几种微生物来源的免疫抑制药在眼角膜移植中的应用

角膜移植是众多器官和组织移植中成功率最高的。然而对于角膜严重血管化、重复移植、全角膜移植患者,角膜植片发生免疫排斥反应的机率高达60%~65%,导致植片混浊、视力下降,手术失败。抑制角膜移植排斥反应的方法目前仍以免疫抑制剂药为主。到目前为止,有近30种不同微生物来源的     

雷帕霉素微乳滴眼剂的制备及其在大鼠角膜移植排斥反应的应用

目的 制备雷帕霉素微乳滴眼剂,评价其抑制大鼠角膜移植排斥反应的疗效.方法 采用微乳制备方法,研制雷帕霉素微乳滴眼剂;通过大鼠双眼滴加药液进行粘膜刺激性试验和对大鼠角膜移植排斥反应的作用,评价雷帕霉素微乳滴眼液治疗大鼠角膜移植的效果.结果 雷帕霉素微乳滴眼剂为透明或半透明的淡蓝色均一溶液,其平均粒径129.5nm,对粘膜刺激性小;有效减少角膜移植排斥反应的发生,显著延长角膜植片的存活时间.结论 雷帕霉素微乳滴眼剂能够用于治疗大鼠角膜移植手术后的排斥反应.     

环孢素A滴眼液防治兔角膜移植术后的免疫排斥反应

目的:观察环孢素A(CsA)滴眼液对兔角膜移植术后免疫排斥反应的影响。方法:20只日本大耳白兔随机分成CsA联合妥布霉素组和妥布霉素对照组,每组10只。建立左眼角膜碱烧伤型动物模型,15 d后实施同种异体角膜移植术,术后治疗组给予1%CsA滴眼液联合0．3%妥布霉素滴眼液各1～2滴,对照组给予0．3%妥布霉素滴眼液1～2滴;每日滴3次,共30 d。观察移植术后角膜水肿情况及植片透明情况等,计算排斥反应指数(RI),并测定用药30 d后兔的肝、肾功能生化指标。结果:对照组角膜植片先后出现不同程度水肿混浊,角膜新生血管增加,RI为6．96±2．12;治疗组角膜植片基本透明,RI为5．28±1．69,显著低于对照组(P＜0．05)。两组肝肾功能均无明显变化。结论:1%CsA滴眼液能够有效地抑制兔角膜移植术后免疫排斥反应的发生。     

环孢素A滴眼液在角膜移植免疫排斥中应用观察

目的探讨环孢素A（CsA）滴眼液应用于角膜移植手术后防治角膜移植排斥反应的疗效。方法对在我院施行穿透性角膜移植术的33例（33眼）病例,术后7d33眼均应用1％CsA滴眼液和妥布霉素地塞米松滴眼液至6个月。结果角膜移植术后出现角膜排斥反应有6例（6眼）,经治疗有5例（5眼）植片排斥反应得到控制,植片恢复透明,有效率83．3％。结论证明在角膜移植求后应用1％CsA滴眼液防治角膜移植排斥反应确实有效。     

小鼠视网膜神经上皮层移植后诱发免疫排斥和赦免反应的观察

目的　观察眼内不同部位移植视网膜神经上皮层后诱发的免疫排斥 /赦免反应。方法　将新生小鼠视网膜神经上皮层分离后移植到受鼠眼结膜下、玻璃体腔和视网膜下间隙 ,术后 2、6、12、18、35 d用光镜观察移植物的存活 /排斥情况。结果　位于结膜下移植物 2 d内发生排斥反应 ,而位于玻璃体腔和视网膜下间隙的移植物不仅未被排斥 ,而且能进一步生长发育。结论　玻璃体腔和视网膜下间隙是免疫赦免区     

抗排斥新卫士

目前，造成角膜移植失败的最主要原因是术后免疫排斥反应，尤其是在二次移植、有新生血管化植床等高危因素的患者中，术后近期的免疫排斥发生率高达50％～90％。尽管这些患者术后已常规使用免疫抑制剂，但术后1年的移植物存活率仍不超过10％。因此，术后的免疫排斥问题已严重影响和阻碍了移植科学的发展。     

受体血清保存植片角膜移植术后排斥反应的实验研究

目的和方法：通过建立兔穿透性角膜移植（PKP）模型，对在受体血清和Hanks液分别进行了24h和72h保存后的兔角膜植片PKP术后的排斥反应指数（RI）进行比较，对受体血清保存的植片能否减轻排斥反应作出 初步的评价。结果：72h保存组的RI明显低于其余3组，而血清和Hanks液两之间保存时间相同的情况下，差异无显著性。结论：支持植片保存液24h公上保存比24h以内者排斥反应发生率低的假说；不支持受体血清保存植片能较其它保存方法减少PKP术后排斥反应率的论断。     

他克莫司滴眼液抑制家兔全角膜移植免疫排斥反应

目的通过家兔全角膜移植动物实验,考察他克莫司滴眼液抑制家兔角膜移植免疫排斥反应的量效关系,为他克莫司滴眼液的临床应用提供实验依据。方法建立家兔全角膜移植排斥反应模型,随机分成A组、B组、C组、D组、E组和F组。其中A组为溶剂对照组,B组、C组、D组、E组质量分数分别为0.01%、0.025%、0.05%、0.1%的他克莫司滴眼液,F组为环孢霉A滴眼液。用裂隙灯记录比较各组排斥反应指数(rejection index,RI)和植片存活时间,连续给药28 d后摘取角膜进行组织学检查。结果术后B组、C组、D组、E组和F组各组与A组比较,角膜植片RI和植片存活时间均有显著差异(P<0.05或P<0.01),呈剂量-效应关系,淋巴细胞浸润及新生血管生成均明显减少。结论质量分数0.05%的他克莫司滴眼液可抑制家兔全角膜移植免疫排斥反应。     

LX201获快速通道审批地位

美国FDA授予LuxBiosciences公司用于预防角膜移植排斥的LX201（I）快速通道审批地位。该产品是置于眼睑下方的眼内植入物，它将在一年内稳定地向眼内释放环孢素A（ciclosporinA）（Ⅱ）（已经用于预防肾以及其它实体器官移植的排斥）。（I）的两项重要的为期一年的Ⅲ期临床试验是LUCIDA项目的一部分，目前正在进行中。第一项试验在175例免疫排斥高危的患者中进行，以免疫排斥和移植物丧失为主要终点。第二项试验涉及240例在角膜移植后经历了排斥事件的受试者，以移植后52周内免疫性的移植物排斥事件或移植失败为主要终点。     

他克莫司滴眼液对高危角膜移植术后免疫排斥反应的影响观察

摘要：目的:观察他克莫司滴眼液在预防高危角膜移植术后免疫排斥反应中的作用。方法:眼科行高危角膜移植术患者98例(100眼)随机分为他克莫司组49例(50眼)、环孢素组49例(50眼)。他克莫司组术后局部应用0.1%他克莫司滴眼液环孢素组局部应用1%环孢素A滴眼液起始给药剂量均为1滴,qid,根据患者恢复情况调整剂量,连续给药12个月。分别于术后1 2,12个月时进行复查,记录免疫排斥反应发生情况,比较两组患者术后12个月的视力、眼压变化及眼部体征,包括角膜水肿、角膜基质混浊、角膜上皮缺损、角膜新生血管程度。结果:术后1个月,两组免疫排斥反应发生率比较差异无统计学意义(P>0.05),术后12个月,他克莫司组免疫排斥反应发生率(4.00%)明显低于环孢素组(26.00%)(P<0.05)。他克莫司组术后12个月的角膜水肿评分、角膜基质混浊评分、新生血管分布评分均优于环孢素组(P<0.05);两组最佳矫正视力比较,差异无统计学意义(P>0.05)。两组术后眼压升高例数与眼压范围比较差异均无统计学意义(P>0.05),未见其他相关并发症出现。他克莫司组的不良反应发生率低于环孢素组(P<0.05)。结论:0.1%他克莫司滴眼液用于高危角膜移植术后免疫排斥反应安全、有效,其短期预防作用与环孢素A滴眼液相当,长期预防作用优于环孢素A滴眼液。     

Patterns of graft and patient survival following renal transplantation and evaluation of serum creatinine as a predictor of survival: a review of data collected from one clinical centre over 34 years

ABSTRACT

Background: The pattern of renal transplantation has never been described since the introduction of the technique. The purpose of this study was therefore to characterise the pattern of renal transplantation from 1967 to 2000, focusing on renal graft function as a predictor of survival.

Methods: This study was a retrospective analysis of an electronic database. The setting was a single renal transplant centre in the United Kingdom covering a population of 2.2 million and included patients who received at least one renal transplant over the study period (?n = 1516). The main outcome measures were patient and graft survival, acute rejection episodes and patterns of graft function, as measured by creatinine levels.

Results: There were 559 (36.8%) female patients; 109 (7.2%) patients had pre-existing diabetes. Patient survival was adversely affected by increased age at transplant (?p < 0.001): 5‐year patient survival from first transplant was 82% for patients aged 0 to 17 years, 80% for 18 to 49 years and 61% for > 49 years. Pre-existing diabetes also adversely affected survival (?p < 0.01): 5‐year graft survival was 63% for patients with diabetes versus 74% for those without. Graft survival was significantly associated with serum creatinine levels recorded 1 year post-primary transplant (?p < 0.001) and with three or more acute rejection episodes (?p < 0.05). Neither gender nor diabetes status were statistically significant in predicting graft survival. The number of acute rejection episodes was significantly greater in patients with pre-existing diabetes than those without (61% versus 42%, respectively; p < 0.001). There were no differences in the number of acute rejection episodes occurring across age groups.

Conclusion: Patient and graft survival improved markedly over the 34‐year study period, although patient survival has changed little since 1990. Serum creatinine levels are a reliable predictor of graft survival.     

Tregs对同种异体牙移植免疫排斥反应的抑制作用

目的探讨Tregs对同种异体牙移植术后免疫排斥反应的抑制作用,提供一种免疫移植方法。方法免疫抑制剂Tregs给予白鼠尾巴静脉注射1周,建立白鼠同种异体牙移植模型,术后观察移植牙存活、排异发生率及程度。结果同种异体牙均诱发免疫排斥反应,但Tregs注射后免疫排斥反应的时间缓慢,组织切片存活时间显著延长(P<0.01)。结论使用免疫抑制剂是预防同种异体牙移植免疫排斥反应的有效方案,可以使同种异体牙移植免疫排斥反应延迟,存活时间延长。     

Pharmacotherapy of corneal transplantation

INTRODUCTION: Corneal transplantation is a surgical procedure in which damaged or diseased cornea is replaced by cadaveric corneal tissue. It is the most common form of solid-tissue transplantation in humans but its pharmacotherapy (in relation to graft rejection) has changed little for several decades. The mainstay of treatment of corneal graft rejection remains corticosteroids but these are variably effective and are associated with potentially serious adverse effects. Newer immunosuppressive drugs are increasingly being employed to manage high-risk grafts. However, these drugs are also not without side-effects, some of which can be severe and life-threatening. AREAS COVERED: This review outlines the corneal transplant procedure and the treatment options available in the management of transplant rejection. EXPERT OPINION: The surgical technique of corneal lamellar grafting has allowed for transplantation of smaller quantities of donor tissue to the recipient, thereby reducing the antigen load as a means of preventing a rejection episode. With greater understanding of the underlying molecular mechanisms involved in corneal transplant rejection pathology, potentially newer medications that will target specific cytokines or cells involved in rejection, whilst minimizing the potential side effects to the graft recipient, will be made available.     

Pharmacotherapy of corneal transplantation

Introduction: Corneal transplantation is a surgical procedure in which damaged or diseased cornea is replaced by cadaveric corneal tissue. It is the most common form of solid-tissue transplantation in humans but its pharmacotherapy (in relation to graft rejection) has changed little for several decades. The mainstay of treatment of corneal graft rejection remains corticosteroids but these are variably effective and are associated with potentially serious adverse effects. Newer immunosuppressive drugs are increasingly being employed to manage high-risk grafts. However, these drugs are also not without side-effects, some of which can be severe and life-threatening.

Areas covered: This review outlines the corneal transplant procedure and the treatment options available in the management of transplant rejection.

Expert opinion: The surgical technique of corneal lamellar grafting has allowed for transplantation of smaller quantities of donor tissue to the recipient, thereby reducing the antigen load as a means of preventing a rejection episode. With greater understanding of the underlying molecular mechanisms involved in corneal transplant rejection pathology, potentially newer medications that will target specific cytokines or cells involved in rejection, whilst minimizing the potential side effects to the graft recipient, will be made available.     

Towards graft-specific immune suppression: Gene therapy of the transplanted kidney

Kidney transplantation remains the best therapeutic option for patients with end-stage renal disease. Immunosuppressive therapy has largely resolved the issue of acute transplant rejection. However, because of its systemic nature, immunosuppressive therapy trades off efficacy against side-effects and its chronic use has been associated with severe infections and malignancy. Moreover, long-term survival of renal grafts did not change over the past twenty years. This situation may be improved by using gene therapy as an alternative or add-on strategy to the classic, systemic immune suppression. This review discusses gene therapy approaches in kidney transplantation by addressing the essentials of delivery vectors and by outlining strategies to achieve local immunosupression and allograft-specific tolerance, both in acute rejection and chronic transplant dysfunction. Employing such strategies, local suppression of the immune response and induction of transplantation-specific tolerance have been accomplished in experimental gene therapy. If successful in the clinical setting, gene therapy may (partially) substitute systemic, non-selective immunosuppressive medication, with a major impact on the quality of life and survival of the transplanted patients as well as on the waiting time for receiving a renal graft.     

Negative inotropic effect of selective AT2 receptor stimulation and its modulation by the endocardial endothelium

Kidney transplantation represents the therapy of choice for many patients with end-stage renal disease. However, the success of renal engraftment is hindered by a number of factors, the most important of which being adverse effects of systemic immunosuppressive therapy, chronic transplant dysfunction and a severe shortage of donor kidneys. Gene therapy approaches may provide valuable strategies in each of these areas. First, gene therapy holds the potential of local therapy, thus circumventing systemic side effects of chronic immunosuppression. Second, chronic transplant dysfunction may be addressed by innovative strategies to induce local immune tolerance, immune suppression and additional graft protecting mechanisms. Third, gene therapy may be instrumental in increasing the quality of the grafts by limiting ischemia-reperfusion injury, especially in non-heart beating donors, thereby expanding the donor pool. In this article, we give an overview of the current state of gene therapy in experimental models of kidney transplantation.     

Myeloid-derived suppressor cells in transplantation tolerance induction

Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous cells derived from bone marrow. These cells are developed from immature myeloid cells and have strong negative immunomodulatory effects. In the context of pathology (such as tumor, autoimmune disease, trauma, and burns), MDSCs accumulate around tumor and inflammatory tissues, where their main role is to inhibit the function of effector T cells and promote the recruitment of regulatory T cells. MDSCs can be used in organ transplantation to regulate the immune responses that participate in rejection of the transplanted organ. This effect is achieved by increasing the production of MDSCs in vivo or transfusion of MDSCs induced in vitro to establish immune tolerance and prolong the survival of the graft. In this review, we discuss the efficacy of MDSCs in a variety of transplantation studies as well as the induction of immune tolerance to prevent transplant rejection through the use of common clinical immunosuppressants combined with MDSCs.     

Administration of Antithymocyte Globulin (Rabbit) to Treat a Severe,Mixed Rejection Episode in a Pregnant Renal Transplant Recipient

Pregnancy in solid organ transplant recipients carries numerous risks to the mother such as increased risk of rejection, gestational diabetes mellitus, and preeclampsia. The developing fetus is subjected to risks such as birth defects, preterm delivery, and low birth weight. Typically, these risks can be managed through intensive, multidisciplinary prenatal care and a proper immunosuppressive regimen. In the setting of rejection, however, little data are available to suggest safe and effective treatment of acute cellular rejection, antibody‐mediated rejection, or mixed rejection episodes in the pregnant solid organ transplant recipient. We describe the first case, to our knowledge, in which antithymocyte globulin (rabbit) was used to successfully treat a pregnant renal transplant recipient who experienced a mixed rejection episode. A 22‐year‐old, African American woman with stage 6 chronic kidney disease received a deceased donor renal transplant after undergoing hemodialysis for 3 years. Her maintenance immunosuppressive regimen at the time of transplantation consisted of tacrolimus, prednisone, and mycophenolate mofetil. Despite counseling efforts on the importance of having a planned pregnancy after kidney transplantation so that her immunosuppressive medications could be optimized, the patient became pregnant 12 months later; her mycophenolate mofetil was changed to azathioprine to reduce the risk of fetal deformities or death. Three months later, the patient was admitted for biopsy of her transplanted kidney and was evaluated for possible kidney rejection. After confirmation of a mixed 1B acute cellular rejection and antibody‐mediated rejection episode, the patient decided to pursue resolution of her rejection episode and continue the pregnancy despite the potential risks to the fetus. She was treated with high‐dose corticosteroids, intravenous immunoglobulin, plasmapheresis, and antithymocyte globulin (rabbit). Twenty‐nine months after transplantation, the patient was induced and gave birth to a healthy baby boy. Our patient's case offers unique insight into the potential management of a rejection episode requiring aggressive immunosuppressive therapy. Although potent immunosuppressive therapies were successfully used in our patient, further studies are needed to make definitive recommendations regarding the use of such therapies for treatment of rejection episodes in pregnant solid organ transplant recipients. The risks and uncertainties of treating rejection episodes should always be discussed with and understood by the patient before an informed decision is made.     

移植途径对骨髓间充质干细胞调节小鼠心脏移植排斥反应的影响

目的 探讨不同途径注射骨髓间充质干细胞（BMSCs）对调节小鼠心脏移植排斥反应的影响。方法 BALB/c和C57小鼠分别作为供体和受体,建立颈部心脏移植模型,随机分为4组,每组12只,A组在移植成功后立即经移植心脏升主动脉注射C57来源绿色荧光BMSCs悬液30 μL（含1×106细胞）,B组同样时间点经移植心脏右心室腔内注射相同数量细胞,C组同样时间点移植心脏心肌内注射相同数量细胞,D组为空白对照组。移植后第7天各组处死4只小鼠,切取移植心脏,荧光显微镜下观察绿色荧光细胞的存活情况,HE染色观察移植心脏的病理学改变,流式细胞学检测移植物浸润白细胞中巨噬细胞的比例,其余8只小鼠用来观察移植心脏的存活时间。结果 术后第7天,仅A组移植心脏内可见绿色荧光细胞,病理学检测发现A组排斥反应受到明显抑制,心肌间质内细胞浸润明显减少,局灶性的心肌细胞损害,B组和C组移植心脏间质内可见多灶性淋巴细胞浸润并伴有心肌细胞变性坏死,而D组小鼠心脏见满视野大量白细胞浸润,心肌结构消失,心肌坏死。流式细胞学检测发现A组移植心脏内巨噬细胞的比例明显高于其他3组,A组的心脏存活时间明显长于其他3组。结论 BMSCs能减轻心脏移植排斥反应,动脉途径注射优于静脉和心肌局部注射途径,其机制可能与骨髓间充质干细胞在移植心脏内存活时间以及巨噬细胞比例增加有关。     

Current pharmacotherapeutical options for the prevention of kidney transplant rejection

Introduction: Advances in immunosuppression and medical care over the past years resulted in better short- and long-term graft survival following kidney transplantation. Novel potent immunosuppressive agents, combinations of proven substances and the steadily expanding knowledge on the pathophysiology of kidney transplant rejection allows the extension of donor and recipient criteria, including the usage of organs from ABO-incompatible and crossmatch-positive donors, to overcome the increasing problem of organ shortage.

Areas covered: Immunosuppressive regimens for the prevention of kidney transplant rejections with a focus on regimens aiming at calcineurin inhibitor or steroid minimization, withdrawal or avoidance. Prevention of antibody-mediated rejections in standard-risk and sensitized recipients, as well as newly introduced immunosuppressive substances are covered.

Expert opinion: Currently applied immunosuppressive regimens are associated with excellent short-term graft survival. However, the long-term outcomes of different regimens substantially differ with regard to potential side effects, graft function, rejection and sensitization rates. The adverse effects of effective immunosuppression must carefully be balanced against the benefit, e.g., prevention of the development of donor-specific human leukocyte antigen antibodies and chronic (antibody-mediated) rejection. The choice of the appropriate immunosuppressive regimen requires clinical experience and careful consideration of recipient and transplant characteristics to achieve an optimal long-term graft survival.