调节性B细胞与肾移植免疫状态关系及其机制的研究

发布时间：2018-03-10 13:06

本文选题：B细胞　切入点：调节性B细胞　出处：《复旦大学》2012年博士论文　论文类型：学位论文

【摘要】：目的：通过造血干细胞与肾脏联合移植来诱导受体产生对移植肾免疫耐受,研究受者外周血B细胞活化因子(BAFF)动态变化,并比较不同免疫状态及服用环孢素、他克莫司及雷帕霉素的肾移植受者外周调节性B细胞亚群及功能变化,探讨B细胞在建立并维持肾移植免疫耐受中所起的作用及其初步机制。方法：利用造血干细胞联合肾脏移植的新方案,对符合条件的肾移植受者进行免疫耐受诱导。将肾移植受者分为接受造血干细胞联合肾脏移植免疫耐受诱导组(TOL)、传统方案移植肾功能稳定组(STA)、传统方案急排组(AR)、传统方案慢性移植物肾病组(CR)及肾移植术后感染组(INF),另设健康对照组(HC)。纵向比较BAFF在TOL受者术后不同时间点的差异,并横向比较其在不同组之间的水平：分析不同组间潜在调节性B细胞亚群及B细胞分泌IL-10的潜能,探讨B细胞的活化、重建及调节性B细胞对移植受者术后免疫耐受建立及维持的作用及其机制。并通过观察服用环孢素(CsA组)、他克莫司(FK506组)、雷帕霉素(Rap组)移植肾功能稳定受者外周血调节性B细胞亚群的比例,明晰环孢素、他克莫司、雷帕霉素对移植受者外周调节性B细胞的影响。结果：移植术后TOL组BAFF水平显著高于接受传统方案受者,且这一差异可持续至术后一年。TOL受者及健康志愿者外周血B细胞水平显著高于AR组、CR组及STA组受者。这两组患者中,CD19+CD24hiCD27+及CD19+CD24hiCD38hi表型B细胞占全B细胞比例明显高于其它组。发现在TOL及健康志愿者体内,外周血B细胞具有较高分泌抑制性细胞因子IL-10的能力。需要指出的是,虽然TOL及健康志愿者组内CD19+CD24hiCD38hiIL-10+及CD19+CD24hiCD27+IL-10+B细胞比例较其它组高,但由于其仅占这两群细胞的一小部分,因此仍不能确定分泌IL-10的B细胞的特定表型。进一步分析环孢素、他克莫司、雷帕霉素对移植稳定受者外周血B细胞亚型影响,发现服用雷帕霉素的肾移植受者CD19+CD24hiCD27+及CD19+CD24hiCD38hi亚型B细胞比例较之服用FK506及CsA等CNI类受者显著升高。结论：本研究提示B细胞的活化、增殖可能参与了造血干细胞联合肾脏移植后免疫耐受的建立；多种B细胞亚型包括CD19+CD24hiCD27+及CD19+CD24hiCD38hi与免疫耐受状态的维持关系密切,可能是潜在的调节性B细胞表型。虽然调节性B细胞具有较大的异质性,但分泌具有免疫调节作用的细胞因子IL-10可能是调节性B细胞参与免疫调节与耐受建立的途径之一。本研究还进一步表明雷帕霉素作为具有诱导外周耐受的免疫抑制剂,可增高外周调节性B细胞亚型比例,提示其还可能通过影响B细胞功能,促进免疫耐受的建立。
[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.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R392.4

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