1、CAMS/PUMC,里谢.C.R （Charles Robert Richet, 18501935） 法国生理学、细菌学、病理学家 1913年获诺贝尔生理学及医学奖,他关于血清治疗法的来源、对过敏性的研究两大重要发现，是对医学的重大贡献。他发现将一个免疫动物的血清输到第二个动物身上，第一个动物的免疫性也就传给第二个动物。1890年12月16日，他使人类第一次利用血清注射体内治疗成功。这消息很快传遍全球，血清疗法为现代医学开创了一条新路。另外他还对过敏反应作出了理论解释。,CAMS/PUMC,波威特.D.（Daniel Bovet, 1907） 瑞士生理学家、药理学家 1957年获诺贝尔生理学及
2、医学奖,当他在巴黎的巴斯德研究所工作时，就开始研究免疫及过敏现象并对自主神经系统对不同化学物质的反应做了充分的探讨。舒尔兹戴尔现象的发现（豚鼠子宫角体外过敏实验用少量抗原加到浸有致敏子宫角的组织液中，能引起致敏的子宫肌收缩）提供了体外研究过敏现象的极好模型，可用于澄清其发生机制。他发现了组胺是过敏反应中最主要的因子，此外还有5羟色胺以及其它一些活性因子。正是在此基础上他开始寻找可以对抗组胺的药物，最终发现了对哮喘和枯草热有显著疗效的药物。除此之外，他还研究了箭毒的作用机理并将其用于制造松弛药、镇静药和麻醉药 由于他在治疗过敏症方面的重大发现荣获1957年诺贝尔生理学及医学奖。,CAMS/PUM
3、C,自身免疫病,Graves Disease,CAMS/PUMC,免疫缺陷病,CAMS/PUMC,AIDS: THE PUBLIC FACE OF IMMUNOLOGY, 1986 TO THE PRESENT,The earliest cases of Acquired Immune Deficiency Syndrome (AIDS) appeared in 1982, as a series of otherwise unusual infections and malignancies in male homosexual patients.,CAMS/PUMC,Danger mode
4、l proposes that damage, rather than foreignness, is what initiates an immune response.,危险理论,CAMS/PUMC,1959 Bunet, Medawar,The elegant and simple version of the SNSD model,识别自身与非己理论,CAMS/PUMC,1969 Brestche, Langman and Cohn,MHC-peptide,CD40-CD40L IL-2,IL-4,IL-5,识别自身与非己理论,Associative Recognition model
5、: Two Signal model,CAMS/PUMC,1974Lafferty and Cunningham,识别自身与非己理论,Costimulatory model,CAMS/PUMC,1989Charlie Janeway,Binding bacteria to PRRs induce activation activation of APCs,Two different types of nonself recognition A genetically encoded set of PRRs assigned to the cells and molecules of the i
6、nnate immune system a somatically generated set of receptors expressed by the cells of adaptive immune system,识别自身与非己理论,CAMS/PUMC,Danger model,1994 Polly Matzinger,Activation state of an APC depends on the health of the cells in its neighbourhood Injured (distressed) cells, namely cells that are abn
7、ormally distressed, damaged, die an abnormal death, or are destroyed necrotically, should activate their local APCs A foreign entry that does no injury should not evoke a response,regardless of abnormality of physiology that cause stress or injury to a tissues could kindle a response in the absence
8、of any foreignness,CAMS/PUMC,PAMPs and PRRs,1989 Charlie Janeway,Binding bacteria to PRRs induce activation of APCs,Two different types of nonself recognition A genetically encoded set of PRRs assigned to the cells and molecules of the innate immune system a somatically generated set of receptors ex
9、pressed by the cells of adaptive immune system,CAMS/PUMC,A perfect example for achievement of systems biology,CAMS/PUMC,14,In addition to its role in the early phase of defense, innate immunity in mammals appears to play a key role in stimulating the subsequent, clonal response of adaptive immunity.
10、,Pathogen-Associated Molecular Patterns (PAMPs) The surfaces of microorganisms typically bear repeating patterns of molecular structurePattern Recognition Receptors (PRRs),CAMS/PUMC,TLR-mediated signaling,CAMS/PUMC,Effect of TLR on innate immunity and adaptive immunity,Early innate resistance,Late i
11、nnate resistance,Adaptive immunity,CAMS/PUMC,The first paper that directly showed depletion of a particular T cell subpopulation can break natural self-tolerance and cause a variety of autoimmune diseases in mice similar to their human counterparts.,Organ-specific autoimmune diseases induced in mice
12、 by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. Sakaguchi, S., Fukuma, K., Kuribayashi, K. & Masuda, T.J. Exp. Med. 161, 72-87 (1985) Transfer of CD5lo cells into nu
13、de (nu/nu) mice induced autoimmunity, whereas transfer of CD5hi cells did not. Transfer of both subsets together prevented disease. The CD5hi cells were subsequently shown to be CD25+ Treg cells. This work demonstrated that suppression can be a mechanism of preventing autoimmune disease.,CD5lo cells
14、,CD5hi cells,CD5lo cells,CD5hi cells,autoimmunity,Preventing autoimmunity,No autoimmunity,CD25+ regulatory T cells,CAMS/PUMC,CD1 antigen presentation,CD1 is a non-polymorphic MHC class I like molecule. Comes in 4 forms CD1a, b, c, d. Similar architecture to classical MHC class 1. Cleft is much narro
15、wer and deep with hydrophobic residues. Binds things other than peptides,CAMS/PUMC,CD1 ligands,a-galactosyl ceramide(半乳糖神经酰胺)(sponge) Phophatidyl choline Lipoarabinomannan (LAM) Sulphatide(神经节苷脂) Many lipids mostly associated with mycobacteria Some self antigens such as Ganglioside GM1 significance
16、to autoimmunity.,CAMS/PUMC,CAMS/PUMC,CD1d structure with a GALCer Recognized by iNK-T cells,Gal,Ceramide,CAMS/PUMC,CD1d structure with a GALCer Recognized by iNK-T cells,SIDE,TOP,CAMS/PUMC,Invariant MHC (CD1) present non-peptides such as lipids to g/d T cells and special NK T cells.,CAMS/PUMC,Immuno
17、logical focus (one) Regulatory T cells,CAMS/PUMC,The first experimental evidence of the existence of a subset (CD45RBlo) of peripheral CD4+ T cells that negatively regulates CD4+ effector T cells.,OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22low
18、 subset. Powrie, F. & Mason, D.J. Exp. Med. 172, 1701-1708 (1990) MRC Cellular Immunology Unit, Sir William Dunn School of Pathology, Oxford, UK,CAMS/PUMC,The identification of CD25 as a marker of natural Treg cells and initial characterization of the function of CD25+CD4+ Treg cells returned credib
19、ility to the idea of suppression. This work allowed the field to focus on the same subset of cells.,Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor -chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. Sakaguchi, S.,
20、 Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. J.Immunol. 155, 1151-1164 (1995) Approximately 10% of peripheral CD4+ cells and less than 1% of CD8+ cells in normal unimmunized adult mice express the IL-2 receptor alpha-chain (CD25) molecules.,CAMS/PUMC,Two papers reporting a simple in vitro assay fo
21、r Treg cell function, making it possible to analyze Treg cells in rodents and humans. These were also the first papers to present an extensive characterization of Treg cell properties in vitro.,Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of
22、 autoimmune disease by breaking their anergic/suppressive state. Takahashi, T., Kuniyasu, Y., Toda, M., Sakaguchi, N., Itoh, M., Iwata, M., Shimizu, J. & Sakaguchi, S. Int. Immunol. 10, 1969-1980 (1998) CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting i
23、nterleukin 2 production.Thornton, A. M. & Shevach, E. MJ. Exp. Med. 188, 287-296 (1998),CAMS/PUMC,Identification of GITR as a potential marker of Treg cells.,CD4+CD25+ immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor.McHugh, R.S
24、., Whitters, M.J., Piccirillo, C.A., Young, D.A., Shevach, E.M., Collins, M. & Byrne, M.C. Immunity 16, 311-313 (2002) Multiple cell surface receptors also had increased expression in CD4(+)CD25(+) cells, including GITR, a member of the TNF receptor superfamily. Importantly, antibodies to GITR abrog
25、ated suppression, demonstrating a functional role for this receptor in regulating the CD4(+)CD25(+) T cell subset.,CAMS/PUMC,Three papers showing Foxp3, encoding a member of the forkhead transcription factor family, is a master control gene for the development and function of natural CD4+CD25+ Treg
26、cells. This work also indicated that abnormality in Treg cells can be a cause of human autoimmune disease, allergy and inflammatory bowel disease, as in the human syndrome IPEX.,Control of regulatory T cell development by the transcription factor Foxp3.Hori, S., Nomura, T. & Sakaguchi, S.Science 299
27、, 1057-1061 (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Fontenot, J.D., Gavin, M.A. & Rudensky, A.Y. Nat. Immunol. 4, 330-336 (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells.Khattri, R., Cox, T., Yasayko, S.A. & Ramsdell, F.Nat. Immunol. 4
28、, 337-342 (2003),CAMS/PUMC,Foxp3 programs the development and function of CD4+CD25+ regulatory T cells Jason D. Fontenot, Marc A. Gavin & Alexander Y. Rudensky,Figure 1. Foxp3 is specifically expressed in CD4+CD25+ regulatory T cells. (a) Real-time quantitative PCR for Foxp3 from purified T cell sub
29、sets. (b) Western blot analysis of Foxp3 in purified T cell subsets using rabbit anti-Foxp3 IgG.,CAMS/PUMC,An essential role for Scurfin in CD4+CD25+ T regulatory cells Roli Khattri, Tom Cox, Sue-Ann Yasayko & Fred Ramsdell. Nature Immunology 4, 337 - 342 (2003),Figure 2. Foxp3 expression is specifi
30、c to CD4+CD25+ TR cells. Foxp3 expression was determined in cDNA samples by a real-time RT-PCR method using Dad1 as an endogenous reference gene. Shown is the analysis of freshly isolated cell subsets from wild-type (WT) or sf mice and a no-template control (NTC) sample (a) and freshly isolated and
31、pre-activated CD4+CD25+ and CD4+CD25- T cells from wild-type mice (b). Normalized Foxp3 values were derived from the ratio of Foxp3 expression to Dad1 expression. Data are representative of three independent experiments.,CAMS/PUMC,In vivo dynamics of antigen-specific regulatory T cells not predicted
32、 from behavior in vitro Klein, L., Khazaie, K. & von Boehmer, H.Proc. Natl. Acad. Sci. USA 100, 8886-8891 (2003),In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitroKlein, L., Khazaie, K. & von Boehmer, H.Proc. Natl. Acad. Sci. USA 100, 8886-8891 (2003),CAMS/P
33、UMC,Fig. 2. Transferred CD4CD256.5 T cells retain their phenotypic and in vitro regulatory properties in the absence of antigen and suppress endogenous anti-HA-specific T cells after immunization. (a) CD4CD256.5 T cells (4106) from Thy1.2/ pgk-HATCR-HAmice were transferred into BALBc Thy1.1/ mice. S
34、ix days after transfer, the recipients were killed. Peripheral lymph nodes and spleen were pooled and stained for CD4, Thy1.2, CD25, and 6.5. The frequency of donor-derived cells among CD4 T cells is shown together with the sorting gate used for reisolation of cells. (Right) Purity of reisolated cel
35、ls. (b) Reisolated Thy1.2/ cells 6 days after transfer were tested for their proliferative response after stimulation with HA-peptide and their suppressive potential when cocultured with naive cells,(c) Recipients of 3 105 CD4CD256.5 T cells (dashed lines) or untreated BALBc mice (solid lines) were
36、immunized with HA-peptide (100 g) in IFA. Eight days later, draining lymph node cells were harvested and stimulated in vitro with titrated amounts of HA-peptide for 90 h. Incorporation of 3Hthymidine (3H-Tdr) within the last 20 h was measured. The graph shows the data for three immunized mice of eac
37、h group representative for three independent experiments.,CAMS/PUMC,CD4+CD25+Foxp3+ regulatory T cells (Treg),Essential in immune tolerance Regulation in inflammation Influence tumor immunity Involve in HIV infection,CAMS/PUMC,Tumor and Treg cells,CAMS/PUMC,Immunological focus (two),Dendritic cells
38、induce expression of tissue-homing receptors on T cells following their priming in regional lymph nodes.,CAMS/PUMC,免疫学应用,免疫预防：DNA疫苗 免疫诊断：抗体为核心的诊断手段 免疫治疗：基因工程重组蛋白：细胞因子、其它蛋白；免疫细胞治疗；人源化抗体,CAMS/PUMC,生物药物研发的拥堵态势,371 biotechnology medicines in development by 144 companies and the National Cancer Institute
39、 for nearly 200 diseases. These potential medicines, all of which are either in human clinical trials or under review by the Food and Drug Administration, will bolster the list of 95 biotechnology medicines already approved and available to patientPhRMA， 2006,CAMS/PUMC,Monoclonal Antibody-1975,The N
40、obel Prize in Physiology or Medicine 1984 for the discovery of the principle for production of monoclonal antibodies,CAMS/PUMC,Monoclonal Antibody and cancer therapy,CAMS/PUMC,Published Papers with keywords “Monoclonal Antibodies and Cancer”,2231 papers,About 1600,CAMS/PUMC,Antibody Forms for Therap
41、eutics,Human Adalimumab,Chimeric Abciximab Rituximab Basiliximab Infliximab Cetuximab,Humanized Daclizumab Omalizumab Palivizumab Efalizumab Trastuzumab Bevacizumab Alemtuzumab (Natalizumab) Gemtuzumab ozogamicin,Murine Muromonab-CD3 90Y-Ibritumomab (tiuxetan) 131I-Tositumomab,Years,18 Ab therapeuti
42、cs for diseases, among which 8 for cancers,CAMS/PUMC,Functionalized Ab Technology,Immunotoxins Drug conjugates Enzyme fusions Bispecifics,Target cell,CAMS/PUMC,Antibody Therapeutics Approved by the US FDA(9 up to 2000),Antibody Company Indications Approval Year,Orthoclone OKT3 Ortho Biotech Transpla
43、ntation 1986 (US)ReoPro Centocor Blood Clot 1994 (US)Rituxan (Mabthera) Genentech/IDEC/Roche NHL 1997 (US), 98 (EU)Zenapax Hoffmann La-Roche Transplantation 1997 (US), 99(EU)Simulect Novartis Transplantation 1998 (EU)Remicade Centocor Crohns Disease 1998 (US)Synagis MedImmune RSV Infection 1998 (US)
44、, 99 (EU)Herceptin Genentech Breast Cancer 1998 (US)Mylotarg Wyeth-Ayerst AML 2000 (US),CAMS/PUMC,Antibody Therapeutics Approved by the FDA(18 up to 2004) _ Year Name Antibody Indication(s) Company _ 1986 OKT3 Murine IgG Transplant rejection Ortho Biothch 1994 ReoPro Chimeric Fab Cardiac ischemia Ce
45、ntocor 1997 Rituxan Chimeric IgG NHL IDEC/GenentechZenapax Humanized IgG Transplant rejection Roche 1998 Herceptin Humanized IgG Metatastic Breast Ca Genentech/RocheRemicade Chimeric IgG Arthritis/Crohns CentocorSynagis Humanized IgG RSV infection MedImmuneSimulect Chimeric IgG Transplant rejection
46、Novartis 2000 Mylotarg Humanized IgG AML Wyeth _ 2001 Campath Humanized IgG B-CLL Millennium/Berlex 2002 Humira Human IgG Arthritis Abbott LabZevalin 90Y-Murine IgG NHL IDEC 2003 Bexxar 131I-Murine IgG NHL CorixaXolair Humanized IgG Allergies Genentech/Roche/TanoxRaptiva Humanized IgG Psoriasis Gene
47、ntech/Xoma 2004 Erbitux Chimeric IgG Refractory CRC ImClone/BMSAvastin Humanized IgG CRC Genentech/RocheTysabri Humanized MS Biogen Idec _,CAMS/PUMC,Antibody-based therapeutics for cancers in market,CAMS/PUMC,Monoclonal Antibody Therapeutics - Current Market Dynamics & Future Outlook,The global mark
48、et for Monoclonal Antibody (Mab) Therapeutics reached a total of $11.2 billion in 2004. The market has been growing at an impressive compound average annual growth rate of 42% over the previous five years. The key advantage of Mab Therapeutics is their high levels of specificity for the relevant disease targets. This pinpoint specificity also serves to prevent harm to healthy cells and, hence, typically results in fewer adverse effects compared to other medicines.,
