Composite tissue allotransplantation a new era in plastic surgery?

Transcription

1 The British Association of Plastic Surgeons (2004) 57, Composite tissue allotransplantation a new era in plastic surgery? Shehan Hettiaratchy a, *, Mark A. Randolph b, François Petit c, W.P. Andrew Lee d, Peter E.M. Butler e a Division of Plastic Surgery/Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, WACC-453, Boston, MA 02114, USA b Plastic Surgery Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, USA c Department of Plastic, Reconstructive and Aesthetic Surgery, Henri-Mondor University Hospital, Paris XII, France d Division of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, USA e Department of Plastic and Reconstructive Surgery, Royal Free Hospital, London, UK Received 1 November 2002; accepted 17 February 2004 KEYWORDS Composite tissue transplantation; Immunosuppression; Tolerance Summary Composite tissue allotransplantation (CTA) holds great potential for reconstructive surgery. The recent hand transplants have made this a clinical reality. However, concerns about CTA have divided the medical community. The current transplants require life-long immunosuppression, which could place the recipients at risk of serious complications. In addition despite potent immunosuppression, chronic rejection may still negate any early favourable results. This article will outline the clinical experience of CTA, the major problems of the technique and the potential solutions to these problems. Q 2004 The British Association of Plastic Surgeons. Published by Elsevier Ltd. All rights reserved. In the 3 rd Century AD, two saints-cum-surgeons Cosmos and Damian, were faced with a challenging clinical problem. One of their most important clients was brought to them with a tumourous growth affecting his leg. He asked that they cure him yet not leave him a cripple. Faced with this seemingly impossible request, they performed the procedure that guaranteed their fame; they amputated the diseased leg and replaced it with the limb *Corresponding author. Tel.: þ ; fax: þ address: shehan_h@hotmail.com from a dead moor (Fig. 1). The tale, though obviously apocryphal, illustrates the surgeon s desire to use cadaveric tissue for reconstruction. Within the last few years, reconstructive cadaveric transplantation has become a clinical reality. To date, 16 patients have received hand transplants and others have undergone transplants such as knees, flexor tendon apparatus, nerves and a larynx. These initial transplants have generated much excitement as well as controversy. This article will describe the current clinical experience of reconstructive transplantation, examine the S /$ - see front matter Q 2004 The British Association of Plastic Surgeons. Published by Elsevier Ltd. All rights reserved. doi: /j.bjps

2 382 S. Hettiaratchy et al. in some form for over 30 years (Box 1). There has been an evolution of transplanting increasingly complex combinations of tissues culminating in the recent whole hand transplants. These initial studies provide a significant amount of preliminary data on CTA and are worth reviewing. For reference, the immunosuppressants most commonly used in these procedures appear in Box 2. Initial experience with composite tissue allografts First hand transplant The first hand transplant was performed in 1963 in Ecuador. 1 This operation was prior to the modern era of calcineurin inhibitor-based immunosuppressive regimens and relied on steroids and azathioprine to prevent rejection. Not surprisingly, the hand was rejected after 3 weeks. Transplantation of composite tissue allografts was not attempted again until the 1990 s. Figure 1 Cosmos, Damian and the dead moor s leg. The unlucky moor can be seen under the bed. major problems that the field faces and finally look at what solutions, we can expect in the future. Clinical experience Composite tissue allotransplantation (CTA) refers to the transplantation of an allograft consisting of heterogeneous tissues, such as a hand. This contrasts to routine solid organ transplantation where the allografts are mostly of one tissue type, such as a kidney or heart. CTA has been attempted Knee The clinical introduction of cyclosporine A greatly improved the effectiveness of immunosuppression for transplantation. In this setting, CTA was revisited. Between 1996 and 2000, Hoffman in Germany transplanted three femoral diaphyses and five whole knees into patients who required the resection of large amounts of skeletal tissue for tumours or trauma. 2 The immunosuppressive regimen used was extrapolated from protocols then being employed in solid organ transplantation and consisted of cyclosporine, azathioprine, methylprednisolone and anti-thymocyte globulin. Despite this potent immunosuppressant regimen, the longterm results were not good. None of the diaphyseal transplants and only two knee allografts were still viable at 2 years; the remainder had all been rejected. The two patients who did not reject their transplants had good function but with an efficacy of only 25%, the regimen could not be deemed a success. Box 1. Composite tissue allografts to date 1963: First hand transplant (rejected after 3 weeks). 1988: Nonvascularised nerve transplantation. 1988: Flexor tendon apparatus transplanted. 1996: Knee transplantation. 1998: Second hand transplant. 1998: Laryngeal transplantation : 18 hand transplants in 24 patients.

3 Composite tissue allotransplantation a new era in plastic surgery? 383 Box 2. Commonly used immunosuppressants and their actions Steroids prednisolone, methylprednisolone nonspecific actions to decrease immune reactivity Calcineurin inhibitors cyclosporine A, FK 506 (tacrolimus) prevent the production of IL-2, an important cytokine in T-cell activation and proliferation Anti-proliferative agents azathioprine, mycophenolate mofetil prevent the expansion of activated T cells Antibodies anti CD25, anti CD3 (lymphocyte surface markers) anti-thymocyte globulin (ATG) target and take out specific cells or cytokines involved in rejection. Flexor tendon apparatus Perhaps one of the most unusual attempts to perform CTA was in hand reconstruction during the late 1980 s. Guimberteau 3 in France transplanted vascularised flexor tendon apparatus based on the ulnar vessels in two patients. One allograft was from a cadaveric donor whereas the other was from a living nonrelated donor, who had to undergo amputation of the little finger to provide the requisite tissues. Immunosuppression consisted of cyclosporine monotherapy for 6 months. At one year follow-up, the functional results were good with reasonable range of motion. Nerve Though not technically a composite tissue, nonvascularised nerve allografts are the most extensively studied reconstructive transplants. The largest clinical series with the longest follow up is Mackinnon et al. s series of seven patients 4 with peripheral nerve allografts. These allografts were either used as the sole treatment for large peripheral nerve defects ðn ¼ 2Þ or in conjunction with the patient s own nerve autografts ðn ¼ 5Þ: All patients were young (mean age ¼ 15 years, range 3 24) and most had suffered their injury within 5 months of transplantation. Immunosuppression consisted of FK506 or cyclosporine A, azathioprine and prednisolone. In addition, the nerve allografts underwent cold preservation at 5 8C for 7 days. This last technique, only possible in nonvascularised allografts, decreases the immunogenicity of the transplant by decreasing the expression of major histocompatibility complexes on the surface of cells. All immunosuppression was stopped once there was evidence of neuronal regeneration distal to the allograft nerve (between 12 and 26 months).the results of these transplants were mixed. One patient rejected their allografts at 3 months. In the remainder, some functional recovery was achieved in the four patients that had received both auto and allografts. The two patients that received allografts alone showed worse results, with some sensory recovery but no motor recovery. It was not clear, therefore, how much functional recovery, if any, was due to the transplanted nerves and how much was due to the recipient s own autografts. In addition, it should be remembered that in this situation the allografts served only as temporary scaffolds for the recipient neuronal tissue to grow down and did not have to survive long-term. This was a different scenario to true CTA, 5 where the donor tissue persists in the recipient. Despite these limitations, Mackinnon s series was the first to demonstrate that transplantation could potentially provide a solution to problems that cannot be solved adequately by autologous tissue. Larynx One of the most remarkable examples of CTA was the laryngeal transplant performed by Marshall Strome in 1998 for a 40 year old man. 6 This situation perhaps most clearly demonstrates the need for CTA. The patient had suffered severe laryngeal trauma at the age of 21. Despite repeated attempts to reconstruct his larynx, he remained aphonic. It was felt that the only way to restore his voice was by laryngeal transplantation. After appropriate physical and psychological investigation, surgery was agreed upon. An immune matched donor was

4 384 S. Hettiaratchy et al. Box 3. Hand transplants to date Date Surgical team September 1998 Lyon (France) Unilateral removed at 28 months January 1999 Louisville (USA) Unilateral September 1999 Guangzhou (China) Unilateral removed at 20 months September 1999 Guangzhou (China) Unilateral January 2000 Lyon (France) Bilateral January 2000 Guangxi (China) Unilateral January 2000 Guangxi (China) Unilateral March 2000 Innsbrück (Austria) Bilateral May 2000 Kuala-Lumpur (Malaysia) Unilateral (between identical twins) September 2000 Guangzhou (China) Bilateral October 2000 Monza (Italy) Unilateral January 2001 Harbin (China) Bilateral February 2001 Louisville (USA) Unilateral October 2001 Monza (Italy) Unilateral June 2002 Brussells (Belgium) Unilateral November 2002 Milan (Italy) Unilateral February 2003 Innsbrück (Austria) Bilateral May 2003 Lyon (France) Bilateral TOTAL 18 patients 24 hands found and transplant performed. The entire pharyngolaryngeal complex, including six tracheal rings, the thyroid and parathyroid glands were removed. The donor larynx and five tracheal rings together with the thyroid and parathyroid glands were transplanted. It was based on the left and right superior thyroid arteries (anastomosed to the recipient s left and right superior thyroid arteries), the right internal jugular vein (anastomosed to the recipient s common facial vein) and the left middle thyroid vein (anastomosed to the recipient s left internal jugular vein). Both superior laryngeal nerves and the right recurrent laryngeal nerves of the allograft were sutured to the equivalent recipient nerves. Initial immunosuppression consisted of anti-cd3 monoclonal antibodies, cyclosporine, methylprednisolone and mycophenolate mofetil. Maintenance immunosuppression was cyclosporine (switched to FK 506 after 1 month), mycophenolate mofetil and decreasing dose of prednisolone. At follow-up 2 years later, the patient had regained a human sounding voice, with good force and intonation. Inevitably there were some problems. The patient initially required a tracheostomy, which has yet to be closed. There has been one episode of rejection that required treatment with steroids. Despite these problems, the procedure was hailed as a success. The patient states that the quality of his life has been increased immeasurably. Prior to injury, he was unemployed. Today, he is a motivational speaker, evidence of the good function of his allograft. Perhaps the most convincing testimony to the success of the procedure came from Tony Monaco, 7 himself an eminent transplant surgeon who had undergone a laryngectomy for malignancy 7 years previously. Having reviewed the case and the outcome he said that, if he had his time again, he would opt for a transplant. Current hand The largest series of composite tissue allografts is the current cohort of hand transplants, the first of which was performed in The basis for this initial operation had been developed over the preceding 4 years. There were two main obstacles that needed to be overcome. Firstly, a successful immunosuppressive regimen had to be developed that would prevent the rejection of all the tissues in a hand, in particular the skin. Secondly, ethical agreement had to be reached as to when a hand transplant should be attempted and in what kind of patient. The first of these problems was partially solved be experiments performed in Louisville, USA. A swine model of limb transplantation was developed and various immunosuppressive

5 Composite tissue allotransplantation a new era in plastic surgery? 385 protocols were experimented with. One of these that used FK506, mycophenolate mofetil and prednisolone was found to prevent allograft rejection and was, therefore, put forward as a clinically valid regimen. 8 However, the experimental data for this protocol was not good. Of the nine animals treated with it, three died from sepsis and one from a gastric rupture. The remaining five (55%) showed no signs of rejection at time of sacrifice at 90 days post transplant, though there was a high incidence of infective complications. Nonetheless, given that similar immunosuppressive regimens were successful in solid organ allografting, the protocol was accepted as one that could be tried in hand transplants clinically. The second challenge of when and in whom it would be ethical to perform a hand transplant was more controversial. The main problem, as with any novel procedure, was that both the outcome and the risk of the operation were unknown. A consensus opinion was sought at the first CTA conference at Louisville in Experts in the fields of transplantation, hand surgery and ethics debated when the first hand transplant should be performed and in what type of patient. A unanimous decision was not reached but the majority felt that it would probably be reasonable to perform a transplant on a patient who had lost both hands. 9 This qualified endorsement was nonetheless taken as a green light for hand transplantation and the first procedure was performed 1 year later. Over the last 6 years, 24 transplants have been performed in 16 patients worldwide 10 (Box 3). The immunosuppressive regimens used have been based on protocols developed in solid organ transplantation. Most involve the combination of FK 506, mycophenolate mofetil and prednisolone. 11 Some centres have also added monoclonal antibodies during the initial therapy. The candidates for these operations have all been male and relatively young. They have all been in good health with only one patient having any significant intercurrent chronic illness (type 1 diabetes mellitus). The results of these transplants have stimulated great debate and have been used to argue both for and against the procedures The complications that have been reported so far are mostly infections secondary to immunosuppression. These have included chronic viral and fungal infections (four patients) requiring treatment with appropriate anti-viral and anti-fungal agents. Four patients developed transient hyperglycaemia secondary to steroids and FK 506. The first Chinese recipient developed the clinical manifestations of Cushing s syndrome due to high doses of steroids. 13 So far none of the patients have shown any drug toxicity problems (neuro- and nephrotoxicity). The most significant complications have been rejection episodes. The first hand transplant recipient suffered repeated episodes of epidermal rejection that were treated with increased systemic immunosuppression. 11 Eventually this patient stopped taking his medication, inevitably leading to rejection of the allograft and amputation. The second French patient, both the US patients and the first Italian patient have all suffered episodes of rejection that have required increased systemic immunosuppression. 13 It has recently been reported that one of the Chinese recipients has had his transplant removed. The patient developed refactory sutanes rejection and was being treated with subcutaneous steroid injections. Unfortunately one of these was placed intra-arterially which led to graft loss (personal communication, WP Andrew Lee). The outcomes of these hand transplants have been mixed. Only the results of the first four transplants have been published but others have been presented at various meetings around the world. Videos of the first five transplants show good finger flexion and extension based on the preexisting extrinsic muscles. Intrinsic function has been poorer. There is electromyographic evidence of intrinsic reinnervation and also some functional evidence of thenar muscle activity in the first US, second French and one of the Chinese recipients. 12 However, in general intrinsic function appears to be poor, necessitating tendon transfers to improve hand position and function. Sensory reinnervation has also not been as good as was predicted. It was hoped that reinnervation in the hand transplants might be faster than in replants as it has been shown that FK 506 has some neurotrophic effects. 15 This does not appear to be the case. The first four patients did show advancing Tinel s sign and some showed histological evidence of nerve regeneration. 16 However, the only patient to have Semmes Weinstein testing documented (the first US recipient) showed diminished protective sensation in his thumb but no protective sensation in the other digits 3 years post-transplant. 11 This lack of even protective sensation in most of the hand significantly compromises the usefulness of the transplant. The overall functional outcome of the hand transplants has been assessed using the Carroll test. 11 This objective assessment determines the ability to perform 33 different tasks. The maximum score is 99. Excellent is scored.85, good 74 85, fair is scored and scores,51 are graded as poor. The first US transplant scored 61 (fair) at

6 386 S. Hettiaratchy et al. three years post-transplant and the second US transplant scored 50 (poor) at one year postoperation. The first two Chinese recipients scored better (65-fair and 75-good) but this was only 7 months after the transplant. The average for these first four procedures is 63. This compares to a Carroll score of 51 for a prosthetic limb and 70 for replants distal to the elbow. 17 Despite these average objective results, proponents of hand transplants believe that this equates to a return to reasonable function 12 and argue that the operations have transformed the recipients lives. While this may be true for the bilateral hand transplants, it is not clear how much benefit the unilateral recipients have obtained from their allografts. Challenges Despite the aforementioned limitations, the current hand transplants have exceeded many people s expectations. Some predicted that all the transplants would be rejected within a year; few would have expected all but two to still be viable. However, numerous obstacles must be overcome before reconstructive transplantation can be accepted as a routine technique. One challenge that is particular to CTA is the additional donor recipient matching that is required compared with solid organ transplantation. The other main challenges are to reduce or eliminate the need for continuous immunosuppression and prevent chronic rejection from compromising long-term results of transplantation. There is no ready solution to the first of these problems but the latter two are the focus of extensive research. Donor recipient matching for CTA All organ transplantation requires some form of screening. The donor and recipient must be of the same blood group to prevent hyper-acute rejection due to preformed antibodies. Ideally, the recipient and donor should be of the same cytomegalovirus (CMV) status as this virus can lead to serious complication post transplantation. The other matching issue that should be addressed is the degree of immunological similarity or histocompatibility there is between the recipient and donor. It has been shown in solid organ transplants that the more the donor and recipient differ immunologically, the higher the incidence of rejection. This has lead some groups performing CTA to attempt some form of histocompatibility matching. The two Chinese hand transplant recipients had three out of the main six histocompatibility antigens matched whereas the laryngeal transplant had all six antigens matched. It is not clear yet whether this amount of matching will have a significant influence on allograft survival. However any reliance on histocompatibility matching to prevent rejection would seriously limit the number of donor recipient combinations in CTA and would, therefore, preclude the widespread use of CTA. There are some screening issues that are unique to CTA. Most reconstructive allografts are visible and, therefore, must be cosmetically matched to the recipient. Broadly this means that the donor and recipient should be of the same sex, ethnicity and also be of similar age. The amount of cosmetic matching required will depend on the transplant being performed; the matching for a face transplant would have to be more accurate than that for a hand transplant. Conversely, a double hand transplant may not have to be as carefully matched as a single hand transplant. Either way this additional matching required for CTA means that donor recipient pairing will be much harder than for solid organ transplantation. This may require the initiation of international recipient databases and a high level of collaboration between units if the use of all potential donors is to be maximised. The risk of immunosuppression The other major problems facing CTA are the requirement for immunosuppression and the occurrence of chronic rejection. Great advances have been made in immunosuppression over the last 30 years. There has been a reduction in the adverse effects of immunosuppressants and an increase in the specificity of their actions. However, even modern immunosuppressive drugs can be deleterious to a patient s health. 13 The incidence of these side-effects is important to clarify in order to determine the risk to patients undergoing CTA. The side effects from modern immunosuppressants can be divided into three categories; drug toxicity, opportunistic infections and finally malignancies. The main classes of immunosuppressants that are used in transplantation are calcineurin inhibitors (cyclosporine, tacrolimus), anti-proliferative agents (mycophenolate mofetil, MMF) and corticosteroids (prednisolone). These all have specific side-effects. Cyclosporine is nehprotoxic, can induce hypertension, hyperglycaemia, hyperlipidaemia and also gastro-intestinal complications. Tacrolimus is neuro- and nephrotoxic and can also induce diabetes. Though the incidence of these complications varies, nephrotoxicity of some form

7 Composite tissue allotransplantation a new era in plastic surgery? 387 has been reported in up to 70% of patients. 18 MMF causes gastro-intestinal upset in up to 30% of patients and leucopenia in 20 40%. 19 Steroids are associated with a wide variety of problems, in particular delayed wound healing, diabetes and gastrointestinal perforations. Eighty percent of solid organ transplant recipients develop some form of infection and 40% of post-transplant deaths are due to infective causes. 20 Of all infections, 55% are bacterial, 30% viral and 15% fungal. In addition up to 10% of transplant patients develop a chronic viral infection (Hepatitis B or C), which can lead to liver failure or hepatocellular carcinoma. 21 The most serious complication from immunosuppression is the occurrence of malignancies. The incidence of malignancy in transplant patients ranges between 4 and 20%, depending on the immunosuppressive regimen. 22 Most of these malignancies are skin cancers that can be dealt with by surgery but 20% are nonskin malignancies. 23 For renal transplant patients, the risk of developing post-transplant lymphoproliferative disease is between 2 and 10%. 24 This disorder, usually characterised by a proliferation of host B cells, has no effective treatment and can be fatal. Given that the immunosuppressive regimens of hand transplant patients is similar to that for renal transplant recipients, the incidence of malignancies that can be expected in the CTA population will be similar to the documented incidence in solid organ transplant recipients. As well as these direct problems with immunosuppression, there is a secondary problem that can be caused by the combination of immunosuppression and organ transplantation; graft-versus-host disease (GvHD). This is a situation where the cells from the transplanted organ, in particular donor T lymphocytes, migrate out of the allograft and attack the host tissue. Common sites affected include the haematopoietic tissues, leading to neutropenia, the gastro-intestinal tract and the skin. The incidence of GvHD is related to the tissue transplanted but any tissue that is rich in donor lymphocytes has potential to cause GvHD. This may be particularly problematic in a composite tissue allograft that contains a bone marrow compartment, such as a hand transplant, as this is a repository of donor lymphocytes. The concern that the bone marrow in a hand allograft could cause GvHD has lead some groups to irradiate the limb prior to transplantation or even to physically scoop out the bone marrow from the transplanted radius and ulna. It can be seen that immunosuppression potentially poses significant risks to the recipients of composite tissue allografts. This may be harder to justify in the context of CTA than solid organ transplantation. Most solid organ recipients are suffering from a chronic disease that can only be improved/cured by a transplant. Patients who require CTA are usually fit and well except for the defect that is to be reconstructed. Transplantation, with its required immunosuppression, can only make them physically less well. This is the basis for the primum non nocere argument used by critics of the procedure. Accepting risk is common to all forms of reconstructive surgery. The new dilemma that CTA brings is that the risk is not just at the time of surgery but continues as long as the patient is on immunosuppression. This may be more difficult to justify than the one off, contained risk of other reconstructive procedures. Proponents of immunosuppression based CTA argue that it is the patient s choice as to how much risk they are willing to trade for improved quality of life. This is of course true; we cannot imagine how disabled a bilateral upper limb amputee feels. However, if the risk of CTA could be reduced, then the procedure would be more acceptable to both patients and the medical community. It is easy to be side-tracked into arguments about risk-benefit equations when discussing reconstructive transplantation. The debate will always come down to a matter of opinion because the key benefit, improved quality of life, is subjective. There is, however, an objective reason why it would be beneficial to move away from immunosuppressive protocols. That reason is chronic rejection. Chronic rejection Chronic rejection is a major challenge for CTA. It is a poorly understood phenomenon that has a multifactorial aetiology, including ischaemic damage at time of transplantation and immune reactivity to the allograft. 25 In solid organ transplants, chronic rejection leads to a gradual attrition in organ function so that by 10 years only 50% of renal allografts are still functional. Chronic rejection may have an even greater impact in CTA for several reasons. Given that half of the hand allografts have suffered some form of acute rejection, one would predict that these transplants would have a significant incidence of chronic rejection. This may only manifest itself between 5 and 10 years post-transplant. The nature of composite tissue allografts may make them more vulnerable to chronic rejection than solid organ transplants. Solid organs, such as kidneys, are homogeneous structures. If 50% of a kidney s

8 388 S. Hettiaratchy et al. nephrons are lost that kidney will still be able to fulfil its functional role of maintaining a normal serum creatinine. However, if a hand allograft were to suffer the same amount of damage, it would become functionally impaired, if not useless. Finally, the incidence of chronic rejection increases with time. For solid organ transplants, this may not be significant as these organs are often put into patients who have a limited life span and may not outlive their allografts. Hand transplants, however, are being performed in young patients and so the allografts need to survive and function for years. All of these factors mean that the current success with hand transplants may be short lived as chronic rejection negates any early favourable results. If this is the case then CTA will only be a temporary solution to reconstructive problems and its inherent risk becomes harder to justify. In addition coping with allograft rejection may be much more difficult in CTA than in other forms of transplantation. If a renal or cardiac allograft rejects, then a retransplantation can be performed and function can be immediately regained. However, if a hand required retransplantation then the recipient would have to begin again the long rehabilitation required to regain hand function. Some reconstructive allografts may not be salvageable if they are rejected. A face transplant, for example, where there has been extensive resection of the recipient tissue at time of transplantation, may be impossible to reconstruct if rejected. The challenge in CTA, even more so than in solid organ transplantation is to remove the spectre of rejection. Fortunately, eliminating all forms of rejection is one of the major research goals in transplantation and success may soon be achieved. Research solutions The main challenges facing CTA, to minimise immunosuppression and prevent chronic rejection, are also the main problems facing solid organ allotransplantation. Various solutions are being explored both clinically and experimentally. One solution is to try and improve the efficacy of the immunosuppressive regimens that are available. Over the last 30 years there have been numerous innovations in the field of immunosuppression, with novel agents and dosing regimens. This has lead to a decrease in the incidence and severity of the morbidity of immunosuppression. However, though these new drugs have decreased the incidence of acute rejection, there has been no impact on graft loss due to chronic rejection. 25 Given this fact, it is unlikely that the solution to the problem of chronic rejection will lie with newer immunosuppressants. There is a more ambitious solution to the double obstacles of immunosuppression and chronic rejection. This is to generate recipient tolerance to the transplanted tissue. In this situation, the recipient does not mount an immune response to donor tissue but tolerates it as his/her own tissue. 26 The recipient can respond normally to all other challenges and, therefore, remains immunocompetent. This means that the risk of opportunistic infections or any of the other problems caused by generalised immunosuppression is greatly reduced. Most importantly, the lack of immune reactivity between the recipient and the donor tissue decreases, if not eliminates, the incidence of chronic rejection, thus ensuring good long-term graft function. Tolerance is one of the most sought after goals in transplantation and excitingly, clinical tolerance has recently been achieved. Tolerance The only way that tolerance has been generated clinically is by using bone marrow transplantation. Such transplants lead to situation known as haematopoietic chimerism, where the recipient has haematopoietic cells, including cells of the immune system, of both its own and donor origin. This leads to a fundamental reprogramming of the recipient s immune system so that it recognises and accepts the donor tissue as it s own. The fact that this can lead to allograft tolerance in humans was first seen in a patient who had multiple myeloma. 27 The patient required a bone marrow transplant from a sibling. Despite a successful bone marrow transplant, the patient went into renal failure due to myeloma kidney and required a renal transplant. The same sibling who had originally donated bone marrow agreed to donate a kidney. This was transplanted successfully and was accepted without any immunosuppression. A trial is now being conducted in Boston, USA to perform simultaneous bone marrow and renal transplants without longterm immunosuppression. All the patients that have undergone the procedure to date have accepted their kidneys without long-term immunosuppression. Though, these patients prove that tolerance can be achieved clinically, they required a toxic conditioning regimen for their bone marrow transplants. In particular, high dose whole body irradiation was used to ablate their own bone marrow prior to the donor bone marrow being infused. This procedure, though appropriate when dealing with a haematological malignancy, would

9 Composite tissue allotransplantation a new era in plastic surgery? 389 Box 4. Glossary Composite tissue allotransplantation: transplantation of tissue that is diverse in nature, e.g. a hand cf a solid organ transplant, e.g. a kidney that is largely homogenous. Histocompatibility: the amount of immunological similarity between one individual and another. Chronic rejection: a poorly understood phenomenon that leads to allograft loss over a number of years due to both immunological and nonimmunological factors. Tolerance: a situation where a transplant recipient does not mount an immune response to the donor tissue but remains responsive to all other stimuli. Graft-versus-host disease: a scenario post-transplantation where immunocompetent cells of donor origin attack the recipient. not be acceptable for a tolerance protocol for CTA. The challenge now is to generate a nontoxic tolerance protocol that could be used in routine organ transplantation. Several experimental approaches have been developed. Sykes et al. 28 showed that if high dose bone marrow was given in conjunction with drugs that prevent full T-cell activation (known as co-stimulatory blockade) then all forms of irradiation could be avoided in the mouse model. In larger animals, Sachs and Huang 29 have developed a regimen to induce hematopoietic chimerism in swine that requires minimal irradiation. This involves using an immunotoxin that binds to the recipient T cells and depletes them. Donor hematopoietic stem cells are then infused intravascularly and engraft in the host bone marrow and thymus. The thymus is where T-cells are educated and where self-tolerance is determined. The presence of donor cells in the thymus leads to the development of tolerance to these donor cells and hence donor allograft acceptance. This regimen has successfully generated tolerance to renal 29 and cardiac allografts 30 in the swine model and a similar protocol induces tolerance to kidneys in the monkey model. 31 We are currently evaluating a protocol based on these studies in the swine limb transplantation model that requires no irradiation. Our preliminary studies are very promising, as all animals so far ðn ¼ 7Þ have accepted limb allografts across a complete major histocompatibility barrier. 32 The protocol developed by Sachs and Huang may soon be realised clinically. The key elements of this model, such as the use of T-cell depletion and haematopoietic stem cells, are already being used clinically in transplantation. Calne et al. 33 have used a T cell depleting agent, CAMPATH-1H in patients receiving kidney allografts. In their series, these patients could be maintained on low dose cyclospsorine alone and did not require any steroid based therapy. Obtaining clinical tolerance with a minimal recipient conditioning regimen may be achieved in the next 5 years. This would significantly improve the risk-benefit ratio of all transplantation, in particular CTA. Future outlook The arguments for and against CTA are currently raging. 10,34 There is no doubt that reconstructive transplantation has great potential. It is the only form of reconstruction that truly upholds Gillies principle of replacing like with like. It is the sole surgical solution for certain conditions that cannot be reconstructed with autologous tissues, such as the loss of a hand or larynx. The survival of the current hand transplants is far better than many Box 5. Keypoints Composite tissue allotransplantation, in particular hand transplantation is currently being performed around the world. Most hand transplants have been successful though function may not be as good as was hoped for. Chronic rejection may compromise long-term function. Research is focussing on ways of transplanting without using immunosuppression to reduce risk and prevent chronic rejection. The current hand transplant experience could form the basis for other transplants, such as face transplants.

10 390 S. Hettiaratchy et al. Box 6. Further information information on all the hand transplants to date. Louisville, USA team s site with general information and specific data on US hand transplant recipients. American Society for Surgery of the Hand site with debate on hand transplantation. website proposing the rationale for face transplantation. for a good series of articles for and against hand transplantation try: * Breidenbach WC, Tobin GR, Gorantla VS et al. A position statement in support of hand transplantation. J Hand Surg 2002;27A: * Jones NF. Concerns about human hand transplantation in the 21st Century. J Hand Surg 2002;27A: predicted. The fact that just one transplant has been rejected is testament to the determination of the various transplant teams around the world. However, the function of these hand transplants may be falling short of what was hoped for. In addition chronic rejection may further compromise long-term results. Only time can tell whether the current transplants will be a success or not. Even if the current batch of transplants are successful in the long-term, CTA is unlikely to be a panacea for all large or complex tissue defects. CTA will face the same problem that plagues solid organ transplantation, a lack of suitable donors. The situation will be worse for reconstructive transplantation, as donor recipient combinations will require cosmetic matching in addition to immunological screening. It is unlikely that we will be able to develop a completely morbidityfree protocol for using cadaveric tissue. Immunosuppressants, no matter how specific, will have side-effects. Tolerance induction regimens, even if highly effective, will have some morbidity. Because of these factors a solution to a surgical problem that uses autologous tissue will always be preferable to one that requires allogenic tissue. However, for those situations where reconstruction with autologous tissue is not possible, transplantation may significantly improve our ability to reconstruct the human body. Though it may not be a new era in plastic surgery, reconstructive transplantation has the potential to be one of its greatest advances (Box 4 6). Acknowledgements We would like to thank Dr Carolyn Hemsley for help with the text. References 1. Gilbert R. Hand transplanted from cadaver is reamputated. Med Trib Med News 1964;5: Hofmann GO, Kirschner MH, Wagner FD, et al. Allogenic vascularized transplantation of human femoral diaphyses and total knee joints first clinical experiences. Transplant Proc 1998;30: Guimberteau JC, Baudet J, Panconi B, et al. Human allotransplant of a digital flexion system vascularized on the ulnar pedicle: a preliminary report and 1-year follow-up of two cases. Plast Reconstr Surg 1992;89: Mackinnon SE, Doolabh VB, Novak CB, et al. Clinical outcome following nerve allograft transplantation. Plast Reconstr Surg 2001;107: Hettiaratchy SP, Mathes DW, Petit F, et al. Neuronal allografting represents a unique scenario. Plast Reconstr Surg 2002;109: Strome M, Stein J, Esclamado R, et al. Laryngeal transplantation and 40-month follow-up. N Engl J Med 2001;344: Monaco AP. Transplantation of the larynx a case that speaks for itself. N Engl J Med 2001;344: Jones Jr JW, Ustuner ET, Zdichavsky M, et al. Long-term survival of an extremity composite tissue allograft with FK506-mycophenolate mofetil therapy. Surgery 1999;126: Siegler M. Ethical issues in innovative surgery: should we attempt a cadaveric hand transplantation in a human subject? Transplant Proc 1998;30: Lee WPA. The debate over hand transplantation. J Hand Surg 2002;27A: Francois CG, Breidenbach WC, Maldonado C, et al. Hand transplantation: comparison and observations of the first four clinical cases. Microsurgery 2000;20: Breidenbach WC, Tobin GR, Gorantla VS, et al. A position statement in support of hand transplantation. J Hand Surg 2002;27A: Jones NF. Concerns about human hand transplantation in the 21st Century. J Hand Surg 2002;27A: Hettiaratchy SP, Butler PEM, Lee WPA. Lessons from hand transplantation. Lancet 2001;357: Steiner JP, Connolly MA, Valentine HL, et al. Neurotropic actions of non-immunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporine A. Nat Med 1997;3: Kanitakis J, Jullien D, De Boer B, et al. Regeneration of

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