Composite tissue allotransplantation.

Composite tissue allotransplantation (CTA) recently took its first steps in the clinical arena in 1998 with the successful hand transplant performed in Lyons, France. That single operation represented a culmination of many years of laboratory research in multiple fields involving integumentary/musculoskeletal transplantation. Here we review the prerequisite developments in the field of immunology, microsurgery, and pharmacotherapy that helped bring CTA to clinical reality. This new field still has many unanswered questions which are addressed below. Additionally, new evolving research in CTA is also discussed.     

Composite tissue allotransplantation in chimeric hosts part II. A clinically relevant protocol to induce tolerance in a rat model

BACKGROUND: We and others have shown that mixed allogeneic chimerism induces donor-specific tolerance to composite tissue allografts across major histocompatibility complex barriers without the need for immunosuppression. However, a delay period between bone marrow transplantation and limb allotransplantation is required, making such protocols impractical for clinical application. This study eliminates this delay period in a rat hind limb allotransplantation model by performing mixed allogeneic chimerism induction and transplantation "simultaneously." METHODS: Group 1 included controls in which na?ve Wistar Furth (WF) hosts received ACI hind limbs. Group 2 included (ACI-->WF) chimeras that received limbs from third-party donors (Fisher), and group 3 included chimeras that received irradiated (1,050 cGy) ACI limbs. In group 4, WF hosts conditioned with 950 cGy received irradiated (1,050 cGy) ACI limbs followed by infusion of 100 x 10(6) ACI T-cell-depleted bone marrow cells and immunotherapy (tacrolimus and mycophenolate mofetil) for 28 days. Group 5 animals received the same treatment as group 4 animals without immunotherapy. RESULTS: The rats in groups 1 and 2 rejected their limbs within 10 days. Only one rat in group 4 survived to the end of the study. Groups 3 and 5 demonstrated long-term limb survival without rejection or graft-versus-host disease. High levels of donor chimerism (>80%) were achieved and maintained throughout the study. Mixed lymphocyte reaction assays in both groups revealed donor-specific hyporesponsiveness with vigorous third-party reactivity. CONCLUSIONS: This study demonstrated that infusion of donor bone marrow cells into conditioned hosts immediately after limb transplantation results in stable mixed chimerism, robust tolerance, and reliable limb allograft survival.     

Composite tissue allotransplantation in newborns: A swine model

BackgroundManagement of congenital limb aplasia or facial malformations could be improved by composite tissue allotransplantation (CTA), a technique that has never been performed in newborns. For this, however, the induction of donor-specific tolerance would be mandatory, as long-term immunosuppression is not acceptable in this non-lifesaving procedure. Induction of tolerance has been shown to be possible in a newborn CTA rat model but has never been tested in large-animal models. Our goals were to establish a model of CTA in newborn swine to see if tolerance could be obtained without immunosuppression and to assess rejection or tolerance properties via clinical and histologic examinations.Materials and methodsWe applied a CTA heterotopic knee swine model. We performed two series of surgical procedures: Series 1 was 20 autografts in 6-day-old (1–10) 2,544 kg (1,140–4,060 kg) piglets; Series 2 was 10 allografts without immunosuppression between outbred animals aged 7.8 d (6–10) and weighing 2,770 kg (2,200–3,550 kg).ResultsIn Series 1, six early deaths and two cases of vascular failure were observed. In Series 2, no spontaneous deaths were observed and all piglets presented clinical and histologic rejection.ConclusionsOur findings strongly suggest that newborn immunologic status is not sufficient for the development of tolerance in large animals without immunologic intervention. Complications and animal death after transplantation correlate with age and weight. Low rates for both vascular failure and postoperative death permit the use of this model in piglets weighing over 2 kg and aged more than 6 d for research on newborn CTA.     

Immunology of vascularized composite allotransplantation: a primer for hand surgeons

Vascularized composite allotransplantation is a recent innovation in the fields of transplantation surgery, plastic and reconstructive surgery, and orthopedic surgery. The success of hand and face transplantation has been based on extensive experience in solid organ transplantation. Advances in understanding the immunology of transplantation have had a major role in achieving excellent results in this new field. The purpose of this article is to introduce the basics of human immunology (innate and adaptive systems) and the immunological basis of human transplantation (the importance of human leukocyte antigen, direct and indirect pathways of antigen recognition, the 3 signals for T-cell activation, and mechanisms and types of allograft rejection) and focus on the mode of action of immunosuppressive drugs that have evolved as the mechanisms and pathways for rejection have been defined through research. This includes recent studies involving the use of costimulatory blockade, regulatory T cells, and tolerance induction that have resulted from research in understanding the mechanisms of immune recognition and function.     

Composite tissue allotransplantation: development of a preclinical model in nonhuman primates

BACKGROUND: Composite tissue allotransplantation (CTA) has been recently introduced as a potential treatment for tissue loss secondary to burns, injuries, or resections. However, the optimal strategies to prevent CTA rejection remain undefined. Presently, no CTA model exists to evaluate human-specific immunosuppressants or the relative immunogenicity of all CTA tissues. METHODS: We established a NHP CTA model utilizing a sensate osteomyocutaneous radial forearm flap that avoids functional impairment even in the case of graft loss. The model was evaluated in19 monkeys that underwent auto- or allotransplantation, with or without subtherapeutic immunosuppression to temporarily characterize rejection. RESULTS: Autografts showed no evidence of rejection. Nonimmunosuppressed allografts were rapidly rejected showing a perivenular T-cell infiltrate. This was associated with subsequent alloantibody formation and led to graft thrombosis without prominent dermal infiltration. Subtherapeutically immunosuppressed animals also developed alloantibody and rejected in a delayed fashion exhibiting a marked dermal lymphocytic infiltrate similar in magnitude and distribution to previously reported human cases. CONCLUSION: Our NHP model for CTA is well tolerated by NHPs, results in allosensitization, is responsive to immunosuppression, allows for the evaluation of CTA histology and can be used for the systematic preclinical evaluation of therapeutic maneuvers to improve allograft survival.     

Immunosuppression in an emerging field of plastic reconstructive surgery: composite tissue allotransplantation.

Composite tissue transplantation (CTA) refers to the transplantation of an allograft consisting of heterogeneous cadaveric tissues. It provides a means of restoring structural, functional and aesthetic form in severely injured patients. Recent progress in facial transplantation has highlighted the immense strides made in this field of reconstructive surgery. However the potential for improvements in quality of life must be offset by the need for life-long immunosuppression in adults with non life-threatening injuries. The benefits and difficulties of immunosuppressive drugs have been established in solid organ transplantation. Regimens derived from renal transplantation have been successfully applied to CTA. However the published incidence of complications seen in organ transplant recipients may not be easily extrapolated to potential CTA candidates and may be overstated. Accepted views that high dose immunosuppression would be needed to overcome highly antigenic tissues such as skin have not been borne out by clinical experience. It is therefore important to assess the current state of affairs, attempt to quantify the perceived risks and explore novel research methods being investigated. In doing so one can make a well-informed judgment of the potential benefit of this surgical modality as an integral part of the reconstructive ladder.     

Composite tissue allotransplantation of the face: Decision analysis model

BACKGROUND:

Facial composite tissue allotransplantation is a potential reconstructive option for severe facial disfigurement. The purpose of the present investigation was to use decision analysis modelling to ascertain the expected quality-adjusted life years (QALYs) gained with face transplantation (versus remaining in a disfigured state) in an effort to assist surgeons with the decision of whether to adopt this procedure.

STUDY DESIGN:

The probabilities of potential complications associated with facial allotransplantation were identified by a comprehensive review of kidney and hand transplant literature. A decision analysis tree illustrating possible health states for face allotransplantation was then constructed. Utilities were obtained from 30 participants, using the standard gamble and time trade-off measures. The utilities were then translated into QALYs, and the expected QALYs gained with transplantation were computed.

RESULTS:

Severe facial deformity was associated with an average of 7.34 QALYs. Allotransplantation of the face imparted an expected gain in QALYs of between 16.2 and 27.3 years.

CONCLUSIONS:

The current debate within the medical community surrounding facial composite tissue allotransplantation has centred on the issue of inducing a state of immunocompromise in a physically healthy individual for a non-life-saving procedure. However, the latter must be weighed against the potential social and psychological benefits that transplantation would confer. As demonstrated by a gain of 26.9 QALYs, participants’ valuation of quality of life is notably greater for face transplantation with its side effects of immunosuppression than for a state of uncompromised physical health with severe facial disfigurement.     

Composite tissue allotransplantation and reconstructive surgery: first clinical applications

OBJECTIVE: To review the first clinical cases of composite tissue allotransplantation (CTA) for reconstructive surgery and to discuss the outcome of and indications for these procedures in the context of chronic immunosuppression. SUMMARY BACKGROUND DATA: The first human hand transplant was performed in 1998. This procedure, as well as other composite tissue transplants, offers the potential for correcting untreatable large tissue defects. However, concerns remain regarding obligatory chronic immunosuppression and long-term functional results. METHODS: All the CTAs performed in humans that have been published or documented were reviewed. The preexisting clinical conditions and surgical procedures and the immunosuppressive therapy are described. The functional results and the complications or side effects of the treatment are detailed. RESULTS: Vascularized tendons (two cases), vascularized femoral diaphyses (three cases), knees (five cases), hands (four bilateral and seven unilateral cases), larynx (one case), and nonvascularized peripheral nerves (seven cases) have been transplanted in humans in the past decade. Rejection was prevented in most cases without difficulty. Early results are encouraging, particularly for hand and larynx transplants, but will need to be evaluated in the long term and in a larger number of patients. CONCLUSIONS: CTA holds great potential for reconstructive surgery but is at present restricted by the risks of chronic immunosuppression and uncertain long-term results.     

Interventions in atherosclerosis: a review for surgeons.

For the surgeon, atherosclerosis is defined by a variety of aneurysmal, occlusive, or ulcerated lesions in major arteries. These end-stage lesions often require operative treatment. However, just as advanced atherosclerosis presents complex clinical phenomena, so its earlier stages display many underlying mechanisms promoting lesions. To arrest or control atherosclerosis, the disease must be approached with knowledge about diverse biological processes. These include ceullar and systemic aspects of lipoprotein metabolism, reactions and metabolism of endothelium and smooth muscle cells of the arterial wall, and interaction of platelets with the arterial intima. The chronic nature of this process is such that surgeons are involved intimately with overall management as well as with surgical procedures. We will review underlying biological processes of atherosclerosis as related to interventions in patients with clinically apparent disease.     

Composite tissue allotransplantation in chimeric hosts: part I. Prevention of graft-versus-host disease

BACKGROUND: Mixed allogeneic chimerism (MAC) has been shown to induce tolerance to composite tissue allografts (CTA). However, transplantation of unmanipulated donor-specific limbs results in severe graft-versus-host disease (GVHD). This suggests that nontolerant mature donor-derived cells in the CTA may affect the stability of chimerism, potentially resulting in GVHD. The aim of this study was to develop an approach to study and prevent GVHD in a mixed chimeric-rat hind-limb transplantation model. METHODS: [ACI-->WF] chimeras received a limb from Wistar Furth (WF) (syngeneic), Fisher (third-party), or ACI (irradiated [1,050 cGy] or nonirradiated) rats. In vitro tolerance was assessed using mixed lymphocyte reactivity (MLR) assays at the time the animals were killed. RESULTS:[ACI-->WF] chimeras with greater than 85% chimerism exhibited rejection-free survival of donor-specific hind limbs. However, 100% of these animals developed lethal GVHD 22.4+/-2.8 days after limb transplantation. [ACI-->WF] chimeras that underwent transplantation with irradiated ACI or syngeneic WF limbs showed no signs of rejection or GVHD at 5 months. Nonchimeric and third-party controls rejected limbs within 10 days. CONCLUSIONS: Conditioning of the host WF rats with 950 cGy of irradiation (sublethal, myeloablative) led to high levels of MAC without GVHD. The mature T-cell content of nonirradiated donor (ACI) limbs was sufficient to induce lethal GVHD in 100% of tolerant mixed chimeric [ACI-->WF] hosts. Irradiation of donor limbs before transplantation resulted in long-term donor-specific tolerance and prevented GVHD. These data demonstrate that (1) established chimeras could be susceptible to GVHD caused by immunocompetent donor cells transferred with the hind limb, and (2) inactivating these cells with irradiation prevents GVHD and destabilization of chimerism, and permits rejection-free graft acceptance.     

Current pharmacotherapy for weight loss: A review and implications for plastic surgeons

Background: Many patients who present for plastic surgery take weight loss drugs that can interact with anesthetics or have other adverse effects. Objective: We examine the implications that pharmacotherapy for weight loss might have for plastic surgery. Methods: The mechanisms of action, drug interactions, and possible adverse effects of sibutramine (Meridia) and orlistat (Xenical), the two medications that have been approved for weight loss by the US Food and Drug Administration, are reviewed. Similarly, the effects of both over-the-counter weight loss medications containing ephedrine and caffeine and serotonin re-uptake inhibitors that are used to augment weight loss are examined. We also report on the status of pharmacologic research on weight reduction agents under development, including leptin, neuropeptide Y, and uncoupling protein UCP-5. Results and Conclusions: The best way to avoid any untoward effects of weight loss medications in combination with surgery is to determine whether patients are taking such medications, counsel them concerning possible complications, and insist on discontinuation of pharmacotherapy for weight loss beginning 2 weeks before surgery.     

Cutaneous leishmaniasis: a diagnostic challenge for plastic surgeons

Owing to the relatively low number of patients with cutaneous leishmaniasis seen in plastic surgery clinics, these lesions may easily be confused with other skin diseases and cutaneous malignancies. Seven patients with cutaneous leishmaniasis, who had been misdiagnosed as cutaneous malignancies, were referred to our plastic surgery department. The final diagnoses were made using a Tzanck smear examination and histopathologic examination. Systemic or intralesional meglumine antimonite was successfully used to treat the lesions. Plastic surgeons should be aware that some atypical skin lesions might be a cutaneous leishmaniasis, even if they have a malignant appearance. Surgery may worsen the course of disease, but early medical treatment prevents severe scarring.