1 / 32

Selective regulation of T cell-mediated immune response by TCM drugs and natural products

Selective regulation of T cell-mediated immune response by TCM drugs and natural products. Qiang Xu, Ph.D. State Key Laboratory of Pharmaceutical Biotechnology School of Life Sciences Nanjing University. Th2-associated Ulcerative colitis Myasthenia gravis Systemic lupus erythematosus

brody
Download Presentation

Selective regulation of T cell-mediated immune response by TCM drugs and natural products

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Selective regulation of T cell-mediated immune response by TCM drugsand natural products Qiang Xu, Ph.D. State Key Laboratory of Pharmaceutical Biotechnology School of Life Sciences Nanjing University

  2. Th2-associated Ulcerative colitis Myasthenia gravis Systemic lupus erythematosus Rheumatic Fever Hemolytic Anemia Membranous glomerulonephritis T-bet GATA-3 T cell-mediated diseases • Th1-associated • Rheumatoid arthritis • Multiple sclerosis • Crohn’s disease • Graft-versus host disease • Insulin-dependent diabetes • Crescentic glomerulonephritis Immunosuppressiveagents

  3. Can we have a safe immunosuppressive therapy without harming innocents?

  4. History of immunosuppressive agentsGlucocorticoidsCytotoxic anti-cancer agentsCyclosporin A、FK-506 Novel immunosuppressants? Why do we target T cells? g I F N - I L - 2 a TNF - M a c r o p h a g e inflammation T h 1 活化 Cellular immunity A P C Reduced anti- infection potential Kidney injury Neurotoxicity Increased oncogenesis …… I L - 1 2 Low selectivity CsA T h 0 I L - 4 Ab formation T h 2 B c e l l I L - 4 I L - 5 IL - 13 Humoral immunity Why the progress in immunology does not accelerate the development of immune drugs? New way?

  5. Novel immunosuppressors？ Higher selectivity !

  6. Effects of several kinds of Chinese herbs and prednisolone on DTH and inflammation

  7. C o - s t i m u l a t o r y m o l e c u l e s 1. Selective inhibition onthe activation of T lymphocytes A P C I L - 1 2 I n f l a m m a t o r y M a c r o p h a g e Ag m o l e c u l e s I F N - g T h 1 a c t i v a t e I L - 2 C e l l u l a r i m m u n i t y T h 0 Function of activated T cells Activation of T cells Differentiation, Proliferation Adhesion, migration… Molecule expression Cytokine production and signaling

  8. Fusaruside Isolated from Fusarium sp. IFB-121

  9. Fusaruside inhibits IFN-g-mediated STAT1 phosphorylation but not STAT1 itself Fusaruside selectively inhibits Th1- but not Th2-like cytokine production

  10. STAT signaling pathway in T cell activation IL-2-activated STAT5 pathway IL-12 -activated STAT4 pathway Steroids IFN-γ -activated STAT1 pathway Leptin-induced STAT3 phosphorylation fludarabine Ser/Thr phospharylation of both STAT1 and STAT3 15dPGJ2 PPAR-g agonist STAT1 and STAT3 pathway IL-12/STAT4 pathway Curcumin Phpsphorylation of STAT3 and STAT5 Int. Immunopharmacol. 2003; 3(6): 783-800

  11. Fusaruside inhibits pSTAT1, increases pSTAT3, but does not influence pSTAT4，5 and 6

  12. Fusaruside enhances IFN-g-induced STAT3 phosphorylation in a manner independent of STAT1 129S1: 129S1/SvImJ IFNR -/- : 129-Ifngrtm1Agt

  13. STAT3-dependent inhibition of STAT1 signaling by Fusaruside

  14. STAT3-siRNA transfection and interference b a Inhibition of pSTAT1 by Fusaruside is dependent on the existence of STAT3

  15. Summary Fusaruside STAT3 pSTAT3 pSTAT1, IFN-g

  16. C o - s t i m u l a t o r y m o l e c u l e s 2. Selective inhibitionon the activated T lymphocytes A P C I L - 1 2 I n f l a m m a t o r y M a c r o p h a g e Ag m o l e c u l e s I F N - g T h 1 a c t i v a t e I L - 2 C e l l u l a r i m m u n i t y T h 0 Function of activated T cells Activation of T cells How to induce dysfunction? Adhesion,migration Cytotoxicity Cytokine production

  17. 30 Control astilbin RSG ext 20 % Apoptotic cells 10 Activated Normal T cells T cells Astilbin M C ast rsg M C ast rsg C ast rsg 0 T cells total Kuppfer HC NPC 800 bp 800 bp 0.16 0.12 IFN-γ(OD540) 0.08 0.04 0 norm cont ast CsA Astilbin, a flavanoid from Rhizoma Smilacis Glabrae selective targeting 1 the T cell population but not other tissue cells; 2 the activated but not non-activated T cell populations; 3 Th1 but not Th2 cells. Pharmacological Research 1997; 36:309-314. Planta Med.1999;65:56-59. Eur. J. Pharmacol. 1999; 377:93-100. Pharm. Pharmacol. Comm. 2000; 6: 41-47. Phytochemistry 2000; 53：1051-1055. Pharmacol. Res. 2001; 44：135-139. Chin. Chem. Lett. 2002; 537-538. J. Ethnopharmacol. 2003; 85(1):53-9. Inflamm Res. 2003;52(8):334-340. J. Pharm. Pharmacol. 2003; 55: 691-696. J. Chromatography B 2004; 805: 357-360.J. Pharm. Pharmacol. 2004; 56: 495-502.

  18. Astilbin shows a strong inhibition on CIA

  19. Negative cytokine regulation by AstilbinJ Allergy Clin Immunol. 2005; 116(6): 1350-1356.

  20. Astilbin selectively induces the apoptosisof activated T cells

  21. Astilbin selectively induces apoptosis of Con A-activated Jurkat T cells

  22. How Astilbin targets activated T cells？

  23. 1 2 3 4 5 6 4 0 A s t i l b i n J u r k a t J u r k a t + A s t i l b i n J u r k a t + C o n A J u r k a t + C o n A + A s t i l b i n ** ** 3 0 ** 2 0 1 0 0 J u r k a t L 9 2 9 E C V 3 0 4 a b c 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 Only the cytosol proteins from Con A-activated and astilbin-treated Jurkat cells induce apoptosis of non-activated Jurkat, L929, ECV cells Astilbin Cytosol protein Streptolysin-O Nuclei from non-activated Jurkat Cytosol proteins Incubation Incubation Astilbin does not target the cytosol or nuclear proteins PI stain Flow cytometry DNA fragmentation electrophoresis Hoechst stain DNA fragmentation

  24. J u r k a t A c t i v a t e d J u r k a t C o n t r o l - 7 1 0 g / m l - 6 1 0 g / m l - 5 1 0 g / m l - 7 - 6 - 5 C o n t r o l 1 0 g / m l 1 0 g / m l 1 0 g / m l 8 7 . 3 % 2 . 1 % 8 8 . 9 % 0 . 9 % 9 0 . 5 % 0 . 4 % 8 3 . 1 % 7 . 9 % J u r k a t 1 . 8 % 2 . 5 % 3 . 5 % 6 . 1 % 8 0 . 7 % 4 . 3 % 8 2 . 1 % 7.9% 5 1 . 7 % 1 2 . 7 % 4 1 . 3 % 1 0 . 4 % A c t i v a t e d J u r k a t 5 . 4 % 5. . 9 % 2 8 . .4 % 4 3 .. 7 % Astilbin selectively disrupts mitochondrial transmembrane potential of Con A-activated Jurkat T cells A C JC-1

  25. B C o n A - + - C o n A + I s o t y p e I s o t y p e C o n t r o l C o n t r o l - 7 - 7 1 0 g / m l 1 0 g / m l - 6 - 6 1 0 g / m l 1 0 g / m l - 5 - 5 1 0 g / m l 1 0 g / m l D 5 0 * 0 10-7 10-6 10-5 A s t 0 10-7 10-6 10-5 C o n t r o l 4 0 - 7 * 1 0 g / m l C - 6 1 0 g / m l C y t 3 0 - 5 1 0 g / m l M * 2 0 1 0 C A I F 0 A c t i v a t e d J u r k a t J u r k a t Astilbin selectively caused cytochrome c release from mitochondria to cytosol in Con A-activated Jurkat cells A C

  26. Non-activated Activated 0 10-7 10-6 10-5 0 10-7 10-6 10-5 M B a d C 0 10-7 10-6 10-5 0 10-7 10-6 10-5 M B a x C 0 10-7 10-6 10-5 0 10-7 10-6 10-5 M B i d C Astilbin selectively translocated Bax and Bad but not Bid from cytosol to mitochondria in activated Jurkat cells

  27. Release of cytochrome c from mitochondria 2. Permeability transition pore (PTP) opening 3. Bcl-2 family homopolymers 1. Mitochondria damage

  28. Flow cytometry DiOC6(3) Incubation Treatment VDAC From mouse liver 0.25%SDS 10-6 g/ml Ast Activ Mito Lysis Nor Mito Lysis (Ast+Nor Mito) Lysis (Ast + Activ) Mito Lysis 5 uM Ca2+ 10-5 g/ml Ast D i OC O ( 3 ) / F L - 1 6 There is an opener of VDAC in the mitochondria of activated T cells after astilbin treatment PTP liposome VDAC ANT C A E B F

  29. astilbin astilbin Surface alterations; Nuclear changes; DNA fragmentation

  30. Conclusion • For T cell activation Si-Ni-San and its components Jie-Xue-Hao, a Tibetan medicine Fumigaclavine C, Fusaruside …… • For the function of activated T lymphocytes Fraxinellone and Obaculactone Astilbin …… • For both T cell activation and functions, as well as other cells current immunosuppressants • Selective immunosuppressive therapy is possible. • 2. A number of selective immunosuppressive agents will be benefitial for the treatment of immune diseases.

  31. Acknowledgements Natural Science Foundation of China 3023039039925041 30070781 39970887 39470815 39270784 陳　婷 譚仁祥 郭子建 孫洋 張先明 費明健 呉雪豊 蔡宇 秦宇 呉興新 燕茹 趙蔚 夏玉貴

  32. Thanks! The ancient building in Nanjing University

More Related