外源性激素对异种移植后人胎卵巢组织的影响

目的:探讨外源性促性腺激素对异种移植后的冻融人胎卵巢组织卵泡发育的影响。方法:将冻融人胎卵巢组织移植到裸鼠肾被膜下,裸鼠随机分为A、B、C 3组,分别以不同方式给予外源性促性腺激素—孕马血清促性腺激素(PMSG),并分别于术后10~14周、18~22周、26~30周回收移植物,行组织学评价和增殖细胞核抗原(PCNA)免疫组织化学分析。结果:10~14周和18~22周各组的原始、初级、次级卵泡数之间差异均无统计学意义(P>0.05)。26~30周,A、B组次级卵泡数显著高于C组,差异均有统计学意义(P<0.05)。各组均可见窦卵泡发育。结论:冻融人胎卵巢组织异种移植于雌性去势裸鼠后,无外源性激素作用环境下卵泡也可发育至窦卵泡;而不同方式的外源性促性腺激素作用均可进一步促进组织中卵泡的发育。     

Preoperative Depletion of C3 Improves the Survival of Guinea Pig-to-Rat Cardiac Xenograft Recipients

Rat strains with congenitally reduced total hemolytic complement activity do not reject cardiac xenografts hyperacutely. Prolongation of graft survival in the guinea pig-to-C6-deficient PVG rat donor/recipient combination has been observed. However, experience with this model has been complicated by a high postoperative mortality from respiratory distress. The authors hypothesized that placement of the xenograft resulted in local activation of complement, which contributed to remote pulmonary injury leading to respiratory dysfunction. To test this hypothesis, an attempt was made to reduce early complement component activation with the use of an antibody to rat C3 in C6-deficient PVG recipients. Six of eight untreated C6-deficient PVG recipients died in the immediate postoperative period with vigorously beating heart grafts, whereas only 2 of 14 C6-deficient recipients pretreated with anti-rat C3 antibody died within 24 h postoperatively. Although pretreatment with antiC3 antibody improved survival of recipients, the duration of cardiac xenograft survival was similar whether the recipients were pretreated or not. The use of anti-C3 antibody in C6-deficient rats is a valid approach to studying xenotransplantation in the absence of hyperacute rejection and has an additional advantage in that it does not require the use of expensive reagents such as cobra venom factor.     

Pig-to-baboon lung xenotransplantation: Extended survival with targeted genetic modifications and pharmacologic treatments

Galactosyl transferase knock-out pig lungs fail rapidly in baboons. Based on previously identified lung xenograft injury mechanisms, additional expression of human complement and coagulation pathway regulatory proteins, anti-inflammatory enzymes and self-recognition receptors, and knock-down of the β4Gal xenoantigen were tested in various combinations. Transient life-supporting GalTKO.hCD46 lung function was consistently observed in association with either hEPCR (n = 15), hTBM (n = 4), or hEPCR.hTFPI (n = 11), but the loss of vascular barrier function in the xenograft and systemic inflammation in the recipient typically occurred within 24 h. Co-expression of hEPCR and hTBM (n = 11) and additionally blocking multiple pro-inflammatory innate and adaptive immune mechanisms was more consistently associated with survival >1 day, with one recipient surviving for 31 days. Combining targeted genetic modifications to the lung xenograft with selective innate and adaptive immune suppression enables prolonged initial life-supporting lung function and extends lung xenograft recipient survival, and illustrates residual barriers and candidate treatment strategies that may enable the clinical application of other organ xenografts.     

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes – Chapter 1: update on national regulatory frameworks pertinent to clinical islet xenotransplantation

Islet xenotransplantation represents an attractive solution to overcome the shortage of human islets for use in type 1 diabetes. The wide‐scale application of clinical islet xenotransplantation, however, requires that such a procedure takes place in a specifically and tightly regulated environment. With a view to promoting the safe application of clinical islet xenotransplantation, a few years ago the International Xenotransplantation Association (IXA) published a Consensus Statement that outlined the key ethical and regulatory requirements to be satisfied before the initiation of xenotransplantation studies in diabetic patients. This earlier IXA Statement also documented a disparate regulatory landscape among different geographical areas. This situation clearly fell short of the 2004 World Health Assembly Resolution WHA57.18 that urged Member States “to cooperate in the formulation of recommendations and guidelines to harmonize global practices” to ensure the highest ethical and regulatory standards on a global scale. In this new IXA report, IXA members who are active in xenotransplantation research in their respective geographic areas herewith briefly describe changes in the regulatory frameworks that have taken place in the intervening period in the various geographic areas or countries. The key reassuring take‐home message of the present report is that many countries have embraced the encouragement of the WHO to harmonize the procedures in a more global scale. Indeed, important regulatory changes have taken place or are in progress in several geographic areas that include Europe, Korea, Japan, and China. Such significant regulatory changes encompass the most diverse facets of the clinical application of xenotransplantation and comprise ethical aspects, source animals and product specifications, study supervision, sample archiving, patient follow‐up and even insurance coverage in some legislations. All these measures are expected to provide a better care and protection of recipients of xenotransplants but also a higher safety profile to xenotransplantation procedures with an ultimate net gain in terms of international public health.     

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes—Chapter 4: pre‐clinical efficacy and complication data required to justify a clinical trial

In 2009, the International Xenotransplantation Association (IXA) published a consensus document that provided guidelines and “recommendations” (not regulations) for those contemplating clinical trials of porcine islet transplantation. These guidelines included the IXA's opinion on what constituted “rigorous pre‐clinical studies using the most relevant animal models” and were based on “non‐human primate testing.” We now report our discussion following a careful review of the 2009 guidelines as they relate to pre‐clinical testing. In summary, we do not believe there is a need to greatly modify the conclusions and recommendations of the original consensus document. Pre‐clinical studies should be sufficiently rigorous to provide optimism that a clinical trial is likely to be safe and has a realistic chance of success, but need not be so demanding that success might only be achieved by very prolonged experimentation, as this would not be in the interests of patients whose quality of life might benefit immensely from a successful islet xenotransplant. We believe these guidelines will be of benefit to both investigators planning a clinical trial and to institutions and regulatory authorities considering a proposal for a clinical trial. In addition, we suggest consideration should be given to establishing an IXA Clinical Trial Advisory Committee that would be available to advise (but not regulate) researchers considering initiating a clinical trial of xenotransplantation.