移植免疫課程班

1、移植免疫Transplantation Immunology,器官移植簡史和概念同種異體器官移植排斥的機(jī)制移植排斥反應(yīng)的類型同種異體器官移植排斥反應(yīng)的防治原理誘導(dǎo)同種移植耐受的基本策略移植相關(guān)的免疫學(xué)問題,同種異體器官移植簡史移植的基本概念同種異體器官移植在臨床中的應(yīng)用移植物來源的分類移植排斥反應(yīng)的影響因素,器官移植簡史和概念,◆ Alexis Carrel reported the first systematic

2、 study of transplantation in 1908; he interchanged both kidneys in a series of nine cats. Some of those receiving kidneys from other cats maintained urinary output for up to 25 days. Although all the cats eventually died

3、.◆ The first human kidney transplant, attempted in 1935 by a Russian surgeon, failed because there was a mismatch of blood types between donor and recipient. ◆ The first successful human kidney transplant, which was be

4、tween identical twins, was accomplished in Boston in 1954.,◆ Today , kidney, pancreas, heart, lung, liver, bone-marrow, and cornea transplantations are performed among nonidentical individuals with ever-increasing freque

5、ncy and success.,同種異體器官移植簡史,移植的基本概念 應(yīng)用自體或異體的正常細(xì)胞、組織或器官，置換病變或功能缺損的細(xì)胞、組織或器官，以維持和重建機(jī)體的生理功能，這種治療方法稱為細(xì)胞移植、組織移植和器官移植。 移植排斥反應(yīng)是移植物（細(xì)胞、組織或器官）抗原可刺激受者的免疫系統(tǒng)從而誘發(fā)免疫應(yīng)答（宿主抗移植物反應(yīng)）;受者組織抗原也可能刺激移植物中的免疫細(xì)胞從而誘發(fā)免疫應(yīng)答（移植物抗宿主反應(yīng)）。

6、 根據(jù)移植物移植的部位不同，可分同位或正位移植及異位移植，即前者是將組織或器官移植至該宿主組織或器官的正常解剖部位，后者是將組織或器官移植該宿主并非其原先的解剖部位。 *供者 — 提供移植物的個體；受者(宿主)— 接受移植物的個體。,,同種異體器官移植在臨床中的應(yīng)用,,根據(jù)移植物的來源和遺傳背景不同，可將移植分為四類： ①自體(autologous)移植② 同系(syngeneic)移植③ 同種異基因(allo

7、geneic) (同種異體)移植④ 異種(xenogeneic)移植,Genetic barriers to transplantation,移植物來源的分類,,異種移植的實驗研究,豬－人異種移植,人畜共患病 (xenozoonosis),異種移植存在的問題,異種移植排斥反應(yīng)比同種移植更強烈、機(jī)制更復(fù)雜異種移植排斥對免疫抑制藥物不敏感畜類微生物感染對人類的潛在威脅異種器官與人類宿主的生理學(xué)不相容性異種移植研究的動物模型有待

8、建立和完善,同種異體器官移植一般均會發(fā)生排斥反應(yīng)，排斥反應(yīng)的強弱取決于:①供受體間組織相容性抗原的差異程度; ②受者的免疫狀態(tài); ③移植物種類; ④防治措施。,移植排斥反應(yīng)的影響因素,一、引起同種異體移植排斥反應(yīng)的抗原二、T細(xì)胞識別同種抗原的機(jī)制三、移植排斥反應(yīng)的效應(yīng)機(jī)制,同種異體器官移植排斥的機(jī)制,1.主要組織相容性抗原2.次要組織相容性抗原3.其他參與排斥反應(yīng)發(fā)生的抗原,一、引起同種異體移植排斥反應(yīng)的抗原,The g

9、enetics of graft rejection. In the illustration, the two different mouse colors represent inbred strains with different MHC haplotypes. Inherited MHC alleles from both parents are codominantly expressed in the skin of an

10、 A × B offspring, and therefore these mice are represented by both colors. Syngeneic grafts are not rejected (A). Allografts are always rejected (B). Grafts from an A or B parent will not be rejected by an (A ×

11、 B)F1 offspring (C), but grafts from the offspring will be rejected by either parent (D). These phenomena are due to the fact that MHC gene products are responsible for graft rejection; grafts are rejected only if they e

12、xpress an MHC type (represented by green or orange) that is not expressed by the recipient mouse.,主要組織相容性抗原,能引起強烈排斥反應(yīng)的移植抗原稱為主要組織相容性抗原(MHC抗原)，在人類最重要者為HLA抗原。本質(zhì)上，供、受者間HLA型別差異是發(fā)生急性移植排斥反應(yīng)的主要原因。,次要組織相容性抗原,次要組織相容性抗原(minor histo

13、compatibility antigen, mH antigen)表達(dá)于機(jī)體組織細(xì)胞表面，由某些具有多態(tài)性的基因編碼，可被MHC分子提呈，主要包括兩類：,1.性別相關(guān)的mH抗原 2.常染色體編碼的mH抗原,Minor H antigens are peptides derived from polymorphic cellular proteins bound to MHC class I molecules. Self prot

14、eins are routinely digested by proteasomes within the Cell’s cytosol, and peptides derived from them are delivered to the endoplasmic reticulum, where they can bind to MHC class I molecules and be delivered to the cell s

15、urface. If a polymorphic protein differs between the graft donor (shown in red on the left) and the recipient (shown in blue on the right), it can give rise to an antigenic peptide (red on the donor cell) that can be rec

16、ognized by the recipient's T cells as nonself and elicit an immune response. Such antigens are the minor H antigens.,This chart gives the rejection times for skin grafts between mice differing at the major histocompa

17、tibility H-2 locus (blue). Grafts which differ at multiple minor loci are rejected as quickly as those that differ at H-2.,Mouse histocompatibility antigens and graft survival,mH抗原誘導(dǎo)同種異型排斥反應(yīng)的特點：①mH抗原以MHC限制性方式被CTL和Th細(xì)胞識別；

18、②不同類型mH抗原可被不同型別HLA分子提呈；③不同mH抗原分子結(jié)構(gòu)不同，其與特定MHC分子結(jié)合的親和力亦各異，故在不同供、受者間進(jìn)行移植，參與排斥反應(yīng)的和占優(yōu)勢的mH抗原種類可能不同；④供-受者間單個mH抗原不相同，一般引起緩慢的排斥反應(yīng); 多個mH抗原不相符,可引起類似于MHC不相符所致的快速排斥反應(yīng)。,其他參與排斥反應(yīng)發(fā)生的抗原,人類ABO血型抗原:ABO血型抗原不僅分布于紅細(xì)胞表面，也表達(dá)于肝、腎等組織細(xì)胞和血管內(nèi)皮細(xì)胞表面。

19、 組織特異性抗原:指特異性表達(dá)于某一器官、組織或細(xì)胞表面的抗原，如血管內(nèi)皮細(xì)胞 (VEC) 抗原；皮膚 (SK) 抗原。,,ABO blood group antigens. A, Blood group antigens are carbohydrate structures added onto cell surface proteins or lipids by the action of glycosyltransferase

20、s (see text). B. Different blood group antigens are produced by the addition of different sugars by different inherited glycosyltransferase. Individuals who express a particular blood group antigen are tolerant to that a

21、ntigen but produce antibodies that react with other blood group antigens.,1.T細(xì)胞在移植排斥反應(yīng)中作用,二、T細(xì)胞識別同種抗原的機(jī)制,先天性無胸腺的嚙齒類動物 (如裸鼠) 體內(nèi)無成熟T細(xì)胞，不能排斥移植物；新生兒期摘除正常大鼠或小鼠的胸腺，會發(fā)生同樣情況；上述情況中，若注射同系正常小鼠T細(xì)胞，則小鼠即可對移植物產(chǎn)生排斥反應(yīng)。,2.T細(xì)胞對移植物抗原的特異性識別

22、直接識別(direct recognition)的特點和機(jī)制間接識別(indirect recognition)的特點和機(jī)制,,First- and second-set allograft rejection. Results of the experiments shown indicate that graft rejection displays the features of adaptive immune response

23、s, namely, memory and mediation by lymphocytes. An inbred strain B mouse will reject a graft from an inbred strain A mouse with first-set kinetics (left panel). An inbred strain B mouse sensitized by a previous graft fro

24、m an inbred strain A mouse will reject a second graft from an inbred strain A mouse with second-set kinetics (middle panel), demonstrating memory. An inbred strain B mouse injected with lymphocytes from another strain B

25、mouse that has rejected a graft from a strain A mouse will reject a graft from a strain A mouse with second set kinetics (right panel), demonstrating the role of lymphocytes in mediating rejection and memory. An inbred s

26、train B mouse sensitized by a previous graft from a strain A mouse will reject a graft from a third unrelated strain with first-set kinetics, thus demonstrating another feature of adaptive immunity, specificity (not show

27、n). Syngeneic grafts are never rejected (not shown).,T細(xì)胞在移植排斥反應(yīng)中作用,參見圖19-2,同種異體間的器官移植一般均會發(fā)生排斥反應(yīng)，本質(zhì)上乃受者免疫系統(tǒng)對供者移植物抗原的免疫應(yīng)答。,Presentation of allograft antigens,1. A high density of graft MHC molecules, which individually rea

28、ct weakly with the TCR may generate a sufficient signal for T cell activation. 2. Graft MHC molecules can present the graft’s own peptides including molecules from both major and minor histocompatibility antigens. 3. Gra

29、ft MHC molecules can present processed antigens of host molecules. 4. Allotypically different graft molecules, including histocompatibility antigens can be taken up by host antigen presenting cells, and be processed and

30、presented on self MHC molecules.,T細(xì)胞對移植物抗原的特異性識別,受者T細(xì)胞可通過直接識別、間接識別和半直接途徑識別同種異型抗原,受者T細(xì)胞對同種異型抗原的識別途徑A: 直接識別：受者同種反應(yīng)性T細(xì)胞的TCR直接識別供者APC所提呈的供者M(jìn)HC分子或外源肽-供者M(jìn)HC復(fù)合物； B. 間接識別：受者同種反應(yīng)性T細(xì)胞的TCR識別經(jīng)受者APC加工處理的供者M(jìn)HC抗原肽；C：半直接識別: 受

31、者同種反應(yīng)性CD8+T細(xì)胞循直接途徑識別供者APC所提呈的同種MHCI類分子；受者同種反應(yīng)性CD4+T細(xì)胞循間接途徑識別經(jīng)受者APC加工、處理和提呈的同種異型MHC分子，并協(xié)助CD8+T細(xì)胞分化。,直接識別的特點 速度快，因為無須經(jīng)歷抗原攝取、處理和加工； 強度大，因為每一個體中，具有同種抗原反應(yīng) 性的T細(xì)胞克隆約占T細(xì)胞庫總數(shù)的1%～10%， 而針對一般異源性抗原的T細(xì)胞克隆僅占總數(shù)的 1/10000～1/

32、100000。直接識別在早期急性排斥反 應(yīng)中起重要作用。直接識別的機(jī)制TCR乃識別抗原肽和MHC分子的復(fù)合結(jié)構(gòu)(pMHC)的特點記憶T細(xì)胞是參與交叉反應(yīng)的主要效應(yīng)細(xì)胞,受者同種反應(yīng)性T細(xì)胞交叉識別pMHC 具有相同或相似復(fù)合結(jié)構(gòu)的不同抗原肽-MHC分子可被同一受者TCR所識別:（A）正常免疫應(yīng)答過程中，受者TCR特異性識別外來抗原肽-自身MHC分子所形成的復(fù)合結(jié)構(gòu)；（B）同種異體移植時，受者同一TCR可識別單

33、一（空載）的供者M(jìn)HC分子；（C）同種異體移植時，受者同一TCR可識別供者自身肽-供者M(jìn)HC分子復(fù)合物。,TCR乃識別抗原肽和MHC分子的復(fù)合結(jié)構(gòu)(pMHC),TCR的CDR3識別抗原肽；CDR1和CDR2識別MHC分子α螺旋的保守序列。① 特異性TCR乃識別pMHC在結(jié)合界面所形成的復(fù)合結(jié)構(gòu)；② TCR對pMHC的識別具有簡并性，即同一TCR可能識別不同的pMHC；③ CDR3的構(gòu)型具有包容性，可通過構(gòu)型改變而識別不同pMHC。

34、,某些情況下，受者同種反應(yīng)性T細(xì)胞還可直接識別供者M(jìn)HC分子，而與后者是否結(jié)合抗原肽無關(guān) (抗原肽的存在僅起穩(wěn)定MHC分子的作用)，此現(xiàn)象稱為MHC分子優(yōu)勢結(jié)合 (MHC-dominant binding)。其機(jī)制是：雖然供者M(jìn)HC分子結(jié)構(gòu)與受者特異性TCR缺乏嚴(yán)格的空間構(gòu)象互補性，即與受者TCR結(jié)合的親和力低，但由于其高表達(dá)于供者APC (及移植物組織細(xì)胞) 表面，仍可激活受者多克隆T細(xì)胞。,TCR識別pMHC特點,實驗研究表明：參與

35、初次移植排斥的同種反應(yīng)性T細(xì)胞中，包括體內(nèi)預(yù)存的某些記憶T細(xì)胞克?。ň哂杏洃浖?xì)胞的表型）。可能與隱性、顯性微生物感染或接觸的外源性抗原各異有關(guān)。,記憶T細(xì)胞是參與交叉反應(yīng)的主要效應(yīng)細(xì)胞,The Journal of Immunology, 2006, 176:2691–2696,在急性排斥反應(yīng)早期，間接識別與直接識別機(jī)制協(xié)同發(fā)揮作用；在急性排斥反應(yīng)中晚期和慢性排斥反應(yīng)中，間接識別機(jī)制起更為重要的作用。,間接識別的特點和機(jī)制,半間接識別(

36、圖19-3),1.急性排斥反應(yīng)的細(xì)胞免疫效應(yīng)機(jī)制2.同種移植急性排斥反應(yīng)的體液免疫效應(yīng)機(jī)制3.參與同種移植急性排斥反應(yīng)損傷機(jī)制的其他 細(xì)胞與組織成分4.參與移植排斥反應(yīng)的非特異性效應(yīng)機(jī)制,三、移植排斥反應(yīng)的效應(yīng)機(jī)制,,,perforin and granzyme,IFN-?、IL-2、 IL-17,IL-1、IL-6、IL-8、TNF-?,急性排斥反應(yīng)的細(xì)胞免疫效應(yīng)機(jī)制,同種移植急性排斥反應(yīng)的體液免疫效應(yīng)機(jī)制,Effector

37、 mechanisms of antibody-mediated disease. A. Antibodies opsonize cells and may activate complement, generating complement products that also opsonize cells, leading to phagocytosis of the cells through phagocyte Fc recep

38、tors or C3 receptors B. Antibodies recruit leukocytes by binding to Fc receptors or by activating complement and thereby releasing by-products that are chemotactic for leukocytes.,參與同種移植急性排斥反應(yīng)損傷機(jī)制的其他細(xì)胞與組織成分,,,Transplante

39、d organ,腎臟,參與移植排斥反應(yīng)的非特異性效應(yīng)機(jī)制,①非特異性效應(yīng)分子 ②固有免疫效應(yīng)細(xì)胞 DAMP和促炎介質(zhì)(炎性細(xì)胞因子/趨化因子等) DC、NK、NKT、M?和中性粒細(xì)胞等,移植排斥反應(yīng)的類型,一、宿主抗移植物反應(yīng)二、移植物抗宿主反應(yīng)三、排斥反應(yīng)的特殊情況,一、宿主抗移植物反應(yīng) (HVGR),HVGR乃宿主免疫系統(tǒng)對移植物發(fā)動攻擊，導(dǎo)致移植物被排斥。各類器官移植排

40、斥反應(yīng)的免疫學(xué)效應(yīng)機(jī)制基本相同，根據(jù)排斥反應(yīng)發(fā)生的時間、強度、機(jī)制和病理表現(xiàn)，大致可分為超急性排斥、急性排斥、慢性排斥反應(yīng)三類。,1.超急性排斥反應(yīng) (hyperacute rejection) 2.急性排斥反應(yīng) (acute rejection) 3.慢性排斥反應(yīng) (chronic rejection),,Histopathology of different forms of graft rejectio

41、n. A, Hyperacute rejection of a kidney allograft with endothelial damage, platelet and thrombin thrombi, and early neutrophil infiltration in a glomerulus. B, Acute rejection of a kidney with inflammatory cells in the co

42、nnective tissue around the tubules and between epithelial cells of the tubules. C, Acute antibody-mediated rejection of a kidney allograft with destructive inflammatory reaction destroying the endothelial layer of an art

43、ery. D, Complement C4d deposition in vessels in acute antibody-mediated rejection. E, Chronic rejection in a kidney allograft with graft arteriosclerosis. The vascular lumen is replaced by an accumulation of smooth muscl

44、e cells and connective tissue in the vessel intima. (Courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.),Steps in the hyperacute reject

45、ion of a kidney graft,超急性排斥反應(yīng),Effector mechanisms involved in allograft rejection (effector stage),Antigen-reactive lymphocytes of the recipient proliferate in response to alloantigens on the graft (sensitization phase)

46、.,急性排斥反應(yīng),機(jī)體針對同種抗原的免疫應(yīng)答（移植排斥）發(fā)生于外周免疫器官,Immunological mechanisms of chronic transplant rejection,慢性排斥反應(yīng),1.參與慢性排斥反應(yīng)的危險因素 （代謝紊亂、藥物毒性和感染）2.適應(yīng)性免疫介導(dǎo) （急性排斥反復(fù)發(fā)作，感染誘導(dǎo)）,HMGB1通過啟動RAGE相關(guān)的信號通路促進(jìn)TGF-?釋放；HMGB1誘導(dǎo)某些整合素家族分子表達(dá),

47、 促進(jìn)TGF-?轉(zhuǎn)化為活性形式；TGF-β刺激多種細(xì)胞（如內(nèi)皮細(xì)胞、平滑肌細(xì)胞、成纖維細(xì)胞等）產(chǎn)生反應(yīng)性氧中介物（ROS），進(jìn)而主動釋放HMGB1；TGF-?誘導(dǎo)巨噬細(xì)胞核內(nèi)HMGB1轉(zhuǎn)位至胞漿，并促進(jìn)HMGB1合成和主動分泌。,HMGB1/TGF-β反應(yīng)環(huán)參與心臟移植物血管病變(CAV) 發(fā)生的機(jī)制,高速泳動族框蛋白I（HMGB1）是重要的DAMP，在介導(dǎo)移植物損傷中發(fā)揮關(guān)鍵作用；TGF-β是參與移植物組織過度修復(fù)的關(guān)鍵因子，可通

48、過啟動Smad3信號途徑而誘導(dǎo)平滑肌細(xì)胞、成纖維細(xì)胞、內(nèi)皮細(xì)胞增殖，并促進(jìn)I型膠原、Ⅲ型膠原等多種細(xì)胞外基質(zhì)合成及分泌，從而參與和促進(jìn)移植物組織慢性修復(fù)。,3.固有免疫與慢性排斥反應(yīng),二、移植物抗宿主反應(yīng)（GVHR）,Graft-versus-host reactions（GVHR）,GVHR是由移植物中抗原特異性淋巴細(xì)胞識別宿主組織抗原所致的排斥反應(yīng)，發(fā)生后一般均難以逆轉(zhuǎn)，不僅導(dǎo)致移植失敗，還可能威脅受者生命。GVHR的發(fā)生依賴于下列

49、條件：① 受者與供者間HLA型別不符；② 移植物中含有足夠數(shù)量免疫細(xì)胞，尤其是成熟的T細(xì)胞；③ 移植受者處于免疫無能或免疫功能極度低下的狀態(tài) (被抑制或免疫缺陷)。,三、排斥反應(yīng)的特殊情況, 機(jī)體某些解剖部位易于接受同種乃至異種組織器官移植，而不發(fā)生或僅發(fā)生輕微排斥反應(yīng)。這些部位稱為免疫赦免區(qū) (immunologically privileged site)，包括角膜、眼前房、軟骨、腦、胎盤滋養(yǎng)層、某些內(nèi)分泌腺等。機(jī)制可能為：

50、這些部位 (如角膜) 缺少輸入血管和淋巴管，故血循環(huán)中的淋巴細(xì)胞難以到達(dá)赦免區(qū)局部，亦不能接觸移植物抗原，從而不易發(fā)生免疫排斥反應(yīng)；體內(nèi)存在特殊的屏障，如血-腦屏障能阻止抗體和免疫活性細(xì)胞進(jìn)入腦組織與之接觸，故腦內(nèi)組織移植易于成功；某些組織，如軟骨組織的免疫原性較弱，故軟骨移植一般不易引起排斥反應(yīng)； 某些(如母胎屏障）免疫赦免區(qū)組織細(xì)胞高表達(dá)免疫抑制分子如FasL、HLA-G、IDO等，微環(huán)境中存在免疫抑制性細(xì)胞。,,Juch

51、et al. –Placenta and HLA. 9-10/2012,,Key?pathways?involved?in?immune?tolerance?toward?the?fetus?during?the?first?trimester?of?human?pregnancy.?Anchoring villous trophoblasts attach to the decidua?and?further?differentiat

52、e?into?syncytiotrophoblasts,?cytotrophoblasts?and?EVTs.?Floating?villous?trophoblasts?carrying?fetal?blood?vessels?are?bathed?in?maternal?blood?and?can?shed?placental?exosomes,?microparticles?and?fetal?stem?cells.?Expres

53、sion?of?chemokine?receptors and their cognate ligands orchestestrate the iinvasion?of?EVTs?and?migration?of?maternal?leukocytes?into?the?decidua.?EVTs?establish?direct?contact?with?DSCs?and?maternal?leukocyte?population

54、s.?Via? IL-15?and?stem?cell?factor?(SCF)?production?by?DSCs,?denovo?generation?of?dNK?cells?occurs?locally?upon?differentiation?of?tissue?resident?linnegCD45+CD34+?decidual?hematopoetic?stem?cells?(dHSCs).?Macrophage?inh

55、ibitory?cytokine-1?(MIC-1),?TGF-β1?and?galectin-1?production?by? DSCs and/or NK cells promotes?the?arrest?of?decidual?DCs?in?a?tolerogenic?state?(tDCs),?and?NK?cell–derived?galectin-1?induces?apoptosis?of?activated?T?cel

56、ls?in vitro . Upon?dNK cell–derived?IFN-γ?secretion,?the?enzymatic?expression?of?IDO?in?human?decidual?CD14+ monocytes, another predominant decidual cell subset of the innate immune system, is upregulated?in vitro.?Mono

57、cyte-derived?IDO?may? enhance?fetal?tolerance?via?the?generation?of?CD4+?Treg?cells?or?selective?apoptosis?of?effector?T?cells 122 .?Synergistically?with?tDCs?and?monocytes,?dNK?cells?promote?the?generation?of?Treg ?cell

58、s?and? apoptosis of effector T cells. Decidualization is modulated by pregnancy hormones?such?as?progesterone.?The?anatomical?position?where?these?maternal daptations occur is indicated by the white square in the insert

59、 of a pregnant uterus.,移植排斥反應(yīng)的防治原理,一、供者的選擇二、移植物和受者的預(yù)處理三、抑制受者的免疫應(yīng)答四、移植后的免疫監(jiān)測,一、供者的選擇,1.紅細(xì)胞血型檢查2.受者血清中細(xì)胞毒性預(yù)存HLA抗體測定3.HLA分型4.交叉配型5.次要組織相容性抗原型別鑒定,Influence of MHC matching on graft survival. Matching of MHC alleles

60、between the donor and recipient significantly improves renal allograft survival. The data shown are for deceased donor (cadaver) grafts. HLA matching has less of an impact on survival of renal allografts from live donors

61、, and some MHC alleles are more important than others in determining outcome. (Data from Organ Procurement and Transplantation Network/Scientific Registry annual report, 2010.),二、移植物和受者的預(yù)處理,1.移植物預(yù)處理 實質(zhì)臟器移植時，盡可能清除

62、移植物中過路細(xì)胞有助于減輕或防止HVGD發(fā)生。2.受者預(yù)處理 實質(zhì)臟器移植中，供、受者間ABO血型物質(zhì)不符可能導(dǎo)致強的移植排斥反應(yīng)。術(shù)前給受者輸注供者特異性血小板；借助血漿置換術(shù)去除受者體內(nèi)天然抗A或抗B凝集素；受者脾切除；免疫抑制療法等。,三、抑制受者的免疫應(yīng)答,1.免疫抑制藥物的應(yīng)用化學(xué)類免疫抑制藥生物制劑中草藥類免疫抑制劑2.清除預(yù)存抗體3.其他免疫抑制方法,Mechanism of action of

63、 immunosuppresive drugs. Each major category of drugs used to prevent or to treat allograft rejection is shown along with the molecular targets of the drugs.,Production of IL-4 is defective in the non-obese (NOD}mouse (1

64、) and diabetes-prone BB rat (2); the disease can be corrected by injection of the cytokine. The same is true for the production of TNFa by the NZBxW lupus mouse (3). Rheumatoid arthritis patients have a poor hypothalamie

65、 response to IL-1 and IL-6(4). The hypothalamic-pituitary axis is defective in the Obese strain chicken and in the Lewis rat which is prone to the development of Freund's adjuvant mediated experimental autoimmune dis

66、ease (5). CRH = corticotrophin releasing hormone; M =macrophage.,糖皮質(zhì)激素（glucocorticoids）,Anti-inflammatory effects of corticosteroid therapy. Corticosteroids regulate the expression of many genes, with a net anti-inflamma

67、tory effect. First, they reduce the production of inflammatory mediators, including cytokines, prostaglandins, and nitric oxide (NO). Second, they inhibit inflammatory cell migration to sites of inflammation by inhibitin

68、g the expression of adhesion molecules. Third, corticosteroids promote the death by apoptosis of leukocytes and lymphocytes. The layers of complexity are illustrated by the actions of annexin-1(originally identified as a