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Immunological effects of dietary proteins Conference presented at the Annual Congress of SBI Sociedade Brasileira de Imunologia Campos do Jordão, SP 2001.

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Presentation on theme: "Immunological effects of dietary proteins Conference presented at the Annual Congress of SBI Sociedade Brasileira de Imunologia Campos do Jordão, SP 2001."— Presentation transcript:

1 Immunological effects of dietary proteins Conference presented at the Annual Congress of SBI Sociedade Brasileira de Imunologia Campos do Jordão, SP 2001 Ana Maria Caetano de Faria

2 Mucosa: margin of the immune system ?

3

4 Mucosal & circulating Immunoglobulins blood & lymph IgMIgG IgA secretions

5 Mucosa: physiology of the immune system

6 300 m 2

7 Ig producing cells in physiological conditions mice 0 2 4 6 8 10 12 14 16 PP humans 0 1.000 2.000 3.000 4.000 5.000 6.000 mLN 10 10 plasm cells BM Spleen LN, SPL, BM gut 10 6 plasm cells gut

8 Lamina Propria e IELs* * * * * * * * * LP CG Peyers Patches GALT

9 Peyers patch lamina propria M cell GALT – Gut Associated Lymphoid Tissue IEL IL-7 SCF c-kit RAG E-cadherin E 7 epithelial Villus GC LT Y Y Y Y Y Y Y Y IgA Y Y Y Y HEV IEL LT LB CD8 + CD4 + Efferent lymphatics M cell Y TGF /IL10/IL-4 IgA IL-6 MAdCAM-1 Epithelial cells

10 Lymphoid cells in the GALT 70% are activated (as opposed to 20% in spleen and peripheral lymph nodes) IL-1, IFN-, TNF-, IL-6, chemokines, prostaglandins IL-4, IL-10, TGF-, PGE-4 Presence of macrophages, eosinophils, mast cells, activated lymphocytes Most activated cells in blood bear

11 microbiota diet Natural sources of antigen in the GALT

12 Immunological alterations in germ-free mice Reduction in the size of Peyers patches Reduction in the size of peripheral lymph nodes (small germinal centers) IgG & IgA levels reduced, normal IgM levels Reduction in the number of intraepithelial lymphocytes (IELs), B and T cells

13 Immunological alterations in antigen-free mice Mucosal associated lymphoid tissue absent Involution of peripheral lymph nodes (no germinal centers) IgG and IgA absent, normal levels of IgM Reduction in the cytotoxic activity of intraepithelial lymphocytes (IELs)

14 Immunological effects of stimulation by food proteins

15 PhD thesis of Juscilene Menezes

16 Components for 1 kg of diet Amid680.0 g Colin4.0 g Metionin10.0 g Vitamins10.0 g Vitamin E1 gota Cellulose10.0 g Minerals50.0 g Soy Oil80.0 g Nitrogen source *150.0 g BHT (preservative)0.1 g Casein amino acids Essencials%for 1 kg Arginina4.16.15 g Histidina3.14.65 g Isoleucina6.19.15 g Leucina9.213.8 g Lisina8.212.30 g Metionina3.24.80 g Fenialanina57.50 g Treonina4.97.35 g Triptofano1.21.80 g Valina7.210.80 g Non essencials%para 1 kg Alanina3.04.50 g Ácido aspártico7.110.65 g Cistina0.30.45 g Ácido glutâmico22.433.60 g Glicina2.74.05 g Prolina11.316.95g Hidroxiprolina00 Serina6.39.45 g Tirosina6.39.45 g Type of diet Control diet Test diet *Nitrogen source Casein Casein amino acids Diet composition

17 . Weaning (3-4 sem) Control Diet Casein Experimental Diet aminoacids Mice C57BL/6 Cas Aa Adults (8-10 sem) Experimental Model..

18 .. IntestineMucus Immunoglobulins Histology Phenotype Effects in the gut CaseinAa

19 Intestinal Morphology Cas Aa 0 100 200 300 400 500 600 700 Duodenum P Jejunum D Jejunum Ileum Micrometers (µm) Cripta Cas Villus Cas Cripta AA Villus AA

20 Casein Aa * * * * * * * * * * * * * * * * * * * * LP * * * * * * * * *

21 IEL 0 2 4 6 8 10 12 14 16 Duodenum Jejunum P Jejunum D Ileum IEL/100 epithelial cells Lamina propria 0 20 40 60 80 100 120 Duodenum Jejunum P Jejunum D Ileum Number of cells/villus Casein AA Number of cells in the GALT

22 IELCasein (%)AA (%) TCR 41.3 ± 3.522.8 ± 3.2p<0.001 TCR Thy1 - 12.9 ± 2.411.4 ± 2.8p< 0.1 TCR Thy1 + 26.3 ± 1.59.9 ± 3.3p<0.001 TCR CD5 - 16.3 ± 2.811.0 ± 2.9p<0.025 TCR CD5 + 23.7 ± 1.210.0 ± 2.4p<0.001 TCR 35.7 ± 2.945.2 ± 5.1p< 0.001 TCR Thy1 - 25.9 ± 1.826.8 ± 6.1= TCR Thy1 + 10.6 ± 1.818.4 ± 1.7p< 0.001 Sub-subsets of IELs

23 Globet Cells Cas Aa Intestinal sIgA 0,00 0,01 0,02 0,03 0,04 0,05 0,06 0,07 CasAa mg/ml *

24 Withdrawl of either the microbiota or of food proteins has similar immunological and morphological effects in the gut

25 Systemic Effects.. Lymphoid organsSerum Immunoglobulins Phenotype Cyotokine, AFC CaseinAa

26 B220 TCR TCR CD3 + CD4 + CD3 + CD8 + CD3 + CD25 + CD3 + CD45RB lo 45.8±3.028.8±6.81.6±0.315.3±3.89.7±2.31.9±0636.4±7.8 41.6±3.022.9±2.42.2±1.012.7±1.09.51±2.21.3±0.346.8±6.1 3.1±0.96.5±2.50.2±0.13.6±1.62.9±1.40.4±0.13.1±1.5 0.6±0.42.0±0.80.1±0.11..40.8±0.50.1±0.10.9±0.5 9.0±3.215.0±3.60.7±0.310.0±2.66.4±1.71.1±0.37.7±1.4 4.0±1.46.8±1.40.3±0.054.2±0.82.9±0.90.8±0.43.5±0.9 6.0±2.011.5±3.90.3±0.17.3±3.14.7±0.81.0±0.45.1±2.3 5.2±2.013.8±6.50.3±0.28.6±4.45.97±2.50.8±0.26.0±2.6 pLN Spl mLN cLN Cas AA Cas AA Cas AA Cas AA Lymphocytes from different organs

27 PhenotypeCasein (%)Aa (%) CD3-CD4+35.81 ± 5.713.43 ± 3.0p<0.05 CD3-CD8+76.47 ± 12.928.47 ± 3.1p< 0.05 CD4+CD8+77.06 ± 13.529.59 ± 3.0p<0.05 CD3+TCR 14.29 ± 5.38.11 ± 2.8= CD3+CD4+ 3.96 ± 1.52.00 ± 0.8 = CD3+CD8+3.69 ± 1.32.17 ± 0.9= T cell precursors in the thymus

28 Serum Imunoglobulins 0,0 0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 IgIgMIgGIgA mg/ml Cas Aa * * * * Spleen 0 1000 2000 3000 4000 5000 6000 7000 8000 IgIgM IgG IgA CFA/106 Cels * * * *

29 C57BL6/J BALB/c In vitro production of IL-2 & IFN- 0 20000 40000 60000 SplpLNcLN 0 20000 40000 60000 SplpLNmLNPP pg/ml mLN 0 40000 80000 120000 SplpLNmLNPP 0 20000 40000 60000 SpleenpLN cLN pg/ml Cas Aa

30 C57BL/6 BALB/c Cas Aa In vitro production of IL-4 & IL-10 0 3000 6000 9000 SplpLNcLN 0 4000 8000 12000 SplpLNPP pg/ml mLN 0 10000 20000 30000 SplpLNcLN 0 15000 30000 45000 SpleenpLN pg/ml mLN

31 Neonate profile Predominance of Th2 type cytokines High IgM production, low IgG and IgA

32 Intestinal Morphology at Weaning

33 Immunological Activities.. Infection with Leishmania major Oral tolerance Systemic immunization CaseinAa

34 Infection with Leishmania major Footpad increment 0,000 0,500 1,000 1,500 2,000 2,500 4 Weeks8 Weeks mm C57BL/6 Cas C57BL/6 Aa BALB/c * *

35 Oral Tolerance Induction and Specific Antibody Production 0,0 2,0 4,0 6,0 8,0 10,0 12,0 water fedOVA fed ELISA* Cas Aa c a b a

36 El-Diet elemental diet available for human use therapeutic for Crohns disease post-surgery procedures, etc

37 GALT Chow El Diet

38 0 2 4 6 8 10 12 14 ChowED IEL/100 células epiteliais * Intraepithelial Lymphocytes Chow El Diet TCR 72 ± 1047 ± 7* TCR Thy1 - 16 ± 69 ± 4 TCR Thy1 + 56 ± 838 ± 4* TCR CD5 - 24 ± 717 ± 7 TCR CD5 + 47 ± 1030 ± 3* TCR 17 ± 727 ± 8* TCR Thy1 - 3 ± 18 ± 1* TCR Thy1 + 14 ± 619 ± 7 IELs

39 Immunoglobulins Serum 0,00 0,50 1,00 1,50 2,00 2,50 Ig TotalIgMIgGIgA Chow El diet * * * Intestinal IgA 0 0,01 0,02 0,03 0,04 0,05 0,06 0,07 ChowEl diet mg/ml * Spleen 0 1000 2000 3000 4000 5000 6000 Ig TotalIgMIgGIgA * * * Bone Marrow IgA 0 200 400 600 800 1000 1200 1400 1600 ChowEl diet * CFA/ 10 6 cells

40 Lymphoid cells B220CD3 + + CD4 + CD3 + CD8 + CD3 + CD45RB lo CD3 + CD62L lo Spleen Chow42.8±8.837.1±6.121.2±3.39.01±2.226.71±4.911.14±2.5 ED40.2±7.137.19±7.022.1±3.09.53±3.336.51±4.817.46±2.7 PP Chow9.21±1.54.83±0.93.48±0.60.89±0.2NF ED2.54±1.9*1.28±0.6*1.14±0.4*0.30±0.1*NF PLN Chow4.74±1.110.27±2.95.28±1.44.27±1.13.49±1.02.15±0.4 ED1.79±0.7*3.64±1.8*1.92±0.9*1.45±0.8*1.65±0.8*0.59±0.2*

41 Therapeutic Applications Immunological disorders where dowmodulation is desirable (Crohns disease, autoimmune diseases, etc)

42 Collaborators Nelson Vaz – UFMG Jacqueline Alvarez-Leite - UFMG Leda Quércia Vieira - UFMG Denise Cara – UFMG Rodrigo Corrêa Oliveira – CPqRR Momtchilo Russo – USP Cláudia Rocha Carvalho - UFMG Daniel Mucida – USP Mariléia Andrade – UFMG Elaine Speziali – UFMG Michele Barsante – UFMG Alice Kamphorst - UFMG Frankcinéia Assis – UFMG Vanessa Pinho – UFMG Virlânia Rodrigues - UFMG Beatriz Senra – UFMG


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