免疫藥理學(xué) ppt課件

1、Immunopharmacology,李春實(shí),Definition:,Immunopharmacology is the intersection of immunology and pharmacology. This research and medical science specialty focuses on drugs that affect the immune system, whether to suppress

2、 it, activate it, or manipulate it in some way. The most well-known immunopharmacology agents include anti-rejection drugs and vaccines.,Normal Immune Responses,Elements of the Immune System,★ The innate immune syste

3、m:,★ The adaptive immune system:,The first line of defense,Including physical (eg, skin), biochemical (eg, complement,lysozyme),and cellular (macrophages, neutrophils) components。,Humoral immunity – B lymphocytes: antibo

4、diesCell-mediated immunity – T lymphocytes,,,,,,,,,,,,,,Antigen,,,,,,,,,,APC(macrophage,dendritic cell),CD4T helpercell,primedCD4T helpercell,CD8 T cell,cytotoxicT cells,plasmacells,1,2,3,4,4,IL-1,IL-2,IL-2,IL-2

5、,MAJOR STEPS IN IMMUNE RESPONSES,B cell,Abnormal Immune Responses,★ Hypersensitivity::,★ Autoimunity:,★ Immunodeficiency diseases:,immediate hypersensitiveity: type I,II,III,delayed hypersensitivity: type IV,RA, SLE

6、, IDDM, IBD,Immune Regulation,(一）抗原與免疫反應(yīng)的調(diào)節(jié),1.抗原特性對(duì)免疫反應(yīng)的影響,蛋白質(zhì)抗原可誘導(dǎo)細(xì)胞、體液免疫；多糖及脂類抗原只能誘導(dǎo)體液免疫，產(chǎn)生的抗體多為IgM。,大劑量或小劑量抗原易引起免疫耐受，只有適中劑量才能有效誘導(dǎo)免疫應(yīng)答。,蛋白質(zhì)抗原皮內(nèi)或皮下注射能有效激發(fā)免疫應(yīng)答，大劑量蛋白質(zhì)抗原口服或靜脈給藥易引起免疫耐受。,2.抗原之間的競(jìng)爭(zhēng)性抑制,兩種不同抗原如果相隔1-2d內(nèi)先后進(jìn)入機(jī)

7、體，則機(jī)體對(duì)后進(jìn)入的抗原反應(yīng)下降。,原因：,APC遞呈先進(jìn)入機(jī)體的抗原后，妨礙了它遞呈緊隨其后的另一種抗原。,Th細(xì)胞受先進(jìn)入的抗原刺激后，會(huì)產(chǎn)生很多細(xì)胞因子，這些細(xì)胞因子可會(huì)抑制對(duì)后來(lái)者的反應(yīng)。,(二）抗體與免疫反應(yīng)的調(diào)節(jié),用抗原免疫動(dòng)物前或免疫初給動(dòng)物輸入針對(duì)該抗原的抗體，則動(dòng)物針對(duì)該抗原產(chǎn)生的抗體量大大下降，這一現(xiàn)象稱為抗體的反饋調(diào)節(jié)。,原因：,1.中和抗原：,2.BCR與Fc受體交聯(lián)→激活胞內(nèi)磷酸酶→與B細(xì)胞關(guān)聯(lián)的細(xì)胞內(nèi)

8、 分子脫磷酸化→（-）信號(hào)轉(zhuǎn)導(dǎo)→（-）B細(xì)胞增殖,（三）免疫細(xì)胞與免疫反應(yīng)的調(diào)節(jié),1．APC的調(diào)節(jié)作用,※APC參與啟動(dòng)特異性免疫應(yīng)答，而APC表面MHC分子和協(xié)同刺激分子的表達(dá)是APC遞呈抗原的關(guān)鍵。,※加入佐劑常能加強(qiáng)免疫應(yīng)答反應(yīng)（佐劑能引起局部炎癥反應(yīng)，這種炎癥反應(yīng)可使APC釋放一些細(xì)胞因子[如IL -12) ]，可促進(jìn)APC表達(dá)協(xié)同刺激分子）。,※佐劑一般都能誘導(dǎo)出強(qiáng)的細(xì)胞免疫應(yīng)答，T細(xì)胞激活后釋放的IFN-γ可以促使

9、巨噬細(xì)胞表達(dá)MHCⅡ類分子和協(xié)同刺激分子，增強(qiáng)它們遞呈抗原的能力。,（∴，疫苗+佐劑(id或ih)→較強(qiáng)的免疫效果）,2．Th1細(xì)胞和Th2細(xì)胞的調(diào)節(jié),調(diào)節(jié)體液免疫和細(xì)胞免疫的關(guān)鍵成分是CD4+T輔助細(xì)胞。,Th1細(xì)胞主要介導(dǎo)細(xì)胞免疫，在抗感染、器官移植排斥反應(yīng)和自身免疫病的誘導(dǎo)過(guò)程中起著重要作用；,Th2細(xì)胞主要介導(dǎo)體液免疫、輔助抗體生成，在過(guò)敏反應(yīng)中起主導(dǎo)作用，使抗原特異的B細(xì)胞分泌IgG和IgE。,Th1和Th2細(xì)胞所誘導(dǎo)的

10、免疫反應(yīng)能互相調(diào)節(jié)或產(chǎn)生交叉調(diào)節(jié)作用。,一此疾病的發(fā)生和發(fā)展往往與Th1細(xì)胞和Th2細(xì)胞的功能失調(diào)有關(guān)。,一般來(lái)說(shuō)，過(guò)敏性疾病與抗原特異性Th2細(xì)胞優(yōu)勢(shì)應(yīng)答密切相關(guān)，器官特異性自身免疫病是由Th1細(xì)胞介導(dǎo)。,選擇性誘導(dǎo)或調(diào)控Th1／Th2細(xì)胞的免疫反應(yīng)，促使Th1／Th2細(xì)胞反應(yīng)的動(dòng)態(tài)平衡，則將十分有利于疾病的轉(zhuǎn)歸。,克羅恩病、IDDM、實(shí)驗(yàn)性過(guò)敏性腦脊髓炎、自身免疫性甲狀腺炎和多發(fā)性硬化癥；,哮喘、SLE、自身免疫性心臟

11、病等,是指在免疫治療中用于刺激、增強(qiáng)或抑制機(jī)體免疫反應(yīng)和免疫功能的藥物，在惡性腫瘤、自身免疫病、免疫缺陷、器官移植和慢性感染性疾病的治療中具有重要意義。,免疫增強(qiáng)劑( immunoenhancer)（～刺激劑, immunostimulant）（～促進(jìn)劑 immunopotentiator),Immunomodulator(免疫調(diào)節(jié)劑）,免疫抑制劑( immunosuppressive agent，ISA)。,細(xì)胞因子的調(diào)節(jié)作用,一

12、、介導(dǎo)和調(diào)節(jié)天然免疫反應(yīng),1.被病毒感染的細(xì)胞識(shí)別病毒雙鏈RNA,2.NK細(xì)胞殺傷病毒感染的細(xì)胞,3.結(jié)構(gòu)不同的細(xì)胞脂質(zhì)被識(shí)別,二、介導(dǎo)和調(diào)節(jié)特異性免疫反應(yīng),IL-12、IL-4和TGF-β，可通過(guò)自分泌方式調(diào)節(jié)分泌細(xì)胞的反應(yīng)性，也可通過(guò)旁分泌方式作用于鄰近的T、B細(xì)胞和其他細(xì)胞；,IFN-Y，IL-5和IL-13則主要通過(guò)調(diào)節(jié)效應(yīng)細(xì)胞如巨噬細(xì)胞、嗜酸粒細(xì)胞和內(nèi)皮細(xì)胞起作用。因而，細(xì)胞因子在T淋巴細(xì)胞依賴性免疫應(yīng)答中起著重要作用，此過(guò)

13、程產(chǎn)生的細(xì)胞因子往往決定了免疫應(yīng)答的性質(zhì)。,三、刺激造血細(xì)胞的生成和分化,如TNF、IFN -γ和TGF -β抑制骨髓祖細(xì)胞的生長(zhǎng)；相反，IL -1和IL-6則增強(qiáng)CSF的作用,四、細(xì)胞因子類免疫調(diào)節(jié)劑,主要有IL-2、IFN -γ、G-CSF、GM-CSF和IL-12,Drugs affcting immune responses,Immunosuppressive drugs,Immunostimulants,Immunosup

14、pressive Drugs,Common characteristics,Deficiency in specific or selectivity: More effective in the first immume response action than in that of the second. Action related to the time of administration of dru

15、gs, the interval of antigen stimulation and subsequence. Non-specific anti-inflammatory effect.,Purpose of Immunosuppressive Drugs,Prevention of organ transplant rejectionTreatment of autoimmune diseases,Multipl

16、e SclerosisLupusRheumatoid ArthritisCrohn’s DiseaseType I Diabetes,Major Classes of Immunosuppressant Drugs,GlucocorticoidsCalcineurin inhibitors 如環(huán)孢素Antiproliferative/Antimetabolic Agents 如西羅莫司、烷化劑Biol

17、ogics (Antibodies),作用機(jī)制,阻斷免疫應(yīng)答反應(yīng)中的關(guān)鍵步驟,,,,,,,,,,,,,,Antigen,,,,,,,,,,antigenpresenting cell,CD4T helpercell,primedCD4T helpercell,CD8 T cell,cytotoxicT cells,plasmacells,1,2,3,4,4,IL-1,IL-2,IL-2,cytokines,SITES

18、OF ACTION OF IMMUNOSUPPRESSIVE DRUGS,X,X,X,X,X,A,B,D,D,E,C,X,,Cyclosporin (CsA)環(huán)孢素，環(huán)孢菌素,Fat-soluble peptide antibiotic,Pharmacokinetics,Slowly and incompletely absorbed after oral administration. Almost totally metabo

19、lized and excreted in the bile.,Pharmacological Effects:,Act at an early stage in the antigen receptor-induced differentiation of T cells and block their activation.Inhibit the gene transcription of IL-2, IL-3, IFN-γ,

20、and other factors produced by antigen-stimulated T cells, but it does not block the effect of such factors on primed T cells nor does it block interaction with antigen.,※～ + cyclophilin → complex → + calcineurin → (-) d

21、ephosphorylation of NFAT → gene transcription ↓ → IL- 2,3,4↓, TNF-α↓, IFN-γ↓,Mechanisms,※cyclosporin → TGF-β↑ → proliferation of T cells induced by IL-2 ↓, cytotoxic T cells↓,Clinical Uses,※Organ transplantation 在腎移

22、植和骨髓移植上用得最多※Autoimmune disorders其中對(duì) I型糖尿病、眼色素層炎、牛皮癬、類風(fēng)濕性關(guān)節(jié)炎和腎病綜合征，效果較好；對(duì)重癥肌無(wú)力、系統(tǒng)性紅斑狼瘡和原發(fā)性膽汁性肝硬變效果較差。,Adverse Effects and CautionsNephrotoxicity Transient liver dysfunctionsecondary infection: viral infectionLympho

23、ma and other cancers (Kaposi’s sarcoma, skin cancer),Tacrolimus (FK506)（他克莫司）,Macrolide antibiotic produced by streptomyces tsukubaensis.It is not chemically related to cyclosporine, but their machanisms of action are s

24、imilar, both bind to cytoplasmic peptidyl-prolyl(脯氨酰) isomerases(異構(gòu)酶).,liver, kidney, heart, pancreas, and bone marrow transplant.,Clinical Uses,Adverse Effects,nephrotoxicity, neurotoxicity, hyperglycemiagastrointesti

25、nal dysfunction.,Sirolimus (Rapamune)( 西羅莫司，雷帕霉素）,Structuremacrolide similiar to tacrolimusMechanismbinds to immunophilin protein that binds to a key regulatory kinase required for T cell activation (new unique mecha

26、nism to inhibit T lymphocyte activation by IL-2)different site of action than cyclosporine and tacrolimus,Inhibits mammalian target of rapamycin (mTOR) mTOR is a protein kinase that plays pivotal role in IL-2 receptor

27、 responsesIL-2 binds to its receptor on T cells and leads to mTOR activationmTOR initiates cascade of events (including cyclin dependent kinases) that promote T lymphocyte proliferation and differentiationInhibition

28、of mTOR blocks IL-2 dependent cell-cycle progression at G1→S phase transition,Consequences of TOR Action,Lymphocyte cell proliferation & differentiationT cellsB cellsAntibody productionMesenchymal cell proliferat

29、ionVascular smooth muscle cellsEndothelial cellsFibroblasts,Properties of TOR Inhibitorssuch as Sirolimus (Rapamune),Selective blockade of cytokine signal transductionInhibition of T cell division and proliferation

30、Potent and effective immunosuppressionPotential for synergy with other immunosuppressants,Sirolimus (Rapamune),other theoretical actions includeblockade of B cell Ig synthesisinhibition of antibody-dependent cellular

31、toxicityinhibition of lymphocyte activated killer cellsinhibition of natural killer cellsinhibition of immune and nonimmune cell proliferation (via inhibition of growth factor signaling) (may explain antitumor actions

32、),Sirolimus (Rapamune),Bioavailabilitylow oral absorptionhepatic metabolism by CYP4503A4 (drug interactions may occur)long half-life (60 hours)Adverse Effectsthrombocytopenia, hyperlipidemia, rashlacks direct end o

33、rgan toxicity but increased incidence impaired renal function when combined with cyclosporine,Adrenocortical Hormones,Inhibition of IL-1 and TNF gene expression and synthesisDecreased activation of T lymphocytes by decr

34、easing IL-1 releaseDecreased neutrophil functions esp chemotaxisDecreased antibody production (high doses)Decreased release of kinins and proinflammatory eicosanoids (prostaglandins and leukotrienes),Corticosteroid Im

35、munosuppression,Decreased cell-mediated immune reactions that mediate rejection of organ transplantsMechanisms:decreased activation of T lymphocytes by inhibition of IL-1 synthesis by macrophages decreased lymphocyte

36、 mobilization out of lymphoid organs (lymphopenia),organ transplantation autoimmune disorders.,Clinical Uses,Adverse reaction,Growth inhibition in pediatric transplantsCataracts (10% incidence)Bone disease (inhibitio

37、n of osteoblastic activity, decreased calcium absorption, increased urinary calcium excretion)Diabetes (insulin-resistance, gluconeogenesis)Hyperlipidemia (40-60% posttransplant accelerated atherogenesis, increased inc

38、idence if combined with calcineurin inhibitors and sirolimus)Hypertension (60-80% in transplant patients)Increased cardiovascular risk factorsPredisposition to infection (decr. PMN, T cell activity),Antimetabolite (抗代

39、謝藥),Including Aza, MTX, 6-MP, et al.Aza is an imidazolyl(咪唑) derivative of 6-MP. Aza is the purine analog that interferes with nucleic acid metabolism at steps that are required for the wave of lymphoid cell proliferat

40、ion which follows antigenic stimulation.T cells is more sensitive than B cells.,Renal allograftTreatment of autoimmune disorders: rheumatoid arthritis, systemic lupus erythematosus, et al.,Clinical Uses,Bone marrow sup

41、pression, gastrointestinal symptoms, hepatic dysfunction.,Adverse Effects,Alkylating(烷化) agent,Cyclophosphamide (CTX) destroys proliferating lymphoid cells but also appears to alkylate some resting cells.B cells is mo

42、re sensitive than T cells.,Organ transplants,Autoimmune disorders.,Clinical Uses,Bone marrow suppression, gastrointestinal symptoms, hemorrhagic cystitis(出血性膀胱炎).,Adverse Effects,Antilymphocyte Globulin (ALG),Antiserum

43、is usually obtained by immunization of large animals with human lymphoid cells or by the hybridoma(雜交瘤) technique for monoclonal antibody generation.Antithymocyte globulin (ATG).Destruction or inactivation of the T cel

44、ls. primary immune response＞secondary immune responseAdverse reactions are mostly those associated with injection of a foreign protein obtained from heterologous serum.,Mycophenolate Mofetil(RS-61443)霉酚酸酯,A semisynthet

45、ic derivative of mycophenolic acid (MPA), isolated from the mold Penicillium glaucum.MPA is the inhibitor of IMPDH. Inhibit the de novo pathway of purine synthesis.Inhibit a series of T and B lymphocyte responses.,Kidn

46、ey and liver transplant, et al.,Clinical Uses,Adverse Effects,mainly gastrointestinal symptoms .,Leflunomide(來(lái)氟米特),A prodrug of an inhibitor of pyrimidine synthesis rather than purine synthesis.Inhibit DHODH through A77

47、1726.It is orally active, and the active metabolite has a long half-life of several weeks.– should be started with a loading dose.,Clinical Uses,Adverse Effects,Mainly for rheumatoid arthritis.,liver damage, renal impa

48、irment, teratogenic(致畸) effects.,Immunostimulants,Increase the immune responsiveness of patients who have either selective or generalized immunodeficiency.Use for immunodeficiency disorders, chronic infectious diseases

49、, and cancer.,Immune Adjuvant,Bacillus Calmette-Guerin-Vaccine (BCG) is a viable(可培育的) strain of Mycobacterium(分支桿菌) bovines(牛型) that has been used for immunization against tuberculosis.Also been employed as a nonspecif

50、ic adjuvant or immunostimulant in cancer therapy.,Cytokines,Interferon (INF): INF-α,β,γAntiviral, anticancer, immunomodulating effects.Antiviral effects : INF-α,β＞ INF-γimmunomodulating effects: INF-γAdverse Effects

51、: flu-like symptoms, fatigue(疲乏), malaise(不適),Cytokines,Interleukin-2 (IL-2)T cell proliferation, TH, NK, LAK cell activationTreatment of malignant melanoma(惡性黑素瘤), renal cell carcinoma, Hodgkin diseaseAdverse Effects

52、: fever, anorexia(食欲缺乏), et al.,Other Immunomodulators,Etanercept(依那西普)Transfer Factor (TF)ThymosinLevamisole (LSM)(左旋(四)咪唑)Isoprinosine(異丙肌苷),,0psonized bacteria,,,,,,,,,,,,Macrophage,APC,,T lymphocyte,IL-2,IL-2,,,,

53、IFN-?,,ActivatedMacrophage,,ActivatedNK cells,ActivatedCytotoxic T cell,,CELL-MEDIATED IMMUNITY,B lymphocyte,,,IL-4,IL-5,TH1,TH2,Memory B Cells,Plasma Cells:IgG - IgM IgA - IgD,,HUMORAL IMMUNITY,IFN-?TNF-

54、?,IFN-?,,Inhibitors of Immune Response (site of action),A- Immune Globulin (antigen recognition)B- Corticosteroids (IL-1 production, cell prolif.)C- OKT3,ATG (T cell receptors/surface prot.)D- Cyclosporine, Tacro

55、limus, (1L-2 gene expr.), Sirolimus (IL-2 signal transduction)E- Rapamycin, Mycophenolate (T cell prolif.), Azathioprine,Cyclophosphamide (all cell prolif.),Sites of Action of Immunosuppressants Inhibiting

56、T Cell Activation,DrugGlucortiocoidsCyclosporine and TacrolimusSirolimusMycophenolate Mofetil,TargetGRE of DNA (regulate gene transcription, inhibit transcription) Calcineurin (inhibit the phosphatase requir

57、ed for IL-2 transcription)Protein kinase involved in cell-cycle progression (inhibits mTOR and inhbits IL-2 signaling)Inosine monophosphate dehydrogenase (inhibits de novo guanine nucleotide synthesis),免疫藥理學(xué)實(shí)驗(yàn)方法與技術(shù)簡(jiǎn)介,

58、一、免疫細(xì)胞的分離與純化,外周血中白細(xì)胞的分離常用自然沉降法和高分子聚合物沉降法；外周血單核細(xì)胞（peripheral mononuclear cells，PMNC）分離多采用密度梯度離心法。,從淋巴組織中分離淋巴細(xì)胞懸液---制備脾細(xì)胞懸液、淋巴結(jié)細(xì)胞懸液、胸腺細(xì)胞懸液。,①分離PMNC中的淋巴細(xì)胞和巨噬細(xì)胞,常用方法有玻璃粘附法、磁鐵吸引法、羰基鐵乳膠分層液法、補(bǔ)體溶解法及葡聚糖凝膠過(guò)濾法等。,②T細(xì)胞、B細(xì)胞及T細(xì)胞亞群的分離

59、純化,E花結(jié)分離法、Percoll非連續(xù)性密度梯度離心分離法、洗淘法（panning）、補(bǔ)體細(xì)胞毒法、尼龍毛分離法、磁性激活細(xì)胞分離器（magnetic activated cell sorter，MACS）分離技術(shù)及流式細(xì)胞術(shù)（flow cytometry，F(xiàn)CM）。,二、藥物對(duì)免疫系統(tǒng)功能影響的實(shí)驗(yàn)技術(shù)簡(jiǎn)介,1、對(duì)免疫細(xì)胞表面抗原分子的影響,對(duì)細(xì)胞表面的CD（cluster of differentiation，分化簇）抗原的檢

60、測(cè)與分析可通過(guò)細(xì)胞毒法、葡萄菌體蛋白A法、免疫細(xì)胞化學(xué)法和免疫熒光染色分析法等，借助流式細(xì)胞儀進(jìn)行的免疫熒光染色分析法使該項(xiàng)技術(shù)的標(biāo)準(zhǔn)化、定量化和自動(dòng)化水平大大提高，體內(nèi)外藥理試驗(yàn)均可采用之。,2、對(duì)免疫細(xì)胞功能的影響,常用：3H-TdR摻入試驗(yàn)、固相抗CD3單克隆抗體誘導(dǎo)細(xì)胞增殖的檢測(cè)、混合淋巴細(xì)胞反應(yīng)、抗原刺激的T細(xì)胞增殖反應(yīng)、預(yù)激淋巴細(xì)胞對(duì)抗原的增殖反應(yīng)等。,3、淋巴細(xì)胞功能的體內(nèi)實(shí)驗(yàn),小鼠接觸性超敏反應(yīng)、移植物抗宿主反應(yīng)

61、（graft-versus-host disease，GVHD）、遲發(fā)性超敏反應(yīng)（delayed-type hypersensitivity，DTH）、體內(nèi)檢測(cè)TH細(xì)胞活性。,4、對(duì)B細(xì)胞影響的體內(nèi)外實(shí)驗(yàn),血清中IgG、IgA、IgM的測(cè)定（單向免疫擴(kuò)散法、散射比濁法）；抗體生成細(xì)胞檢測(cè)（溶血空斑試驗(yàn)、溶血分光光度法）。,5、對(duì)單核巨噬細(xì)胞功能的影響實(shí)驗(yàn),巨噬細(xì)胞吞噬雞紅細(xì)胞實(shí)驗(yàn)、白色念珠菌3H葡萄糖摻入實(shí)驗(yàn)、單核巨噬細(xì)胞對(duì)腫瘤細(xì)

62、胞的細(xì)胞毒反應(yīng)測(cè)定、單核因子測(cè)定等。,6、對(duì)超敏反應(yīng)影響的體內(nèi)外實(shí)驗(yàn),總IgE水平測(cè)定：酶聯(lián)免疫吸附試驗(yàn)（enzyme linked immunosorbent assay，ELISA）、放射免疫單擴(kuò)散法（radioactive single radial diffusion，RSRD）、免疫斑點(diǎn)法（dot immunobinding assay，DIBA）、反向被動(dòng)血凝法（reversed passive hemagllutina

63、tion assay，RPHA）、紙片放射免疫吸附試驗(yàn)（paper radio immunosorbent test，PRIST）。特異性IgE抗體測(cè)定：ELISA、放射過(guò)敏原吸附試驗(yàn)（radioallergosorbent test，RAST）、P-K試驗(yàn)、被動(dòng)皮膚過(guò)敏反應(yīng)（passive cutaneous anaphylaxis，PCA）、皮內(nèi)試驗(yàn)（intradermal test）。人外周血單個(gè)核細(xì)胞體外合成IgE的測(cè)定

64、：微量固相放射免疫測(cè)定法（microtiter solid-phase radioimmunoassay，MSPRIA）和ELISA法。參與I型超敏反應(yīng)介質(zhì)的測(cè)定：相應(yīng)介質(zhì)試劑盒測(cè)定，如LTs試劑盒。動(dòng)物模型：如過(guò)敏性哮喘模型等。,三、影響免疫功能的藥物藥效學(xué)研究原則,1、免疫增強(qiáng)劑和免疫調(diào)節(jié)劑的免疫藥理學(xué)研究,免疫增強(qiáng)劑和免疫調(diào)節(jié)劑可分為兩大類：生物類和化學(xué)合成化合物類。生物制品類包括菌苗、細(xì)菌的某些成分如脂多糖、真菌產(chǎn)物、免疫

65、細(xì)胞的產(chǎn)物如細(xì)胞因子和免疫球蛋白、免疫細(xì)菌如LAK細(xì)胞、自然化合物及中草藥及其單體成分等?；瘜W(xué)合成化合物類包括含硫化合物、多聚核苷酸等。這些藥物的藥理作用因用藥方案不同，如給藥途徑、用藥劑量和用藥時(shí)間等，會(huì)導(dǎo)致不同的藥效；另外，藥物本身的純度和藥物受試對(duì)象的種系、年齡、疾病類型與程度及遺傳背景亦會(huì)對(duì)藥效產(chǎn)生一定的影響，因此，在進(jìn)行實(shí)驗(yàn)設(shè)計(jì)時(shí)要全面考慮這些因素。,臨床上免疫增強(qiáng)劑和免疫調(diào)節(jié)劑主要用于原發(fā)性和繼發(fā)性免疫缺陷病、自身

66、免疫病、腫瘤及慢性微生物感染的治療，故選擇實(shí)驗(yàn)動(dòng)物模型時(shí)，應(yīng)考慮采用免疫缺陷模型動(dòng)物、荷瘤動(dòng)物、自身免疫病模型及相應(yīng)病原體感染動(dòng)物模型。,2、免疫抑制劑的免疫藥理學(xué)研究,免疫抑制劑的篩選程序一般是先進(jìn)行體外實(shí)驗(yàn)，然后進(jìn)行體內(nèi)實(shí)驗(yàn)。動(dòng)物的體內(nèi)實(shí)驗(yàn)多采用實(shí)驗(yàn)性過(guò)敏性腦脊髓炎和淋巴細(xì)胞性脈絡(luò)叢腦膜炎的病理模型和新西蘭NZB小鼠。在動(dòng)物實(shí)驗(yàn)時(shí)，應(yīng)考慮動(dòng)物的品系、對(duì)免疫應(yīng)答所影響的環(huán)節(jié)、治療指數(shù)、給藥途徑、最佳治療方案等。在免疫藥理學(xué)研

67、究之后，還應(yīng)進(jìn)行基礎(chǔ)藥理學(xué)研究、藥物的急性和慢性毒性研究、藥物的動(dòng)力學(xué)研究等。,定義：藥物或能防治疾病的生物活性物質(zhì)對(duì)免疫系統(tǒng)的調(diào)控。,藥物調(diào)控的環(huán)節(jié)：,（1）調(diào)控免疫的發(fā)生、發(fā)展和功能；（2）增強(qiáng)或抑制免疫活性細(xì)胞各亞群的功能（如 Th、Ts等）（3）控制和修復(fù)主要的生物放大系統(tǒng)，如：補(bǔ)體 系統(tǒng)、激肽-血管緩激肽系統(tǒng)（4）調(diào)節(jié)和利用T細(xì)胞釋放的淋巴因子和B細(xì)胞合 成的抗

68、體等。,此外，采用免疫學(xué)的原理和技術(shù)改造藥物或改變其作用以達(dá)到不同的診斷和治療目的。,[免疫藥理學(xué)實(shí)驗(yàn)方法],免疫系統(tǒng)對(duì)藥物極其敏感——實(shí)驗(yàn)方法高度靈敏、定量和可靠。,動(dòng)物選擇：應(yīng)給予更多的注意。,不同種屬和品系的動(dòng)物對(duì)不同抗原或促有絲分裂原的免疫應(yīng)答差別很大。故有高低反應(yīng)品系之分。,豚鼠對(duì)變態(tài)反應(yīng)高度敏感。C3H/HeJ小鼠對(duì)脂多糖的毒性和絲裂原型都不敏感，但對(duì)其他T細(xì)胞絲裂原和B細(xì)胞絲裂原都能反應(yīng)。,Balb/cAnN有高