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41.
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.  相似文献   
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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.  相似文献   
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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.  相似文献   
45.
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.  相似文献   
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Neural transplantation is a promising therapeutic approach for neurodegenerative diseases; however, many patients receiving intracerebral fetal allografts exhibit signs of immunization to donor antigens that could compromise the graft. In this context, we intracerebrally transplanted mesencephalic pig xenografts into primates to identify a suitable strategy to enable long‐term cell survival, maturation, and differentiation. Parkinsonian primates received WT or CTLA4‐Ig transgenic porcine xenografts and different durations of peripheral immunosuppression to test whether systemic plus graft‐mediated local immunosuppression might avoid rejection. A striking recovery of spontaneous locomotion was observed in primates receiving systemic plus local immunosuppression for 6 mo. Recovery was associated with restoration of dopaminergic activity detected both by positron emission tomography imaging and histological examination. Local infiltration by T cells and CD80/86+ microglial cells expressing indoleamine 2,3‐dioxigenase were observed only in CTLA4‐Ig recipients. Results suggest that in this primate neurotransplantation model, peripheral immunosuppression is indispensable to achieve the long‐term survival of porcine neuronal xenografts that is required to study the beneficial immunomodulatory effect of local blockade of T cell costimulation.  相似文献   
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Xenotransplantation may be an alternative source of organs for patients with end-stage organ failure, but problems remain to be overcome. Five factors that are problematic are (a) a sustained systemic inflammatory response in the xenograft recipient, (b) thrombotic microangiopathy and disseminated intravascular coagulation, (c) ischemia-reperfusion injury, (d) complement activation, and (e) vascular endothelial cell injury. In xenotransplantation, histones, which are positively charged proteins, are released into the extracellular space from damaged and activated cells, cause cell and tissue damage, and act as danger/damage-associated molecular patterns (DAMPs) that mediate inflammation, coagulation disorders, an immune response, and cytotoxicity. We have previously demonstrated that serum histones increase after pig-to-baboon organ transplantation and infection. Treatment of the recipient with tocilizumab (interleukin-6 receptor blockade) reduces the level of serum histones and C-reactive protein. In this review, the potential role of extracellular histones in xenotransplantation is discussed, and we briefly summarize the relationship between extracellular histones and the inflammatory response, coagulation dysfunction, ischemia-reperfusion injury, the complement system, and vascular endothelial cell injury.  相似文献   
50.
Acute antibody-mediated rejection (AMR) early after transplant remains a challenge, both in allotransplantation and in xenotransplantation. We report the case of an early and severe acute AMR episode in a kidney transplant recipient that was successfully treated with upfront eculizumab. A 58-year-old woman had been on dialysis since 2014. She underwent a first kidney transplant in 2018 with primary non-function and received several blood transfusions. Postoperatively, she developed anti-HLA antibodies. One year later, she received a second allograft from a deceased donor. At day 0, there was only one preformed low-level donor-specific antibody (DSA) anti-DQ7. After initial excellent allograft function, serum creatinine increased on days 7-9, and this was associated with oligo-anuria. On day 7, there was an increase in her DSA anti-DQ7 and 4 de novo DSA had developed at high MFI values. Allograft biopsy showed severe active AMR with diffuse C4d deposits in peritubular capillaries. The early acute AMR episode was treated with upfront eculizumab administration (2 doses) with efficient CH50 blockade (< 10% CH50). Rituximab was also administered on day 12, and intravenous immunoglobulin (IVIG) was given over the following days. There was an excellent clinical response to eculizumab administration. Eculizumab administration rapidly reversed the acute AMR episode without the need for plasmapheresis. Rituximab and IVIG were also used as B-cell immunomodulators to decrease DSA. Blocking efficiently the terminal complement pathway may become a useful strategy to treat acute AMR in sensitized recipients of allografts, and possibly in recipients of discordant xenografts.  相似文献   
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