* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download PowerPoint 프레젠테이션
Survey
Document related concepts
Lymphopoiesis wikipedia , lookup
Immune system wikipedia , lookup
Molecular mimicry wikipedia , lookup
DNA vaccination wikipedia , lookup
Adaptive immune system wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Food allergy wikipedia , lookup
Innate immune system wikipedia , lookup
Transcript
Immunomodulation by Probiotics in Animal Model of Food Allergy Soo-Young Lee, MD Department of Pediatrics Ajou University School of Medicine Suwon, Korea Contents 1. Basic immuno-pathogenesis and the goals of immunomodulation in allergic disease 2. Innate immune responses of human cells to bacteria and its experimental use 3. Probiotics(Lactic acid bacteria) and its immunomodulatory effect in peanut allergic mice Basic Immuno-pathogenesis of Allergy APC IL-12, IL-18 IFN-a Event in Target Tissues IL-4 IL-4 IFN-g(-) IL-12(-) Plasma cell B IFN-g(-) Th1 Th2 IL-4 IL-10, 4(-) IFN-g IL-2 TNF-a IgE secretion FcR induction MHC II increase Th3 IL-5 IL-4, IL-5 IL-13, IL-9 (-) (-) TGF-b IL-10 IL-4 (-) IL-10 from Tr-1 IL-3 Th2 IL-4 Mast cell IL-3 IL-5 Eosino -phil Differentiation Proliferation FcR increase Mediators release Allergic inflammation Differentiation Survival, FcR increase Mediator production Cellular infiltration Tissue damage Positive & Negative Regulation of Cytokines in Development of Effector Functions of T-helper Cells APC IL-12, IL-18 IFN-a IL-4 IL-4 IFN-g(-) IL-12(-) IFN-g(-) Th1 IFN-g IL-2 TNF-a (-) Th2 Th3 IL-10(-) IL-4(-) IL-4, IL-5 IL-13, IL-9 IL-10 from Tr-1 (-) TGF-b IL-10 IL-4 (-) Goal of Immunomodulation in Allergy 1. Can we re-direct the already existing deviation of Th2screwed immune environment, especially during perinatal or early years in life ? We do actually want ! 2. Are we trying to prevent allergic diseases in the real field ? Yes, we are trying to. 3. Can we reverse or treat the allergic sensitization or expressed clinical allergies with certain type of immunotherapy of immune modulation ? Partly yes, and somehow we might can. • Bacteria and bacterial components : one of candidate for immunomodulation Innate Immune Responses of Human Neonatal Cell to Bacteria from Normal GI Flora Karlsson H etl al., Infect Immunol, 2002 Adult PBMC and cord blood mononuclear cell Culture with bacteria : B. adolescnetis, E. faecalis, B. vulgatus, L. plantarum, S. mitis, C. minutissimum, C. perfringnes, E. coli, P. aeruginosa Cytokine production pattern: IL-12, TNF-a : similar in CD and adult PBMC G+ bacteria : produce more higher level of IL-12 in both CB and adult cells IL-6 : significantly higher in CB cells than adult cells IL-10 : similar in CB and adult cell G+ bacteria : produce higher level of IL-12 and IL-10, G- bacteria : produce less higher level of IL-12, but same level of higher IL-10 DC maturation pattern: L. plantarum : bound or signaled through CD14, TLR-2, and TLR-4, E. Coli : signaled minly through CD14 and TLR4 Microbial products in allergy prevention and therapy - Matricardi PM et al. Allergy 2003, Position paper- Bacterial extract Route: early SQ injection recently PO Experiment : oral bacterial extract spontaneous or PHA-induced TNF-a, IL12, IFN-g production of NK cells In human volunteers, oral bacterial extracts induced an increased of IFN-a, IgA, IL-2 concentrations in the BAL fluid, and increased serum total IgG, and decreased total IgE Proposed rationale : “modulators” of the host local immune response Effect of bacterial immunotherapy : 75 – 87% of childhood asthmatics showed therapeutic effect, but there was no DBPC study. Side effect : minor Conclusions and perspectives : effect is minimal, need dose adjustment and interval Microbial products in allergy prevention and therapy - Matricardi PM et al. Allergy 2003, Position paper- Mycobacteria(M. vaccae) BCG Immunostimulatory sequence of bacterial DNA(ISS-ODN) Lipopolysaccharide(LPS) derivatives of G(-) bacteria In this position paper, there are large amount details about many experimental data, proposed rationale, and clinical studies relating above microbiota and their products. However, those issues will discuss later in another sessions. Microbial products in allergy prevention and therapy - Matricardi PM et al. Allergy 2003, Position paper- Probiotics Term: living or inactivated organisms that are claimed to exertbeneficial effects on health when ingested Experiment: volunteer study, oral ingestion triggers IFN-g production by blood leukocyte / lactobacilli stimulate ample of IL-12 producton in human macrophages in vitro * New experimental data will discuss later. Proposed rationale (epidemiologic aspect) - Early colonization of enterococcus, lactobacilli, eubacteria low allergy, and higher turn over of E. coli strains (Bennet R et al. 1991;Seep E et al. 1997; Adlerberth I et al. 1999) - Swedish and Estonian study ; coli form bacteria were higher in the atopic children while bifidobacteria were more prevalent in controls by 2 years (Bjorksten B et al. 1999) Finland : developing atopic sensitization at 12 mo of age – related with more clostridia and fewer bifidobacteria at 3 week of life (Kalliomaki - Prospective study in M et al.2001) Bacteria-Based immunomodulation 1. Heat-Killed Listeria or E. coli - Studies using animal model of food allergy • Engineered recombinant peanut protein and heat-killed L. monocytogenes coadministration protects against peanut induced anaphylaxis in a murine model. Xiu-Min Li et. al, JACI 2003 • Persistent protective effect of heat-killed E. coli producing “engineered”, recombinant peanut proteins in a murine model of peanut allergy. Xiu-Min Li et. al. JACI 2003 • Effects of lysed E. faecalis FK-23 on allergen-induced serum antibody responses and active cutaneous anaphylaxis in mice. Shimada T et al.,Clin Exp Allergy, 2004 • Allergen immunotherapy with heat-killed L. monocytogenes alleviates peanut and food-induced anaphylaxis in dogs. Frick IL et al., Allergy, 2005 Bacteria-Based immunomodulation(2) 2) Lactic acid bacteria -Introductions• Lactic acid bacteria(LAB) : Lactobacilli, Bifidobacteria • Normal intestinal flora • Maintaining the physiologic inflammation prevent inflammatory diseases(including allergy) in the gut • Possibly increased IgA, IL-10, IL-12, IFN-g • Suppression of TNF-a, and inhibition of T-cell activation • Improves severity of atopic dermatitis in infants with milk allergy • Prevents development of atopy in at-risk infants • Oral delivery, generally safe and well-tolerated Role of intestinal flora in the development of allergy Kalliomaki M, Isolauri E. Curr Opin Allergy Clin Immunol. 2003 Feb;3(1):15-20. Recent findings : 1) Alterations in intestinal microbiota have been detected both in infants suffering from allergic disease and in those later developing the disorder. 2) Delay in the compositional development of gut microflora was a general finding in allergic children. (cont.) Role of intestinal flora in the development of allergy. Subsequent studies : 3) Perinatal administration of lactobacilli halved the later development of atopic eczema during the first 2 years of life. 4) Specific strains of the healthy gut microbiota have been shown to induce the production of IL-10 and TGF-b 5) Probiotics also strengthen gut defense barrier mechanisms and reduce antigen load in the gut. 6) In the intestinal epithelial and antigen-presenting cells , Pattern recognition receptors have been demonstrated to mediate a continuing dialogue between host and gut-microbes 7) Clinical effects has been shown in allergic rhinitis and asthma, and cow’s milk allergy Dendritic cell and Probiotics Innate immunity Adaptive immunity Lactic acid bacteria (+) Figure from Kapsenberg. Nature Review immunol 2003 Dendritic Cells and Probiotics(1) “ By responding differently to different type of microbes, DC can signal the nature of the pathogen(or antigen)” IL-12 E.col DC LPS P. gingivalis Candida albicans Murine CD8aa+DC Th2 No IL-12 Unicellular yeat Hypae Th1 DC IL-12 Th1 Murine DC line Th2 IL-4 Theiler’s virus IL-12 Wild-type DC Variant Th1 Murine spleen DC IL-10 Th2 Dendritic Cells and Probiotics(2) Lactobacilli differently modulate expression of cytokines and maturation surface markers in murine dendritic cells Christensen HR et al., J Immunol, 2002 6 lactobacilli strains : L. reuteri, L. plantarum, L. fermentum, L. casei, L. alactus, L jonsonii DC: bone marrow derived murine DC (C57BL/6), harvest enriched DC (8 day) Cytokine and surface marker induction : DC culture with irradiated lactobacilli Result : 1) IL-12, TNF-a productions : substantial differences among lactobacilli strains 2) IL-6, IL-10 : less pronounced differences 3) MHC class II, B7.2(CD86) : up-regulated by all kinds of lactobacilli 4) Amount of IL-12 production correlated with DC maturation markers 5) Different species of Lactobacillus exert very different patterns of DC activation, and one species may have inhibiting activities of other species (L. casei inhibit the IL-12 production by L. reuteri, and vice versa) potential for Th1/Th2/Th3-driving capacities of the gut DC to be modulated according to composition of cut microflora Dendritic Cells and Probiotics(3) Lactobacilli activate human dendritic cells that screw T cells toward T helper 1 polarization Mohamadzadeh M et al., PNAS, 2005 Human myeloid DC : from PBMC, and enriched and harvested Lactobacilli : L. gasseri, L. johnsonii, L. reuteri / killed by 15 min UV exposure Result : Lactobacilli exposed DCs 1) Up-regulated HLA-DR, CD83, CD40, CD80, CD86 2) Induced bioactive IL-12 and IL-18, but not IL-10 * IL-12 production did not inhibited by LPS from E. coli whereas, LPS induced IL-10 production was greatly inhibited * Amount and pattern of IL-12 or IL-10 productions are strain dependent 3) Induced of T cell proliferation and activation (CD4+CD8+ Th1 cell) 4) Up-regulated TLR-2 by lactobaculli Dendritic Cells and Probiotics(4) Debating points on the modulatory effect of lactobacilli on DCs 1. IL-10 induction 2. IL-12 induction 3. IgG1, IgG2a regulation vs. IgE regulation 4. Half-time of effect, amount of dose, species 5. Non-specific vs. antigen specific For example, regarding the cytokine production ; Drakes et al., Infect Immunol, 2004 : human DC produce IL-10, not IL-12p70 Mohamadzadeh et al., PNAS, 2005 : human DC, produce IL-12p70, but not IL-12 Conclusions 1. Recentrly, immunomodulatory effect of live or killed bacteria(especially probiotics) have been extensively evaluated and reviewed in experimental studies. 2. However, the concept to prevent or modify already existing atopic disease via administration of live bacteria or bacterial components remains to be tested in more randomized and controlled clinical studies before any conclusion can be made on this important matter. 3. We would expect that these types of immunomodulation could be a good candidate for prevention or treatment of allergic disease, especially in infants and children, in near future. Acknowledgement Ajou University School of Medicine Se-Jo Oh, Msc, Gye-Ree Jeon, MD, nahm-Hyang Koo, MD Yonsei University School of Medicine Prof. Kyu-Earn Kim, Prof. Myung-Hyun Sohn, Seoul National Universisy Prof. GE Ji Mount Sinai Medical Center, Xiu-Min Li, MD, Sampson HA, MD Gi-Kang Whang, Msc Thank you for your attention ! 2005.6. Soo-Young Lee, MD.PhD. Department of Pediatrics Ajou University School of Medicine Suwon, Republic of Korea