Evolution of the rat hind limb transplant as an experimental model of vascularized composite allotransplantation: Approaches and advantages (original) (raw)
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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...
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.
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.
Induction of tolerance to composite tissue allograft in a rat model
Microsurgery, 2006
The goal of this study was to establish a rat model that can be used to determine the variables in influencing induction of tolerance to composite tissue allografts. An anti T-cell depleting agent (R73) and 15-deoxyspergualin were given in different doses and schedule to four groups of Lewis rats receiving a limb transplant from Brown-Norway donors. Graft survival prolongation was maximal combining a single dose of R73 and a 20-day administration of 15-deoxyspergualin. Long-term survivors accepted a skin graft from Brown-Norway donors at 80 days, but rejected grafts from an unrelated donor. Skin grafting did not influence survival of the transplanted limb. Mixed allogeneic chimerism was not detectable in peripheral blood by flow cytometry, but immunohistochemistry identified donor-derived cells in the thymus of tolerant recipients at 100 days. These results suggest a state of donor-specific, dynamic tolerance, with potential for future application in human composite tissue allotransplantation.
Composite Tissue Allograft Extends a Helping Hand to Transplant Immunologists
American Journal of Transplantation, 2006
The first successful human hand transplantation, performed on September 1998, has translated the scope of 'composite tissue allotransplantation' from research concepts into clinical practice. Beyond microsurgical problems that have been overcome several years ago, the main obstacle that still prevents the generalization of composite tissue allotransplantation is immunologic.
Immunological Issues in Clinical Composite Tissue Allotransplantation
Transplantation Journal, 2012
Composite tissue allografts are made of histogenetically different tissues and although skin seems to be the most antigenic of them, it is unknown whether the dominant immune response is really directed against the skin or we have insufficient information on the involvement of the other components of these allografts. The first clinical signs of acute rejection manifest on the skin and microscopically the earliest lesions consist in a dermal perivascular lymphocytic infiltrate, predominantly made of CD3+/CD4+ T cells. On the basis of the histological changes, a specific score (Banff score 2007) has been established to assess the severity of rejection. Despite the high incidence of acute rejection episodes, they can be completely reversed when promptly diagnosed and treated. C4d deposits in the skin and circulating donor-specific antibodies are rarely detected, suggesting that humoral rejection does not play a significant role in composite tissue allotransplantation. Chronic rejection features are still unknown. The majority of recipients have been maintained on an immunosuppressive regimen consisting of tacrolimus, steroids, and mycophenolate mofetil. The complications in composite tissue allotransplantation are similar to those usually reported after solid organ transplantation and have prompted different strategies to minimize the maintenance immunosuppression or to induce donor-specific tolerance. Furthermore, to what extent the immunosuppression can be tapered is unknown, as well as the influence of donor bone-marrow infusion in tolerance and chronic rejection. The increasing number of patients and the longer follow-up hopefully will allow answering these questions.
Transplantation, 2004
The experience obtained from the human hand allografts (HHA) performed to date suggests that the skin is a priviledged target of allograft rejection in this setting. The aim of this study was to establish a pathological score for assessing the severity of HHA rejection. The pathological slides of 89 skin biopsies obtained from the allografted limbs of six HHA recipients from day 0 to 5 years post-graft were retrospectively examined. According to the severity of the pathological changes observed, the following grades of rejection are proposed: 0: no rejection, I: mild rejection, II: moderate rejection, III: severe rejection, IV: very severe rejection. This grading system can be used as a basis for monitoring allograft rejection and for assessing the effects of the immunosuppressive treatment aiming at reversing HHA rejection; it can also be used for monitoring rejection of other skin-containing CTA.
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.
Journal of Plastic, Reconstructive & Aesthetic Surgery, 2010
The problem of allogeneic skin rejection is a major limitation to more widespread application of clinical composite tissue allotransplantation (CTA). Previous research examining skin rejection has mainly studied rejection of conventional skin grafts (CSG) using standard histological techniques. The aim of this study was to objectively assess if there were differences in the immune response to CSG and primarily vascularized skin in composite tissue allotransplants (SCTT) using in vivo techniques in order to gain new insights in to the immune response to skin allotransplants.
Immunomodulation in Vascularized Composite Allotransplantation
Annals of Plastic Surgery, 2019
Hand and face transplants are becoming increasingly common, recording progressively more penile, uterus, abdominal wall, and allotransplantation cases reported worldwide. Despite current protocols allow long-term survival of the allografts, the ultimate goal of donor-specific tolerance has not been achieved yet. In fact, the harmful adverse effects related to the lifelong administration of immunosuppressive agents are the main drawbacks for vascularized composite allotransplantations. Research is very active in investigating alternative methods to induce greater tolerance while minimizing toxicity. Adipose-derived stem cells (ASCs) represent promising cell therapies for immunomodulation in preclinical and clinical settings. Their clinical appeal is due to their easy harvest in large quantities through a noninvasive and well-accepted approach; they may well promote donor-specific tolerance and potentially reduce immunosuppression. Several experimental studies exist, but lacking review articles reporting current evidence. This work proposes a literature review on the immunomodulatory role of ASCs in vascularized composite allotransplantations. In vitro and in vivo evidence will be summarized. The role that cell passaging and upstream progenitors-the so-called spheroid ASCs-may play in modulating the immune response will also be discussed. Finally, this article will summarize current knowledge on biodistribution, migration, and homing of injected stem cells. This review may well provide useful information for preclinical and clinical studies, aiming at a breakthrough for donor-specific tolerance.