1 / 86

Immune Regulation

Immune Regulation. 林俊彥醫師 Chun-Yen Lin MD PhD Department of Hepatogastroenterology Linkou Medical Center, Chang Gung Memorial Hospital. 生物醫學的研究. 人體. 器官系統. 組織. 細胞. 蛋白質. 生物原則（渾沌複雜原則）. 核酸. 物理化學原則（化約原則）. Immune System. Overview of Immune System. Innate Immune System.

genera
Download Presentation

Immune Regulation

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. Immune Regulation 林俊彥醫師 Chun-Yen Lin MD PhD Department of Hepatogastroenterology Linkou Medical Center, Chang Gung Memorial Hospital

  2. 生物醫學的研究 人體 器官系統 組織 細胞 蛋白質 生物原則（渾沌複雜原則） 核酸 物理化學原則（化約原則）

  3. Immune System

  4. Overview of Immune System

  5. Innate Immune System

  6. Principles of innate immunity • 不具專一性 • 參與之細胞：Macrophage, neutrophils and NKcell • 產生之反應：inflammatory responses • 症狀：heat 、swelling 、pain

  7. The inter-talk between innate immunity and acquired immunity

  8. Antigen-Presenting Cells • Activated innate immunity could activated antigen-specific cells • Three main kinds of antigen-presenting cells (APC) • Dendritic cells • Macrophages • B- cells • APCs can in turn activate antigen-specific T cell activity

  9. Antigen-Presenting Cells

  10. Principles of adaptive immunity • 具專一性及記憶性 • 參與細胞：T cells (CD4+T cells and CD8+T cells)and B Cells • 反應慢，活化時間長

  11. Acquired immunity • Specificity • Every T cell and B cell has its own unique T cell receptor or B cell receptor • Every TCR/BCR can recognize one specific antigen • Clonal expansion • Proliferation of antigen-specific T or B cells after ligation with APCs • Memory • After activation, T/B cell can differentiate into memory T/B cells

  12. Kinetics of host responses during a primary acute viral infection • Innate Immunity • Acquired Immnuity

  13. HBe Ag SEROLOGY Anti-HBe Ab Non--replicative phase HBV-replicative phase HBV-DNA HCC Cirrhosis ALT/AST Immune Tolerance Immune Clearance Residual Intergrated Stage Natural History of HBV Infection Chu et al Hepatology 1985

  14. Infectious HBV virion Infectious HBV virion Adefovir DNA pol RT Partially double-stranded DNA (-)-DNA Encapsidated pregenomic mRNA A(n) cccDNA mRNA Mechanism of action of anti-nucleotide analog for HBV replication HBsAg envelopes

  15. ALT (xULN) HBV DNA (pg/mL) Lamivudine Follow-up 300 3.5 3 250 2.5 200 HBV DNA 2 ALT 150 1.5 100 1 50 0.5 0 0 0 4 12 20 28 36 44 52 60 68 76 Time (Weeks) Tassopoulos et al. 1999b Post-treatment Responses in HBeAg (-) CHB Patients Treated with Lamivudine

  16. Therapeutic endpoints over time Inhibit virus replication Enhance anti-viral immunity Improvedsurvival Anti-HBs+ Loss of HBsAg Anti-HBe+ Loss of HBeAg Suppress HBV replication Development of Treatment Strategy

  17. Exhaustion of Virus specific CD8+T cells Ahmed; 2004; J. Viol.

  18. Malignancy as the leading cause of mortality

  19. Cancer Studies in Biological Research 各類藥品之市場佔有率 已進入 phase III 的生技候選藥物 資料來源： IMS Health, Deutsche Bank estimates

  20. T cells can kill the tumor cells

  21. Extrinsic Tumor Suppression by Immune System Intrinsic tumor suppression Extrinsic tumor suppression Swann, J. B. et al. J. Clin. Invest. 2007;117:1137-1146

  22. Current Paradigm for Tumor Immunotherapy The not enough of a good thing paradigm Curiel TJ,. J Clin Invest 2007

  23. Tumor vaccine as immunotherapy

  24. Dendritic-cell based Immunotherapy Nestle FO; Nature Medicine  7, 761 - 765 (2001)

  25. Tumor-infiltrating lymphocytes as immunotherapy

  26. Intra-tumor Injection to enhance anti-tumor responses Dendritic cell Cytokine DNA vaccine Tumor vaccine

  27. Immunotherapies for hepatoma Greten TF. J Hepatol 2006

  28. Immunotherapies for hepatoma Greten TF. J Hepatol 2006

  29. Is there any other way to ignite effective anti-tumor/ anti-viral immune responses?

  30. Homeostasis of Immune System Aggressice Immune Responses Regulatory Immune Responses

  31. Homeostasis of Immune System Aggressive Immune Responses Regulatory Immune Responses (Regulatory T cells)

  32. Papers published in PubMed

  33. Milestone for Treg cell discovery

  34. Evidence supporting existence of Treg cells Waldmann, J Exp Med, 1989

  35. Evidence supporting existence of Treg cells Sakaguchi, JI, 1995

  36. Definition of regulatory T cells • A group of T cells that could prevent the development of immunopathology in vivo

  37. In vitro Behavior of Treg cells Inhibition of naïve T cell proliferation Anergized

  38. Characteristics of Treg cells- Dominant Tolerance • Infectious Tolerance • Linked suppression

  39. Infectious Tolerance

  40. Graft B Graft (AxB)F1 Graft A Graft B Linked Suppression

  41. Searching for the markers of Treg cells

  42. The transcription factor Foxp3 • Foxp3 gene : the disease-causative gene in Scurfy mice, which spontaneously develop severe autoimmunity/inflammation as a result of a single gene mutation on the X chromosome • Mutations of the human FOXP3 gene: the cause of a similar human disease called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) • CD25+CD4+ peripheral T cells and CD25+CD4+CD8- thymocytes specifically expressed Foxp3 mRNA

  43. The transcription factor Foxp3 • Retroviral transduction of Foxp3 to normal CD25-CD4+ T cells converted them into phenotypically and functionally TR-like cells. • In BM chimera with a mixture of BM cells from wild-type and Foxp3-deficient mice, Foxp3-deficient BM cells failed to give rise to CD25+CD4+ T cells, while Foxp3-intact BM cells generated them and suppressed disease development. • These findings collectively indicated that the transcription factor Foxp3 could be a master controller of the development and function of natural CD25+CD4+ TR cells.

  44. The transcription factor Foxp3 • Not all Treg cells express Foxp 3 molecule • Not all cell express Foxp 3 could behave like Treg cell • Human CD4+CD25-T cells could transiently express low level of Foxp 3 without suppression function

  45. Heterogeneous groups of Treg cells • Natural Treg cells • Induced Treg cells • TH3 cells (TGF-) • Tr1 (IL-10) • Regulatory CD8+T cell • Regulatory NK T cell • CD4-CD8- (DN) T cells • T cells

  46. Multiple favor of Treg cellsIce-cream flavor Ethan Shevach 2006 immunity

  47. Treg cell mediated phenomenon • Bystander suppression • Infectious tolerance/linked suppression

  48. Treg cell mediated phenomenon • Bystander suppression • suppressive activity of Treg cells requires their prior activation through their T cell receptor • once activated, Treg cells suppress in an antigen-nonspecific way • Treg cells with one antigen specificity can suppress effector T cells (Teff cells) with many other distinct antigen specificities

More Related