelial cells. (Mosmann & Sad, 1996).
  • Certain types of stimulation may also direct this response, such as immune complex deposition within inflammatory sites which increases IL-6 and IL-10 production and inhibits production of TNF ⁇ and IL-l ⁇ thus influencing the Thl/Th2 balance.
  • the correct cytokine network needs to be established.
  • the intracellular bacterium Listeria monocytogenes elicits a Thl response while the extracellular parasite Nippostrongylus brasiliensis requires a Th2 response.
  • Each of these T cell subsets produce cytokines that are autocrine growth factors for that subset and promote differentiation of naive T cells into that subset (Trinchieri et al., ALIM23/C
  • Trl cells have a profound suppressive effect on antigen-specific T cell responses mediated by secretion of IL-10 and TGF ⁇ (Groux et al., 1997) and cytokine independent mechanisms such as direct cell-cell contact.
  • the cytokine networks involved in immune responses are subject to a complex number of control pathways that normally result in restriction of cellular damage and eradication of the infectious organism.
  • unregulated release of these cytokines can have damaging consequences.
  • Thl/Th2 responses contribute to the pathogenesis of certain diseases.
  • the healing form of leprosy (tuberculoid lesion) is associated with a Thl response while uncontrolled leprosy (lepromatous lesion) is associated with a Th2 response.
  • Chronic inflammatory responses can lead to the death of the host. For instance, rats infected with the protozoan parasite Trypanosoma brucei become cachectic, develop anaemia and eventually die.
  • cytokines may be involved in some of the tissue damage seen with this disease (Kannourakis & Abbas, 1994).
  • Rheumatoid arthritis is a chronic inflammatory disease of the synovial joints resulting in cartilage destruction and bone erosion (Kouskoff et al., 1996). Elevated levels of proinflammatory cytokines have been detected from patients with rheumatoid arthritis and these levels could be associated with disease activity, altered energy metabolism and food intake (Roubenoff et al., 1994).
  • cardiovascular shock and organ dysfunction may be initiated by the production of proinflammatory cytokines stimulated by the infectious organism particularly in patients with cerebral malaria (Kwiatkowski et al., 1990). Certain alleles of polymorphic sites associated with TNF ⁇ production have been shown to predict patients with cerebral malaria (McGuire et al., 1994) and severe sepsis ALIM23/C
  • TNF ⁇ tumor necrosis factor
  • IL-1RA reduces the severity of diseases such as shock, lethal sepsis, inflammatory bowel disease, experimental arthritis and proliferation of human leukaemic cells (for review see Dinarello, 1992).
  • Inhibition of TNF ⁇ in septic shock prevents the syndrome of shock and tissue injury despite persistent bacteraemia in animal models.
  • TGF ⁇ refers to a family of closely related molecules termed TGF ⁇ l to - ⁇ 5 (Roberts & Sporn, 1990). All are released from cells in a biologically inactive form due to their association with a latency protein which is believed to be a critical regulatory step. Three receptors have been identified for TGF ⁇ . Only two of these receptors ALI 23/C
  • TGF ⁇ also functions as a chemotactic factor for both monocytes and neutrophils.
  • this cytokine has diverse effects as both pro and anti-inflammatory effects have been described. Aggregated platelets following vascular injury release TGF ⁇ resulting in inflammatory cell recruitment to the tissue.
  • TGF ⁇ Activated monocytes and neutrophils synthesise TGF ⁇ further increasing cellular recruitment.
  • Monocyte integrin expression is also enhanced by TGF ⁇ as is the induction of collagenase type IV which may aid movement through basement membranes into inflamed sites (Wahl et al., 1993).
  • TGF ⁇ increases the expression of Fc ⁇ RIII (CD 16) which recognises antibody bound cells thereby increasing phagocytic activity.
  • the production of inflammatory cytokines by monocytes can also be stimulated by TGF ⁇ .
  • IL-1 receptor antagonist IL-1 receptor antagonist
  • TGF ⁇ is also important as a negative regulatory agent.
  • TGF ⁇ tumor necrosis factor-induced cytokinase
  • NK natural killer
  • LAK lymphokine activated killer
  • TGF ⁇ also has suppressive effects on the release of reactive oxygen and nitrogen intermediates by tissue macrophages (Ding et al., 1990).
  • the immune inhibitory effects of TGF ⁇ can most clearly be observed in its effects on diseases such as experimental arthritis, multiple sclerosis and graft rejection.
  • TGF ⁇ may be important to wound healing which is also indicated by its chemotactic activity for fibroblasts (Roberts & Sporn, 1990). Therefore TGF ⁇ may have important functions with regard to resolution of the inflammatory response and promotion of healing within the inflammatory lesion.
  • IL-10 is produced by T cells, B cells, monocytes and macrophages (De Waal Malefyt et al., 1991). This cytokine augments the proliferation and differentiation of B cells ALIM23/C
  • IL-10 exhibits mostly anti- inflammatory activities. It up-regulates IL-IRA expression by monocytes and suppresses the majority of monocyte inflammatory activities. IL-10 inhibits monocyte production of cytokines, reactive oxygen and nitrogen intermediates, MHC class II expression, parasite killing and IL-10 production via a feed back mechanism (De Waal Malefyt et al., 1991). This cytokine has also been shown to block monocyte production of intestinal collagenase and type IV collagenase by interfering with a PGE2-cAMP dependant pathway (Mertz et al., 1994) and therefore may be an important regulator of the connective tissue destruction seen in chronic inflammatory diseases.
  • Interleukin-8 is one of the cytokines comprising the Macrophage Inflammatory protein family (MIP).
  • MIP-1 and -2 families represent a group of proteins which are chemotactic factors for leukocytes and fibroblasts. This family of proteins are also called intercrines, as cells other than macrophages are capable of synthesising them. These cells include T and B cells, epithelial cells, fibroblasts, endothelial cells, keratinocytes, smooth muscle cells, synovial cells, neutrophils, chondrocytes, hepatocytes, platelets and tumour cells.
  • MlP-l ⁇ , -l ⁇ , connective tissue activating protein (CTAP), platelet factor 4 (PF4) and IL-8 stimulate neutrophil chemotaxis.
  • Monocyte chemotactic protein (MCP-1) and RANTES are chemotactic for monocytes while PF4 and CTAP are chemotactic for fibroblasts.
  • Stimulation of epithelial cells by certain pathogenic bacteria or proinflammatory cytokines, such as TNF results in the release of IL-8 which recruits neutrophils and lymphocytes to damaged or inflamed sites. Roles other than chemotaxis have been described for some of these family members.
  • MCP-1 stimulates monocyte cytostatic activity and superoxide anion release.
  • CTAP and PF4 increase fibroblast proliferation
  • IL-8 increases vascular permeability while MlP-l ⁇ and -l ⁇ are pyrogenic.
  • IL-8 is intimately involved in inflammatory responses within the ALIM23/C
  • IL-8 and other proinflammatory cytokines contributes to the development of gastrointestinal lesions.
  • TNF ⁇ is a proinflammatory cytokine, which mediates many of the local and systemic effects seen during an inflammatory response.
  • This cytokine is primarily a monocyte or macrophage derived product but other cell types including lymphocytes, neutrophils, NK cells, mast cells, astrocytes, epithelial cells (Neale et al., 1995) endothelial cells and smooth muscle cells can also synthesise TNF ⁇ .
  • TNF ⁇ is synthesised as a prohormone and following processing the mature 17.5 kDa species can be observed. Purified TNF ⁇ has been observed as dimers, trimers and pentamers with the trimeric form postulated to be the active form in vivo. Three receptors have been identified for TNF ⁇ .
  • TNF ⁇ production results in the stimulation of many cell types.
  • Significant anti-viral effects could be observed in TNF ⁇ treated cell lines and the IFNs synergise with TNF ⁇ enhancing this effect (Wong & Goeddel, 1986).
  • Endothelial cells stimulated by TNF ⁇ produce procoagulant activity, expression of adhesion molecules, IL-1, hematopoitic growth factors, platelet activating factor (PAF) and arachidonic acid metabolites.
  • TNF ⁇ stimulates neutrophil adherence, phagocytosis, degranulation, reactive oxygen intermediate production and may influence cellular migration (Livingston et al., 1989).
  • Leucocyte synthesis of GM-CSF, TGF ⁇ , IL-1, IL-6, PGE2 and TNF ⁇ itself can all be stimulated upon TNF ⁇ administration (Cicco et al., 1990).
  • Programmed cell death can be delayed in monocytes (Mangan et al., 1991) while effects on fibroblasts include the promotion of chemotaxis and IL-6, PGE2 and collagenase synthesis. While local TNF ⁇ production promotes wound healing and ALIM23/C
  • TNF ⁇ can be severely toxic with effects such as cachexia, fever and acute phase protein production being observed (Dinarello et al., 1988).
  • Inflammation is the term used to describe the local accumulation of fluid, plasma proteins and white blood cells at a site that has sustained physical damage, infection or where there is an ongoing immune response. Control of the inflammatory response is exerted on a number of levels (for review see Henderson B Crow and Wilson
  • Cytokines are low molecular weight biologically active proteins that are involved in the generation and control of immunological and inflammatory responses, while also regulating development, tissue repair and haematopoies ⁇ s. They provide a means of communication between leukocytes themselves and also with other cell types. Most cytokines are pleiotrophic and express multiple biologically overlapping activities. Cytokine cascades and networks control the inflammatory response rather than the action of a particular cytokine on a particular cell type (Arai KI, et al., Annu Rev
  • TNF ⁇ is a pivotal proinflammatory cytokine as it initiates a cascade of cytokines and biological effects resulting in the inflammatory state. Therefore, agents which inhibit TNF ⁇ are currently being used for the treatment of inflammatory diseases, e.g. infliximab.
  • - 20 - therapies for treating IBD are aimed at reducing the levels of these pro-inflammatory cytokines, including IL-8 and TNF ⁇ .
  • Such therapies may also play a significant role in the treatment of systemic inflammatory diseases such as rheumatoid arthritis.
  • strains of the present invention may have potential application in the treatment of a range of inflammatory diseases, particularly if used in combination with other anti-inflammatory therapies, such as non-steroid anti-inflammatory drugs (NSAIDs) or Infliximab.
  • NSAIDs non-steroid anti-inflammatory drugs
  • Infliximab Infliximab
  • LPS lipopolysaccharide
  • the general use of the bacterial strains is in the form of viable cells. However, it can also be extended to non-viable cells such as killed cultures or compositions containing beneficial factors expressed by the bacterial strains. This could include micro-organisms killed by exposure to altered pH or subjection to pressure. With non-viable cells product preparation is simpler, cells may be incorporated easily into pharmaceuticals and storage requirements are not as limited. Lactobacillus casei YIT 9018 offers an example of the effective use of heat killed cells as a method for the treatment and/or prevention of tumour growth as described in US Patent No. US4347240. ALIM23/C
  • probiotic organisms The introduction of probiotic organisms is accomplished by the ingestion of the micro-organism in a suitable carrier. It would be advantageous to provide a medium that would promote the growth of these probiotic strains in the large bowel.
  • the addition of 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 refers to any non-viable food component that is specifically fermented in the colon by indigenous bacteria thought to be of positive value, e.g. bifidobacteria, lactobacilli.
  • Types of prebiotics may include those that contain fructose, xylose, soya, galactose, glucose and mannose.
  • the combined administration of a probiotic strain with one or more prebiotic compounds may enhance the growth of the administered probiotic in vivo resulting in a more pronounced health benefit, and is termed synbiotic.
  • the probiotic strains may be administered prophylactically or as a method of treatment either on its own or with other probiotic and/or prebiotic materials as described above.
  • the bacteria may be used as part of a prophylactic or treatment regime using other active materials such as those used for treating inflammation or other disorders especially those with an immunological involvement.
  • Such combinations may be administered in a single formulation or as separate formulations administered at the same or different times and using the same or different routes of administration.
  • Human colonic epithelial cell lines T-84 and HT-29 were co-incubated with 0, 10, 100 or 1000 ng/ml NGF.
  • IL-6, IL-8, IL-10, TGF ⁇ and NGF mRNA levels were quantified using RT-PCR.
  • NGF increased IL-10 levels in a dose dependant manner (Fig. 1). Maximal induction of IL-10 was observed within one hour of stimulation. None of the other cytokines were induced by NGF stimulation.
  • Example 2 IL-10 stimulation of epithelial cells.
  • IL-10 Human colonic epithelial cell lines T-84 and HT-29 were co-incubated with 0, 1, 10 or 100 ng/ml IL-10.
  • IL-6, IL-8, IL-10, TGF ⁇ and NGF mRNA levels were quantified using RT-PCR.
  • IL-10 selectively increased NGF levels in a dose dependant manner (Fig. 2). Maximal induction of NGF was noted following one hour of stimulation (Fig. 3). None of the other cytokines were induced by IL-10 stimulation.
  • Example 3 Lactobacilli selectively upregulate NGF.
  • Lactobacillus reuteri for 2 hours. IL-6, IL-8, IL-10, and NGF mRNA levels were quantified using RT-PCR. L. reuteri selectively increased NGF levels (Fig. 4). None of the other cytokines were induced by bacterial stimulation.
  • Example 4 Lactobacilli inhibit TNF ⁇ induced IL-8.
  • Human colonic epithelial cell lines T-84 and HT-29 were co-incubated with Lactobacillus reuteri for 2 hours, followed by 30 minutes incubation with lOng/ml ALIM23/C
  • TNF ⁇ TNF ⁇ .
  • IL-8 mRNA levels were quantified using RT-PCR.
  • intracellular IL-8 levels were measured following co-incubation with brefeldin A for 3 hours.
  • Cells were then lysed and IL-8 levels quantified by ELISA.
  • L. reuteri attenuated TNF induced IL-8 production both at the mRNA and protein level (Figs. 5 & 6). Heat inactivated bacterial cells did not maintain this immunomodulatory effect (Fig. 5).
  • Trinchieri G Peritt D, Gerosa F. Acute induction and priming for cytokine production in lymphocytes. Cytokine Growth Factor Rev 1996 Aug;7(2):123-32.
  • CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature, 1997; 389:737-42.
  • Kannourakis G Abbas A. The role of cytokines in the pathogenesis of Langerhans cell histiocytosis. Br J Cancer Suppl 1994 Sep;23:S37-40.
  • NF-kappa B abrogates established experimental colitis in mice. Nat Med 1996 Sep;2(9):998-1004.
  • Tumor necrosis factor-alpha is expressed by glomerular visceral epithelial cells in human membranous nephropathy. Am J Pathol 1995 Jun; 146(6): 1444-54.

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Abstract

L'invention porte sur l'utilisation d'une souche bactérienne ou d'un dérivé actif, d'un fragment ou d'un mutant de celle-ci qui régule sélectivement la production du facteur de croissance du nerf (NGF), le facteur neurotrophique dérivé du cerveau (BDNF), la neurotrophine 3 (NT3) ou la neurotrophine 4 (NT4) dans le traitement et/ou la prophylaxie de divers troubles, notamment les troubles inflammatoires. La souche bactérienne peut être un Lactobacillus, notamment Lactobacillus reuteri.
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