Current issues in allogeneic islet transplantation Purpose of review: Transplantation of allogenic pancreatic islets is a minimally invasive treatment option to control severe hypoglycemia and dependence on exogenous insulin among type 1 diabetes (T1D) patients. This overview summarizes the current issues and progress in islet transplantation outcomes and research.
Recent findings: Several clinical trials from North America and other countries have documented the safety and efficacy of clinical islet transplantation for T1D patients with impaired hypoglycemia awareness. A recently completed phase 3 clinical trial allows centres in the United States to apply for a Food and Drug Administration Biologics License for the procedure. Introduction of anti-inflammatory drugs along with T-cell depleting induction therapy has significantly improved long-term function of transplanted islets. Research into islet biomarkers, immunosuppression, extrahepatic transplant sites and potential alternative beta cell sources is driving further progress.
Summary: Allogeneic islet transplantation has vastly improved over the past two decades. Success in restoration of glycemic control and hypoglycemic awareness after islet transplantation has been further highlighted by clinical trials. However, lack of effective strategies to maintain long-term islet function and insufficient sources of donor tissue still impose limitations to the widespread use of islet transplantation. In the United States, wide adoption of this technology still awaits regulatory approval and, importantly, a financial mechanism to support the use of this technology.
Total pancreatectomy with islet autotransplantation: recent updates and outcomes Purpose of review: Total pancreatectomy with islet autotransplantation (TPIAT) is a reliable therapy to retain endocrine function, to alleviate pain and improve quality of life in adult and pediatric patients suffering from refractory chronic pancreatitis and recurrent acute pancreatitis. Recently, an expansion of indications to include benign and malignant pancreatic disease has been suggested. Improved methods for evaluating the functional quality of islets and predicting transplant outcome have been discussed. Furthermore, this review will discuss the recent advances in the procedure, anti-inflammatory strategies and outcomes of TPIAT.
Recent findings: New assays to measure posttransplant islet damage and improved methods to assess islet quality by monitoring the oxygen consumption rate have shown great promise. Anti-inflammatory strategies such as an interleukin-1 receptor antagonist, α-1 antitrypsin, tumor necrosis factor α inhibitor and an inhibitor of CXCR1/2 have been widely investigated under clinical trials.
Summary: The primary objective of TPIAT, which is to relieve pain and reduce narcotic usage, has been shown to have long-term success. However, achieving long-term insulin independence is still a challenge that needs to be addressed. The mechanism that leads to chronic graft failure in TPIAT needs to be delineated.
Pig islet xenotransplantation Purpose of review: The current article reviews the rationale, sources and preparation of pig islets for xenotransplantation, and presents current progress in solving the problems associated with establishing pig islet transplant as a clinical treatment for type 1 diabetes.
Summary: Islet transplantation is an effective treatment option for type 1 diabetes, but the available supply of human pancreases is insufficient to meet the need and demand for obtaining islets. Pig islets provide a readily available source for islet transplantation, with trials in non-human primates demonstrating their potential to reverse diabetes. The risk of zoonosis can be reduced by designated pathogen-free breeding of the donor pigs, but porcine endogenous retroviruses (PERVs) that are integrated into the genome of all pigs are especially difficult to eliminate. However, clinical trials have demonstrated an absence of PERV transmission with a significant reduction in the number of severe hypoglycemic episodes and up to 30% reduction in exogenous insulin doses. A number of methods such as production of various transgenic pigs to better xenotransplantation efficiency and the encapsulation of islets to isolate them from the host immune system are currently being tested to overcome the xenograft immune rejection. Furthermore, ongoing research is also shedding light on factors such as the age and breed of the donor pig to determine the optimal islet quantity and function.
Immunosuppression maintenance in vascularized composite allotransplantation: what is just right? Purpose of review: Over the last two decades advances in vascularized composite allotransplantation have achieved clinically significant milestones. This review provides a synopsis for immunosuppressive maintenance therapy for VCA and discusses the nuances surrounding the determination of the right amount of immunosuppression in vascularized composite allotransplantation.
Recent findings: Functional results after vascularized composite allotransplantation remain highly encouraging as are the immunologic outcomes, however, challenges persist. Currently, although conventional immunosuppressive protocols have been successful at preventing allograft loss; they have not totally prevented episodes of acute rejection in the skin. Furthermore, vascularized composite allotransplantation carries a significant risk profile attributed to the complications of life-long, high-dose immunosuppression regimens.
Summary: Examining conventional treatment protocols can lead to the development of novel immunosuppression concepts that will ultimately assist in favorably tilting the risk–benefit scale for these life-changing transplants.
Accommodation and related conditions in vascularized composite allografts Purpose of review: The outcome of vascularized composite allografts (VCA) often appear unrelated to the presence of donor-specific antibodies (DSA) in blood of the recipient or deposition of complement in the graft. The attenuation of injury and the absence of rejection in other types of grafts despite manifest donor-specific immunity have been explained by accommodation (acquired resistance to immune-mediated injury), adaptation (loss of graft antigen) and/or enhancement (antibody-mediated antigen blockade). Whether and how accommodation, adaptation and/or enhancement impact on the outcome of VCA is unknown. Here we consider how recent observations concerning accommodation in organ transplants might advance understanding and resolve uncertainties about the clinical course of VCA.
Recent findings: Investigation of the mechanisms through which kidney allografts avert antibody-mediated injury and rejection provide insights potentially applicable to VCA. Interaction of DSA can facilitate replacement of donor by recipient endothelial cells, modulate or decrease synthesis of antigen, mobilize antigen that in turn blocks further immune recognition and limit the amount of bound antibody, allowing accommodation to ensue. These processes also can explain the apparent dissociation between the presence and levels of DSA in blood, deposition of C4d in grafts and antibody-mediated rejection. Over time the processes might also explain the inception of chronic graft changes.
Summary: The disrupted tissue in VCA and potential for repopulation by endothelial cells of the recipient establish conditions that potentially decrease susceptibility to acute antibody-mediated rejection. These conditions include clonal suppression of donor-specific B cells, and adaptation, enhancement and accommodation. This setting also potentially highlights heretofore unrecognized interactions between these ‘protective’ processes.
Pediatric and congenital hand transplantation Purpose of review: We review the approach and challenges associated with pediatric hand transplantation, including new knowledge gleaned from our recent case of bilateral hand–forearm transplantation in an 8-year old child.
Recent findings: Bilateral heterologous hand–forearm transplantation was performed in a child with a prior kidney transplant in July 2015. The initial surgery necessitated a large team of experts in microvascular surgery, transplant surgery, orthopedics and plastic surgery as well as pediatric anesthesia. Medical management has highlighted the need for extensive multidisciplinary support with pediatric expertise in transplant medicine, occupational therapy and rehabilitation, neurology, and neuroradiology. The clinical course has been complicated by the need for robust immunosuppression to control ongoing, even though low-grade, and intermittent rejection. Neurological findings have demonstrated cortical neuroplasticity with reorganization of the somatosensory cortex.
Summary: Heterologous hand–forearm transplantation in a child is feasible and has the potential for functional benefit to improve quality of life; however, immunological and ethical concerns warrant proceeding with caution. More data are needed to inform patient and family selection to achieve optimal functional and quality of life outcomes.
Genitourinary vascularized composite allotransplantation Purpose of review: Genitourinary vascularized allotransplantation (GUVCA) is gaining interest as a treatment option for patients with functional and aesthetic urogenital tissue loss. Only three cases have been done worldwide and research on the implementation and feasibility of this procedure is in an elementary state.
Recent findings: The psychosocial impact and ethical considerations with GUVCA are remote, particularly because of the intimate and personal nature of genital tissue. Though two of the three penile transplantation cases are considered successful, various unexpected factors and complications have been described alongside these successes. Treatment outcome depends on a complex combination of immunological, technical, and psychosocial components that will be different per individual case. Multidisciplinary evaluation and treatment protocols should be established to ensure that the quality of life in GUVCA recipients can be increased in a safe and ethical way.
Summary: Penile transplantation represents challenging new potential to improve phallus reconstruction in patients with severe genital tissue defects, but worldwide experience with GUVCA is limited. Controlled multicenter research is required to better define the risk/benefit ratio of this experimental yet promising treatment option.
Adipose-derived cellular therapies in solid organ and vascularized-composite allotransplantation Purpose of review: Controlling acute allograft rejection following vascularized composite allotransplantation requires strict adherence to courses of systemic immunosuppression. Discovering new methods to modulate the alloreactive immune response is essential for widespread application of vascularized composite allotransplantation. Here, we discuss how adipose-derived cellular therapies represent novel treatment options for immune modulation and tolerance induction in vascularized composite allotransplantation.
Recent findings: Adipose-derived mesenchymal stromal cells are cultured from autologous or allogeneic adipose tissue and possess immunomodulatory qualities capable of prolonging allograft survival in animal models of vascularized composite allotransplantation. Similar immunosuppressive and immunomodulatory effects have been observed with noncultured adipose stromal-vascular-fraction-derived therapies, albeit publication of in-vivo stromal vascular fraction cell modulation in transplantation models is lacking. However, both stromal vascular fraction and adipose derived mesenchymal stem cell therapies have the potential to effectively modulate acute allograft rejection via recruitment and induction of regulatory immune cells.
Summary: To date, most reports focus on adipose derived mesenchymal stem cells for immune modulation in transplantation despite their phenotypic plasticity and reliance upon culture expansion. Along with the capacity for immune modulation, the supplemental wound healing and vasculogenic properties of stromal vascular fraction, which are not shared by adipose derived mesenchymal stem cells, hint at the profound therapeutic impact stromal vascular fraction-derived treatments could have on controlling acute allograft rejection and tolerance induction in vascularized composite allotransplantation. Ongoing projects in the next few years will help design the best applications of these well tolerated and effective treatments that should reduce the risk/benefit ratio and allow more patients access to vascularized composite allotransplantation therapy.
Application and interpretation of histocompatibility data in liver transplantation Purpose of review: There has been a resurgence of interest in histocompatibility as it applies to liver transplantation. The association of persistent and de-novo donor specific antibody (DSA) and outcomes after liver transplantation continues to be investigated.
Recent findings: Consensus continues to evolve regarding the existence of acute and chronic antibody-mediated rejection (AMR) and pathogenicity of DSA and associated pathologic findings after liver transplantation. The presence of persistent high level, complement fixing DSA or emergence of de novo, Class II DSA has been associated with rejection and worse long-term graft and patient survival. Significant adverse associations of DSA extend to patients after simultaneous liver kidney (SLK) transplant as well as in pediatric recipients of liver transplantation. A higher degree of HLA incompatibility has been recently associated with worse outcomes in living donor liver transplant.
Summary: In summary, recent consensus guidelines describe and recognize the existence of acute and chronic AMR and provide a basis upon which to build further investigation. Important adverse outcomes including decreased survival, allograft failure and liver fibrosis have been linked to the presence of DSA. Routine donor and recipient HLA typing and DSA assessment will facilitate diagnosis and provide for baseline data, which may help guide future management. Future investigations may help to clarify the role of therapeutic interventions
Application, technical issues, and interpretation of C1q for graft outcome Purpose of review: Significant interest and controversy surround the use of C1q for determining risk of antibody-mediated rejection (AMR) and graft loss. Alternate models for predicting outcomes have been proposed. This review focuses on the correlation of currently utilized assays for outcome, together with the technical and theoretical limitations, to distill current thinking.
Recent findings: Results demonstrate that C1q status is significantly correlated with AMR and graft loss. There is general consensus that C1q is more clinically relevant for graft outcome than neat IgG MFI. IgG titers, subclass, and other complement assays have now been studied to determine if they are more relevant. Only IgG3 and possibly C3d fixation have shown added value to C1q for outcome correlation. Direct parallel titer comparisons of C1q and IgG are lacking and the correlation is unknown.
Summary: Overall, results confirm the correlation with C1q+ donor-specific antibody (DSA) for AMR and graft loss. The association is stronger posttransplant. C1q+ de novo antibody appears to be especially detrimental portending graft loss in about 1–2.5 years post detection. Recommendations to biopsy and treat at time of de novo C1q+ antibody detection have been suggested by several groups.
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