The Role of Ischemia-Reperfusion Injury in Reconstructive Transplantation (original) (raw)
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Minimization of Immunosuppression and Tolerance Induction in Reconstructive Transplantation
Current Surgery Reports, 2012
Vascularized composite allotransplantation (VCA) is an innovative reconstructive modality for patients sustaining complex injuries not amenable to conventional treatment. Advances in immunosuppression have made VCA a clinical reality and a valid reconstructive option for such patients. The requirement, however, for multi-drug high-dose immunosuppressive regimens with their numerous side effects has hindered widespread clinical application of VCA. There is thus a need for novel immunologic modalities to minimize or even obviate the need for immunosuppression (tolerance induction) while still preserving the allograft and preventing rejection. Recent advances in targeted immunotherapy and cell-based protocols were able to achieve tolerance in selected cases of solid organ transplantation. This paved the way for innovative immunomodulatory protocols now also applied to VCA that aim for minimal immunosuppression or for induction of donor-specific tolerance. These concepts and novel protocols will be discussed in this review.
PloS one, 2017
Hand and face vascularized composite allotransplantation (VCA) is an evolving and challenging field with great opportunities. During VCA, massive surgical damage is inflicted on both donor and recipient tissues, which may contribute to the high VCA rejection rates. To segregate between the damage-induced and rejection phase of post-VCA responses, we compared responses occurring up to 5 days following syngeneic versus allogeneic vascularized groin flap transplantations, culminating in transplant acceptance or rejection, respectively. The immune response elicited upon transplantation of a syngeneic versus allogeneic vascularized groin flap was compared at Post-operative days 2 or 5 by histology, immunohistochemistry and by broad-scope gene and protein analyses using quantitative real-time PCR and Multiplex respectively. Immune cell infiltration began at the donor-recipient interface and paralleled expression of a large group of wound healing-associated genes in both allografts and syn...
Immunologic Aspects and Rejection in Solid Organ Versus Reconstructive Transplantation
2010
The immunosuppressive medications developed over the past 3 decades have paved the way for solid organ transplantation to become the treatment of choice for end-stage organ failure. At the end of the century, composite tissue transplantation in humans was performed with success using the same immunosuppressive medications and therapeutic principles. A decade later, experience from Ͼ100 cases of reconstructive transplantation have increased the knowledge, changed the view, and affected the therapeutic principles in this novel field. We herein portray the evolution of this novel type of transplant with particular reference to immunologic aspects, particularly differences between reconstructive and solid organ transplantation.
Frontiers in Immunology, 2013
Advances in microsurgical techniques and immunomodulatory protocols have contributed to the expansion of vascularized composite allotransplantation (VCA) with very encouraging immunological, functional, and cosmetic results. Rejection remains however a major hurdle that portends serious threats to recipients. Rejection features in VCA have been described in a number of studies, and an international consensus on the classification of rejection was established. Unfortunately, current available diagnostic methods carry many shortcomings that, in certain cases, pose a great diagnostic challenge to physicians especially in borderline rejection cases. In this review, we revisit the features of acute skin rejection in hand and face transplantation at the clinical, cellular, and molecular levels. The multiple challenges in diagnosing rejection and in defining chronic and antibody-mediated rejection in VCA are then presented, and we finish by analyzing current research directions and novel concepts aiming at improving available diagnostic measures.
Clinical and Developmental Immunology, 2013
The emerging field of vascular composite allotransplantation (VCA) has become a clinical reality. Building upon cutting edge understandings of transplant surgery and immunology, complex grafts such as hands and faces can now be transplanted with success. Many of the challenges that have historically been limiting factors in transplantation, such as rejection and the morbidity of immunosuppression, remain challenges in VCA. Because of the accessibility of most VCA grafts, and the highly immunogenic nature of the skin in particular, VCA has become the focal point for cross-disciplinary approaches to developing novel approaches for some of the most challenging immunological problems in transplantation, particularly the early diagnoses and assessment of rejection. This paper provides a historically oriented introduction to the field of organ transplantation and the evolution of VCA.
Anti-inflammatory treatment strategies for ischemia/reperfusion injury in transplantation
Journal of Inflammation, 2010
Inflammatory reactions in the graft have a pivotal influence on acute as well as long-term graft function. The main reasons for an inflammatory reaction of the graft tissue are rejection episodes, infections as well as ischemia/ reperfusion (I/R) injury. The latter is of particular interest as it affects every solid organ during the process of transplantation. I/R injury impairs acute as well as long-term graft function and is associated with an increased number of acute rejection episodes that again affect long-term graft outcome. I/R injury is the result of ATP depletion during prolonged hypoxia. Further tissue damage results from the reperfusion of the tissue after the ischemic insult. Adaptive cellular responses activate the innate immune system with its Toll-like receptors and the complement system as well as the adaptive immune system. This results in a profound inflammatory tissue reaction with immune cells infiltrating the tissue. The damage is mediated by various cytokines, chemokines, adhesion molecules, and compounds of the extracellular matrix. The expression of these factors is regulated by specific transcription factors with NF-κB being one of the key modulators of inflammation. Strategies to prevent or treat I/R injury include blockade of cytokines/chemokines, adhesion molecules, NF-κB, specific MAP kinases, metalloproteinases, induction of protective genes, and modulation of the innate immune system. Furthermore, preconditioning of the donor is an area of intense research. Here pharmacological treatment as well as new additives to conventional cold storage solutions have been analyzed together with new techniques for the perfusion of grafts, or methods of normothermic storage that would avoid the problem of cold damage and graft ischemia. However, the number of clinical trials in the field of I/R injury is limited as compared to the large body of experimental knowledge that accumulated during recent years in the field of I/R injury. Future activities in the treatment of I/R injury should focus on the translation of experimental protocols into clinical trials in order to reduce I/R injury and, thus, improve short-as well as long-term graft outcome.
SAGE Open Medicine
As clinical experience with surgical techniques and immunosuppression in vascularized composite allotransplantation recipients has accumulated, vascularized composite allotransplantation for hand and face have become standard of care in some countries for select patients who have experienced catastrophic tissue loss. Experience to date suggests that clinical vascularized composite allotransplantation grafts undergo the same processes of allograft rejection as solid organ grafts. Nonetheless, there are some distinct differences, especially with respect to the immunologic influence of the skin and how the graft is affected by environmental and traumatic insults. Understanding the mechanisms around these similarities and differences has the potential to not only improve vascularized composite allotransplantation outcomes but also outcomes for all types of transplants and to contribute to our understanding of how complex systems of immunity and function work together. A distinct disadva...
Clinical and Developmental Immunology, 2012
Vascularized composite allotransplantation (VCA) is an effective treatment option for patients suffering from limb loss or severe disfigurement. However, postoperative courses of VCA recipients have been complicated by skin rejection, and long-term immunosuppression remains a necessity for allograft survival. To widen the scope of this quality-of-life improving procedure minimization of immunosuppression in order to limit risks and side effects is needed. In some aspects, the molecular mechanisms and dynamics of skin allograft rejection seem similar to inflammatory skin conditions. T cells are key players in skin rejection and are recruited to the skin via activation of adhesion molecules, cytokines, and chemokines. Blocking these molecules has not only shown success in the treatment of inflammatory dermatoses, but also prolonged graft survival in various models of solid organ transplantation. In addition to T cell recruitment, ectopic lymphoid structures within the allograft associated with chronic rejection in solid organ transplantation might contribute to the strong alloimmune response towards the skin. Selectively targeting the molecules involved offers exciting novel therapeutic options in the prevention and treatment of skin rejection after VCA.