Vascularized composite allotransplantation: Knowledge and attitudes of a national sample of organ procurement organization professionals

With the emergence of vascularized composite allografts (VCAs) for transplantation, donation professionals’ ability to obtain authorization for these anatomical gifts has become paramount for its continued practice. Our national study examines the experience of organ procurement organization (OPO) professionals responsible for presenting the opportunity to donate VCAs to families of deceased donor-eligible patients. Semi-structured telephone interviews conducted with 157 OPO staff assessed experience with VCA discussions, VCA knowledge, and comfort, confidence, and feeling prepared with discussions about different VCA types. Standard procedures were used to code and analyze the qualitative data and summarize the quantitative data. Most respondents (70.1%) never held a VCA donation discussion, but those with experience reported overall low levels of knowledge, comfort, and confidence talking with families about VCA. Although 44.4% of the sample had VCA-related training, many felt unprepared, with most (75.0%) stating the training was insufficient. Participants without experience indicated even lower ratings of the aforementioned constructs. Findings support extant work demonstrating that no standardized procedures exist for VCA donation discussions; however, donation professionals are willing to adopt new VCA-related skills. This report concludes that sustained and content-specific training will elevate donation professionals’ ability to augment the supply of VCAs available for transplantation.     

脂肪干细胞在同种异体复合组织移植中的作用及其临床应用展望

同种异体复合组织移植是临床修复重建的重要手段,但术后长期应用免疫抑制剂所导致的副作用仍是亟待解决的难题,细胞治疗联合传统免疫抑制剂治疗有望解决这一难题。间质干细胞,特别是脂肪干细胞,被认为可用于延长移植物存活及改善免疫排斥情况的发生。其在同种异体复合组织移植中发挥的作用包括旁分泌免疫调节因子抑制免疫排斥反应、诱导调节性T细胞产生、形成嵌合体诱导免疫耐受,以及改善移植过程中缺血再灌注损伤等。但是,该方法要真正应用于临床前,相关问题如使用剂量、时机及安全性等仍需经过进一步深入研究。     

Adoptive Transfer of Renal Allograft Tolerance in a Large Animal Model

Our recent studies in an inbred swine model demonstrated that both peripheral and intra‐graft regulatory cells were required for the adoptive transfer of tolerance to a second, naïve donor‐matched kidney. Here, we have asked whether both peripheral and intra‐graft regulatory elements are required for adoptive transfer of tolerance when only a long‐term tolerant (LTT) kidney is transplanted. Nine highly‐inbred swine underwent a tolerance‐inducing regimen to prepare LTT kidney grafts which were then transplanted to histocompatible recipients, with or without the peripheral cell populations required for adoptive transfer of tolerance to a naïve kidney. In contrast to our previous studies, tolerance of the LTT kidney transplants alone was achieved without transfer of additional peripheral cells and without strategies to increase the number/potency of regulatory T cells in the donor. This tolerance was systemic, since most subsequent, donor‐matched challenge kidney grafts were accepted. These results confirm the presence of a potent tolerance‐inducing and/or tolerance‐maintaining cell population within LTT renal allografts. They suggest further that additional peripheral tolerance mechanisms, required for adoptive transfer of tolerance to a naïve donor‐matched kidney, depend on peripheral cells that, if not transferred with the LTT kidney, require time to develop in the adoptive host.     

Spontaneous Resolution of Acute Rejection and Tolerance Induction With IL‐2 Fusion Protein in Vascularized Composite Allotransplantation

Vascularized composite allotransplantation (VCA) has emerged as a treatment option for treating nonlife‐threatening conditions. Therefore, in order to make VCA a safe reconstruction option, there is a need to minimize immunosuppression, develop tolerance‐inducing strategies and elucidate the mechanisms of VCA rejection and tolerance. In this study we explored the effects of hIL‐2/Fc (a long‐lasting human IL‐2 fusion protein), in combination with antilymphocyte serum (ALS) and short‐term cyclosporine A (CsA), on graft survival, regulatory T cell (Treg) proliferation and tolerance induction in a rat hind‐limb transplant model. We demonstrate that hIL‐2/Fc therapy tips the immune balance, increasing Treg proliferation and suppressing effector T cells, and permits VCA tolerance as demonstrated by long‐term allograft survival and donor‐antigen acceptance. Moreover, we observe two distinct types of acute rejection (AR), progressive and reversible, within hIL‐2/Fc plus ALS and CsA treated recipients. Our study shows differential gene expression profiles of FoxP3 versus GzmB, Prf1 or interferon‐γ in these two types of AR, with reversible rejection demonstrating higher Treg to Teff gene expression. This correlation of gene expression profile at the first clinical sign of AR with VCA outcomes can provide the basis for further inquiry into the mechanistic aspects of VCA rejection and future drug targets.     

同种异体复合组织移植Banff移植病理学诊断标准及进展

同种异体复合组织移植（CTA）是一门新兴的用于治疗功能性组织或肢体缺损的移植学科,由于绝大多数CTA移植物为带血管的移植物,因此也称为带血管的复合组织移植（VCA）。CTA/VCA的移植物包含同种异体的皮肤、皮下组织、骨骼、肌肉、神经和血管等两种或多种组织结构成分。由于大多数CTA/VCA移植物中带有皮肤组织,而皮肤组织是抗原性最强的免疫成分,移植术后的急性排斥反应是导致CTA/VCA移植失败及其移植物失功的首要障碍, 因此CTA/VCA移植物中的皮肤排斥反应的组织病理学特征成为首要的关注点。本文就CTA/VCA的排斥反应等病理学特征、2007年Banff诊断标准及其研究进展予以综述,以期为CTA/VCA的排斥反应及其他并发症的诊断及治疗提供参考。     

Lymphoid neogenesis in skin of human hand,nonhuman primate,and rat vascularized composite allografts

The mechanisms of skin rejection in vascularized composite allotransplantation (VCA) remain incompletely understood. The formation of tertiary lymphoid organs (TLO) in hand transplantation has been recently described. We assess this phenomenon in experimental and clinical VCA rejection. Skin biopsies of human (n = 187), nonhuman primate (n = 11), and rat (n = 15) VCAs were analyzed for presence of TLO. A comprehensive immunohistochemical assessment (characterization of the cell infiltrate, expression of adhesion molecules) including staining for peripheral node addressin (PNAd) was performed and correlated with rejection and time post‐transplantation. TLO were identified in human, nonhuman primate, and rat skin samples. Expression of PNAd was increased in the endothelium of vessels upon rejection in human skin (P = 0.003) and correlated with B‐ and T‐lymphocyte numbers and LFA‐1 expression. PNAd expression was observed at all time‐points after transplantation and increased significantly after year 5. In nonhuman primate skin, PNAd expression was found during inflammatory conditions early and late after transplantation. In rat skin, PNAd expression was strongly associated with acute rejection and time post‐transplantation. Lymphoid neogenesis and TLO formation can be uniformly found in experimental and human VCA. PNAd expression in vascular endothelium correlates with skin rejection and T‐ and B‐cell infiltration.     

Prolonged Cold Ischemia Time Results in Local and Remote Organ Dysfunction in a Murine Model of Vascularized Composite Transplantation

Vascularized composite allotransplantation (VCA) is a viable reconstructive option for complex tissue defects. Although grafts with a large muscular component may be uniquely susceptible to ischemia–reperfusion (I/R) syndrome, the safe cold ischemia time in VCA has not been established. We investigated the effects of cold ischemia on innate immune response and recipient survival in a murine orthotopic hindlimb transplantation model. Surprisingly, mice receiving grafts exposed to 6 h or longer of cold storage demonstrated reduced survival and massive elevations in serum creatinine, blood urea nitrogen, and creatine kinase, compared with 1 h of cold storage recipients. This was accompanied by progressive increase in macrophage and neutrophil cell infiltration in muscle biopsy specimens, altered platelet endothelial cell adhesion molecule‐1 expression, and ultimate renal injury. Multiplex immunoassay analysis identified 21 cytokines in serum and 18 cytokines in muscle biopsy specimens that are likely essential in the complex response to I/R‐triggered injury in VCA. In conclusion, this study, in a mouse model of orthotopic hindlimb transplantation, is the first to document that prolonged cold ischemia triggers progressive I/R injury with vascular endothelial damage and may lead to irrecoverable local and remote organ damage. These experimental findings are important in guiding future therapies for human VCA recipients.     

Sclerostin Antibody Treatment Increases Bone Formation,Bone Mass,and Bone Strength in a Rat Model of Postmenopausal Osteoporosis

The development of bone‐rebuilding anabolic agents for potential use in the treatment of bone loss conditions, such as osteoporosis, has been a long‐standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation, although the magnitude and extent of sclerostin's role in the control of bone formation in the aging skeleton is still unclear. To study this unexplored area of sclerostin biology and to assess the pharmacologic effects of sclerostin inhibition, we used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl‐AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis. Six‐month‐old female rats were ovariectomized and left untreated for 1 yr to allow for significant estrogen deficiency‐induced bone loss, at which point Scl‐AbII was administered for 5 wk. Scl‐AbII treatment in these animals had robust anabolic effects, with marked increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. This not only resulted in complete reversal, at several skeletal sites, of the 1 yr of estrogen deficiency‐induced bone loss, but also further increased bone mass and bone strength to levels greater than those found in non‐ovariectomized control rats. Taken together, these preclinical results establish sclerostin's role as a pivotal negative regulator of bone formation in the aging skeleton and, furthermore, suggest that antibody‐mediated inhibition of sclerostin represents a promising new therapeutic approach for the anabolic treatment of bone‐related disorders, such as postmenopausal osteoporosis.     

Systematic review and pooled analysis of survival rates,success, and outcomes of osseointegrated implants in a variety of composite free flaps

The aim of this review was to provide an update on survival rates of osseointegrated implants into common composite free flaps used for maxillary and mandibular reconstructions and identify factors affecting outcomes. PubMed, Medline, Embase, and Cochrane databases were searched. Included studies reported implant survival by flap type. Results were pooled and survival was estimated with the Kaplan‐Meier method. Variables affecting survival were assessed using Cox regression. Thirty‐two of the 2631 articles retrieved were included, totaling 2626 implants placed into fibula, iliac crest, scapula, and radial forearm free flaps. Pooled survival showed 94% 5‐year survival of implants in fibula and iliac crest with no difference between groups (P = .3). Factors effecting survival included radiotherapy (HR 2.3, 95% CI 1.2‐4.6, P = .027) and malignant disease (HR 2.2, 95%CI 1.6‐3.1, P < .001). Implant survival appears adequate across common flap types; however, there are limited numbers reported in less common flaps.     

Trauma Symptoms in Bone Marrow Transplant Survivors: The Role of Nonmedical Life Events

This cross-sectional study investigated the association of trauma-related symptomatology and recent life events in cancer survivors following bone marrow transplantation (BMT). One hundred adults averaging 4.4 years post-BMT were interviewed. Participants reported their trauma-related symptomatology regarding cancer and its treatment as well as the number and valence of recent life events. Results indicated that the more negative life events a person experienced, the greater his/her trauma-related symptomatology. The association of trauma-related symptomatology with positive events varied by the individuals' level of physical functioning. For individuals with poorer physical functioning, higher levels of trauma-related symptomatology were associated with a greater number of positive events, suggesting the greater vulnerability of these individuals to any type of change in their life.