肾移植术后微嵌合状态与免疫耐受的关系

诱导免疫耐受控制移植物排斥一直是器官移植界所面临的一大难题，故耐受诱导方案的研究成为移植免疫研究的焦点；自1969年微嵌合学说提出以来，引起了移植界的广泛兴趣，但至今仍存在很多争议。本文就微嵌合学说及其与免疫耐受关系的研究作一介绍。     

树突状细胞与移植免疫耐受

树突状细胞 (ＤＣ)是目前已知功能最强的专职抗原递呈细胞。它最大的特点是捕获外来抗原 ,迁移至引流淋巴结 ,发育成熟并递呈抗原 ,启动和诱导Ｔ细胞分化产生免疫反应或直接激活Ｂ细胞及产生免疫记忆[1] ,因此ＤＣ是免疫应答的始动者。本文就近两年ＤＣ与免疫耐受的关系作一综述。一、树突状细胞亚群ＤＣ是一异质的细胞群体 ,其异质性主要表现在不同的细胞起源、不同的成熟状态和功能方面[2 ] 。细胞起源和成熟程度差异决定着ＤＣ的不同功能 ,这与免疫耐受诱导有着十分密切的关系。根据ＤＣ表面蛋白质分子 ,可将源于小鼠骨髓和胸腺或淋巴器…     

微嵌合体诱导移植免疫耐受的研究进展

目前器官移植已经成为终末期器官功能衰竭患者的有效治疗手段,但是排斥反应仍然是器官移植术后早期功能障碍的最常见原因.通过新型免疫抑制剂的使用,可以使急性排斥反应的发生率明显下降,但同时会引起患者许多不良反应,而且免疫抑制剂对于移植慢性排斥反应和移植物的长期存活率无明显改善.     

微嵌合体在移植免疫耐受中的研究进展

微嵌合体及其与移植免疫耐受之间的关系已经成为目前器官移植研究领域的热点之一。微嵌合体的存在常提示受者对移植器官产生耐受,但是微嵌合体在免疫耐受中的真正作用目前尚存在争议。本文从7个方面对微嵌合体的相关研究进行综述。     

移植免疫耐受的研究进展

诱导对移植物的特异性耐受是解决器官移植中排斥反应的理想方法之一，本文综述了器官移植中免疫耐受的机制及诱导和维持免疫耐受的方法。     

同种异体器官移植联合造血干细胞移植与免疫耐受

过去10年,我们对移植免疫排斥机制的理解有了很大提高.在一些同种异体器官移植联合造血干细胞移植的病例,不用免疫抑制剂治疗,受体对移植物仍然保持长期免疫耐受,有作者把这一耐受现象归功于联合了造血干细胞移植.本文就从对这些案例的分析出发,回顾同种异体器官移植后供体特异性移植耐受形成的理论基础和历史沿革,最后阐明供体特异性移植耐受与造血干细胞移植之间并没有直接联系.     

致耐受树突状细胞与移植免疫耐受

致耐受树突状细胞（tolerogenic dendriticcell，Tol DC）有多种细胞亚型，在诱导移植外周免疫耐受中起重要作用。不同来源DC以及DC的不同成熟阶段都可能有致耐受特性。Tol DC诱导免疫耐受的机制主要与T细胞无能或凋亡、Treg细胞增殖和Th1／Th2细胞偏移有关。已有多种方法体外获得Tol DC。     

免疫耐受与移植

本文概述了通过主动诱导、阻断免疫应答和建立白细胞微嵌合体诱导耐受的最新进展。细胞毒性T细胞相关抗原4(CTLA4)可通过阻断共刺激使T细胞无能,诱导耐受。IL-4和IL-10是T辅助细胞(Th)2细胞因子,能诱使免疫向Th2方向偏离,促进耐受形成;IL-10也是细胞因子合成抑制因子,可通过抑制宿主抗原提呈细胞抑制免疫。重点阐述了CTLA4和IL-4、IL-10的作用机制和研究现状,各种诱导方法的联合应用及其在异种移植中的具体实施。在用CTLA4成功诱导同种异体骨移植耐受的基础上,探讨了异种骨移植的特点,以及通过诱导免疫耐受防止异种骨移植排斥的可行性。     

免疫耐受的研究进展

免疫耐受是器官移植领域中重要课题。本文各种免疫耐受现象、机理、诱导方法和临床应用情况进行简述。     

Clinical Operational Tolerance After Solid Organ Transplantation

Clinical operational tolerance (COT) is a clinical condition obtainable with difficulty after solid organ transplantation (SOT). It is characterized by perfectly normal graft function in the total absence of maintenance immunosuppression. Major benefits deriving from the onset of COT are the reduction of risk for immunosuppression-related side effects and the improved quality of life. Currently, COT can be safely achieved in stable liver transplant recipients; it remains a challenge after renal transplantation. Only 1 case of COT has been reported after lung transplantation; no cases have been described after other types of SOT. Overall, mechanisms of COT are unclear and strategies to induce COT cannot be applied on a regular base to a large cohort of SOT recipients. Due to the failure of molecularly based tolerogenic protocols, great hope relies in the adoption of cell-based strategies.     

Predictors of Organ Allograft Tolerance Following Hematopoietic Cell Transplantation

Using the miniature swine large animal model we have attempted to determine the relationship between tolerance and the presence of donor cells in the bone marrow, thymus and lineages of peripheral blood in a series of hematopoietic cell transplant recipients receiving delayed donor allografts without immunosuppression. Twenty-two animals receiving hematopoietic cell transplantation and a delayed organ allograft were analyzed. Assays for presence of donor CFUs in bone marrow (by PCR), thymic chimerism (by FACS and PCR/Southern Blot), peripheral blood chimerism (by FACS), and in vitro responsiveness to donor MHC were performed. Presence of donor BM CFUs, thymic chimerism and multilineage peripheral blood chimerism at the time of organ transplantation all correlated precisely with subsequent allograft tolerance (p < 0.001, p < 0.001, p < 0.005 respectively). These parameters were therefore accurate predictors (Positive Predictive Value (PPV) = 100% in all) of tolerance. In vitro assays of responsiveness were also highly associated (p < 0.002, p < 0.002 respectively), but were not as accurate predictors of subsequent organ tolerance (CML PPV = 80%). Engraftment, as indicated by the presence of donor derived CFU in the bone marrow, detectable thymic chimerism and multilineage peripheral blood chimerism are reliable predictors of subsequent donor allograft acceptance in hematopoietic cell transplant recipients.     

Early Microchimerism in Peripheral Blood Following Kidney Transplantation

Background

The role of microchimerism found in the peripheral blood of renal transplant recipients remains a matter of debate. We assessed the frequency of microchimerism after kidney transplantation and examined its influence on clinical courses over a 12-month follow-up period.

Patients and Methods

Ten single-kidney recipients underwent microchimerism detection at 2 days, 2 weeks, and 1, 3, 6, and 12 months after transplantation, with mismatch human leukocyte antigen (HLA)-A, -B, and -C used as markers.

Results

Microchimerism was detected in 8 (80%) patients at 2 days after kidney transplantation. In 3 of those, microchimerism became negative within 3 months after transplantation, whereas it remained present for up to 12 months in 3 patients (33 %). There was 1 acute rejection episode in a patient in whom microchimerism became negative within 3 months. Protocol renal graft biopsy specimens obtained 3 months after transplantation revealed no acute cellular-mediated rejection (ACMR) or acute antibody-mediated rejection (AAMR) in the 5 patients positive for microchimerism at 3 months.

Conclusions

Microchimerism was frequently detected after kidney transplantation. Microchimerism that remained for more than 3 months post-transplantation might be correlated with a lower incidence of rejection, thus its monitoring may help identify recipients with a low rejection risk.     

Induction of Tolerance in Solid Organ Transplantation: The Rationale to Develop Clinical Protocols in Liver Transplantation

Minimization or withdrawal of immunosuppressive treatments after organ transplantation represents a major objective for improving quality of life and long-term survival of grafted patients. Such a goal may be reached under some clinical conditions, particularly in liver transplantation, making these patients good candidates for tolerance trials. In this context in liver transplantation, the central questions are (1) how to promote the natural propensity of the liver graft to be accepted, (2) which type of immunosuppressive drug should be used for induction and maintenance, and (3) which biomarkers could be used to discriminate tolerant patients from those requiring long-term immunosuppression. Induction therapies using aggressive T-cell-depleting agents may favor graft acceptance. However, persistent and/or rapidly reemerging cell lines, such as memory-type cells or CD8⁺ T cells, could represent a significant barrier for induction of tolerance. The type of maintenance drugs also remains questionable. Calcineurin inhibitors may be eventually deleterious in the context of tolerance protocols, through inhibitory effects on regulatory T cells, that are not observed with rapamycin. In conclusion, significant efforts must be made to achieve reliable strategies for immunosuppression minimization or withdrawal after organ transplantation into the clinics.     

Virologic and Immunologic Monitoring of Cytomegalovirus to Guide Preemptive Therapy in Solid‐Organ Transplantation

Control of human cytomegalovirus (HCMV) infection during the posttransplant period was investigated in 134 solid‐organ transplant recipients by monitoring in parallel virologic and immunologic parameters for at least 1 year of follow‐up. Virologic monitoring was achieved by determining HCMV DNAemia with real‐time PCR, using the threshold of 300 000 DNA copies/mL blood as a cutoff for starting preemptive therapy. Immunologic monitoring included measurement of HCMV‐specific CD4+ and CD8+ T cells by cytokine flow cytometry, using HCMV‐infected dendritic cells as a stimulus. HCMV infection was diagnosed in 110 (82%) and required treatment in 49 (36%) patients. At 12 months after transplantation ‘protective’ immunity (≥0.4 CD4+ and CD8+ HCMV‐specific T cells/μL blood) was achieved in 115/129 (89%) patients. During the entire study period, 122 patients reconstituting HCMV‐specific CD4+ and CD8+ T‐cell immunity at 60 days posttransplant onward were able to control HCMV infection, except for one patient who developed HCMV disease because of a rejection episode. Patients reconstituting HCMV‐specific CD8+ only did not control HCMV infection. In conclusion, the presence of both HCMV‐specific CD4+ and CD8+ T cells ≥ 0.4/μL blood appears to be protective against HCMV disease. This result does not apply to patients undergoing antirejection treatment, or reconstituting HCMV‐specific CD8+ T cells only.     

Infection in Organ Transplantation

The prevention, diagnosis, and management of infectious disease in transplantation are major contributors to improved outcomes in organ transplantation. The risk of serious infections in organ recipients is determined by interactions between the patient's epidemiological exposures and net state of immune suppression. In organ recipients, there is a significant incidence of drug toxicity and a propensity for drug interactions with immunosuppressive agents used to maintain graft function. Thus, every effort must be made to establish specific microbiologic diagnoses to optimize therapy. A timeline can be created to develop a differential diagnosis of infection in transplantation based on common patterns of infectious exposures, immunosuppressive management, and antimicrobial prophylaxis. Application of quantitative molecular microbial assays and advanced antimicrobial therapies have advanced care. Pathogen‐specific immunity, genetic polymorphisms in immune responses, and dynamic interactions between the microbiome and the risk of infection are beginning to be explored. The role of infection in the stimulation of alloimmune responses awaits further definition. Major hurdles include the shifting worldwide epidemiology of infections, increasing antimicrobial resistance, suboptimal assays for the microbiologic screening of organ donors, and virus‐associated malignancies. Transplant infectious disease remains a key to the clinical and scientific investigation of organ transplantation.     

Organ Transplantation in Taiwan

Abstract: We performed the first successful kidney transplantation in Taiwan on May 27, 1968. Since then, kidney, heart, lung, pancreas, liver, and heart-kidney transplantations have been increasingly successful in restoring lives of otherwise dying patients with organ failure. The first successful kidney, liver, and heart transplantations in Asia were achieved in Taiwan in 1968, 1984, and 1987, respectively. Individual organ transplantation, organ transplant recipient survival, graft survival, and problems and pitfalls encountered in the care of organ transplantation recipients are analyzed. Using polymerase chain reaction amplification with sequence-specific primers, donor-specific DNA was detected in the peripheral blood of the patient who survived the longest (26 years) in this series. Interestingly enough, recently, we had a patient undergoing cadaveric renal transplantation in whom chi-merism was detected in her lymph nodes and skin only 3 years after transplantation. Organ procurement in Taiwan is the greatest problem, and we have been exerting our maximal effort to establish a transplantation coordination team to create a central network and to educate, procure, preserve, distribute, and increase the availability of organs and tissues for transplantation.