本文選題：B細胞　切入點：調(diào)節(jié)性B細胞　出處：《復旦大學》2012年博士論文　論文類型：學位論文

【摘要】：目的：通過造血干細胞與腎臟聯(lián)合移植來誘導受體產(chǎn)生對移植腎免疫耐受,研究受者外周血B細胞活化因子(BAFF)動態(tài)變化,并比較不同免疫狀態(tài)及服用環(huán)孢素、他克莫司及雷帕霉素的腎移植受者外周調(diào)節(jié)性B細胞亞群及功能變化,探討B(tài)細胞在建立并維持腎移植免疫耐受中所起的作用及其初步機制。 方法：利用造血干細胞聯(lián)合腎臟移植的新方案,對符合條件的腎移植受者進行免疫耐受誘導。將腎移植受者分為接受造血干細胞聯(lián)合腎臟移植免疫耐受誘導組(TOL)、傳統(tǒng)方案移植腎功能穩(wěn)定組(STA)、傳統(tǒng)方案急排組(AR)、傳統(tǒng)方案慢性移植物腎病組(CR)及腎移植術后感染組(INF),另設健康對照組(HC)。縱向比較BAFF在TOL受者術后不同時間點的差異,并橫向比較其在不同組之間的水平：分析不同組間潛在調(diào)節(jié)性B細胞亞群及B細胞分泌IL-10的潛能,探討B(tài)細胞的活化、重建及調(diào)節(jié)性B細胞對移植受者術后免疫耐受建立及維持的作用及其機制。并通過觀察服用環(huán)孢素(CsA組)、他克莫司(FK506組)、雷帕霉素(Rap組)移植腎功能穩(wěn)定受者外周血調(diào)節(jié)性B細胞亞群的比例,明晰環(huán)孢素、他克莫司、雷帕霉素對移植受者外周調(diào)節(jié)性B細胞的影響。 結(jié)果：移植術后TOL組BAFF水平顯著高于接受傳統(tǒng)方案受者,且這一差異可持續(xù)至術后一年。TOL受者及健康志愿者外周血B細胞水平顯著高于AR組、CR組及STA組受者。這兩組患者中,CD19+CD24hiCD27+及CD19+CD24hiCD38hi表型B細胞占全B細胞比例明顯高于其它組。發(fā)現(xiàn)在TOL及健康志愿者體內(nèi),外周血B細胞具有較高分泌抑制性細胞因子IL-10的能力。需要指出的是,雖然TOL及健康志愿者組內(nèi)CD19+CD24hiCD38hiIL-10+及CD19+CD24hiCD27+IL-10+B細胞比例較其它組高,但由于其僅占這兩群細胞的一小部分,因此仍不能確定分泌IL-10的B細胞的特定表型。進一步分析環(huán)孢素、他克莫司、雷帕霉素對移植穩(wěn)定受者外周血B細胞亞型影響,發(fā)現(xiàn)服用雷帕霉素的腎移植受者CD19+CD24hiCD27+及CD19+CD24hiCD38hi亞型B細胞比例較之服用FK506及CsA等CNI類受者顯著升高。 結(jié)論：本研究提示B細胞的活化、增殖可能參與了造血干細胞聯(lián)合腎臟移植后免疫耐受的建立；多種B細胞亞型包括CD19+CD24hiCD27+及CD19+CD24hiCD38hi與免疫耐受狀態(tài)的維持關系密切,可能是潛在的調(diào)節(jié)性B細胞表型。雖然調(diào)節(jié)性B細胞具有較大的異質(zhì)性,但分泌具有免疫調(diào)節(jié)作用的細胞因子IL-10可能是調(diào)節(jié)性B細胞參與免疫調(diào)節(jié)與耐受建立的途徑之一。本研究還進一步表明雷帕霉素作為具有誘導外周耐受的免疫抑制劑,可增高外周調(diào)節(jié)性B細胞亞型比例,提示其還可能通過影響B(tài)細胞功能,促進免疫耐受的建立。
[Abstract]:Objective: to study the dynamic changes of B cell activating factor (BAFFF) in peripheral blood of recipients and to compare the immune status and cyclosporine administration by inducing the receptor to develop immune tolerance by combined transplantation of hematopoietic stem cells and kidney, and to study the dynamic changes of B cell activating factor (BAFFF) in peripheral blood of recipients. The changes of peripheral regulatory B cell subsets and their functions in renal transplantation recipients of tacrolimus and rapamycin were studied to investigate the role of B cells in the establishment and maintenance of immune tolerance in renal transplantation. Methods: using a new regimen of hematopoietic stem cells combined with kidney transplantation, The recipients of renal transplantation were divided into three groups: hemopoietic stem cells combined with kidney transplantation immune tolerance induction group (Tol), renal transplantation stable group with traditional regimen, ARA group with acute renal transplantation, and the renal transplantation recipients were divided into three groups: one group received hematopoietic stem cells combined with kidney transplantation immune tolerance induction group, the other was the group with stable renal function. Chronic graft nephropathy (CRT) and infection after renal transplantation (infra) were performed in the traditional regimen, and a healthy control group was set up. The difference of BAFF in different time points after TOL operation was compared longitudinally. The potential regulatory B cell subsets and the potential of B cells to secrete IL-10 were analyzed, and the activation of B cells was discussed. The effects and mechanisms of reconstructed and regulated B cells on the establishment and maintenance of immune tolerance after transplantation were observed in patients receiving CSA, tacrolimus FK506, rapamycin Rap). Percentage of B cell subsets in peripheral blood, Understand the effects of cyclosporine, tacrolimus, rapamycin on peripheral regulatory B cells in transplant recipients. Results: the level of BAFF in TOL group after transplantation was significantly higher than that in recipients of traditional regimen. The level of B cells in peripheral blood of Tol recipients and healthy volunteers was significantly higher than that of AR group, CR group and STA group, and the percentage of CD19 CD24hiCD27 and CD19 CD24hiCD38hi phenotype B cells was significantly higher in these two groups than in AR group and STA group. In other groups. Found in TOL and healthy volunteers, It should be pointed out that although the proportion of CD19 CD24hiCD38hiIL-10 and CD19 CD24hiCD27 IL-10 B cells in TOL and healthy volunteers is higher than that in other groups, they only account for a small part of these two groups. Therefore, the specific phenotype of B cells secreting IL-10 can not be determined. Further analysis of the effects of cyclosporine, tacrolimus, rapamycin on the B cell subtypes in peripheral blood of stable recipients, It was found that the percentage of B cells in CD19 CD24hiCD27 and CD19 CD24hiCD38hi subtypes in renal transplant recipients taking rapamycin was significantly higher than that in CNI recipients such as FK506 and CsA. Conclusion: this study suggests that the activation and proliferation of B cells may be involved in the establishment of immune tolerance after hematopoietic stem cells combined with renal transplantation, and that several B cell subtypes, including CD19 CD24hiCD27 and CD19 CD24hiCD38hi, are closely related to the maintenance of immune tolerance. It may be a potential regulatory B cell phenotype. Although regulatory B cells have greater heterogeneity, However, the secretion of cytokine IL-10 with immunomodulatory effect may be one of the ways for regulatory B cells to participate in the establishment of immunomodulation and tolerance. This study further indicates that rapamycin is an immunosuppressant with induction of peripheral tolerance. It can increase the proportion of peripheral regulatory B cell subtypes, suggesting that it may also promote the establishment of immune tolerance by affecting the function of B cells.
【學位授予單位】：復旦大學
【學位級別】：博士
【學位授予年份】：2012
【分類號】：R392.4

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