Immunosuppression

We easily forget that the first kidney transplant in France only survived 3 weeks,¹⁴ as was the case for the first heart transplant¹⁵ and the first liver transplant.¹⁶ It is the understanding of Joseph Murray that the rejection was mostly due to an immunological phenomenon which led to intense research in immunology.¹⁷ In 1972, Joseph Murray¹⁸ explained his views on organ replacement and restoration of facial deformities, in his discourse to the Massachusetts Medical Society. Kidney transplantation was a developing field at that time, and face transplantation was not even a concept. Immunology was not then ready for CTA. In 1963, the first hand transplant was attempted and did not survive more than 3 weeks^19,20 because of lack of immunosuppressive therapy at the time. In the years after the first heart transplant, the mortality rate was such a concern that many teams abandoned the principle, even though the surgical technique was well established. Starting in 1976, cyclosporine²¹ significantly improved the survival rate of patients by combining effective prevention of graft rejection and lack of hematologic toxicity. Other immunosuppressive agents introduced in recent years (tacrolimus,²² mycophenolate mofetil,²³ monoclonal antibodies,^24,25 antilymphocyte serum²⁶), have expanded the range of available therapeutic drugs in organ transplantation, allowing to cope with almost all situations of rejection. The standard immunosuppressive treatment of CTA is a scheme suitable for high immunological risk transplantation such as lung transplants.²⁷ It combines induction most of the time with antilymphocyte serum, which will cause lysis of effector cells responsible for acute cellular rejection, CD3+ T-lymphocytes, followed by maintenance therapy consisting of a three immunosuppressive drugs. Long after the first experimental work of Medawar,^28,29 the skin appeared to be the ultimate barrier requiring anti-rejection drug too toxic to be tolerated long term. Furthermore, the complexity of the human immune system and the presence of the immunocompetent element in transplanted tissue during CTA^30,31 could even be a threat by inducing graft-versus-host disease (GVHD) due to the presence of bone marrow and/or lymph nodes potentially involved in immune response. Since 1990, numerous studies were conducted in animals and in 1998, a team from Louisville showed that an immunosuppressive therapy combining Tacrolimus, Mycophenolate Mofetil and prednisone, could prevent the rejection of a complete transplanted limb, without major toxicity in a pre-clinical animal model (adult pig).³² All this knowledge has led to relatively standardized protocols. Thus, the Lyon team, led by Dubernard^10,33 renewed the attempt to graft a hand, first unilateral then bilateral. If the unilateral graft eventually resulted in failure, this was due to the discontinuation of the patient, the first bilateral hand transplant was undoubtedly a success that has brought CTA to a clinical reality.³⁴

We will focus here on the practical aspects of the treatment used in CTA. Today the standard treatment begins with an induction by injection of monoclonal or polyclonal antilymphocyte antibody. There is insufficient data so far between the choice of a monoclonal versus a polyclonal antilymphocyte antibody.³⁵ In practice (Table 20.1), injection of antilymphocyte serum begins in the operating room just after the end anastomosis. The induction is then followed by a tri-therapy combining mycophenolate mofetil (MMF) and FK506 (tacrolimus) and steroids. The monitoring of this treatment requires accurate dosing in the days after surgery. Antilymphocyte serum needs a daily dosage of CD3+ T-lymphocytes. For tacrolimus, it is necessary to have a blood level of 10–15 ng per mL. For the Cellcept, repeated testing is performed to estimate the average concentration by using the area under curve (AUC) concept, which should be in the range of 40–50 ng/mL.

Table 20.1 Induction protocol

Other treatments are currently under study.³⁶ Apart from drugs, research protocols are directed towards tolerance induction. The concept was mostly developed by Starzl.^37–39 The principle is to prepare the donor or the graft so that the antigens of the transplanted organ are recognized as the antigens of the recipient. Many protocols exist in animals, but most involve a preparation by radiation which is not compatible with clinical practice. Recent approaches applicable in humans consist of a concomitant injection of hematopoietic stem cell from the donor. This bone marrow transplant can be a myeloablative protocol, i.e., removing the bone marrow recipient, which will change the immune system of the recipient and may cause a GVHD reaction. Thus, although particularly effective myeloablative approach is only used if there is a need for bone marrow associated to a solid organ transplant, as in the case in patients with myeloma with kidney failure, it is not applicable in the field of functional transplantation, as are CTAs. Nonmyeloablative protocols have been used in many animal models with success,^40,41 but we do not have conclusive results in humans. For some, the presence of bone marrow in the bones of the donor’s hand is a true hematopoietic stem cell transplant and would explain the good results of these grafts. However, the comparison between the first three facial CTAs shows similar results in terms of immunosuppression with or without hematopoietic stem cells transplantation, as in the first transplant, or without, as in the two following. For others, the bone marrow transplant is only effective when transplanted with a vascularized bone which is the case in the hand and in transplants with mandible. This is not the case for the maxilla due to the relative paucity of bone marrow in the maxilla.

Some more subtle approaches seek a peripheral tolerance by treatment of blood cells trying to reduce the response of T-cells by causing antigen-presenting cells to a tolerogenic phenotype through apoptotic elements. This is the case of extracorporeal chemo-phototherapy (ECP),^42–44 where leukocyte cells are irradiated with UVA after leukapheresis and pretreated with psoralen. The principle of ECP is to induce apoptosis with UVA radiation after their presentation by psoralens. These leucocytes are immediately reinfused into the patient, where they undergo early apoptosis. Following apoptosis, the leucocytes are engulfed by macrophage or other antigen presenting cells such as immature cells in an anti-inflammatory environment. The anti-inflammatory pattern and the engulfment by immature cells without co-stimulatory molecules induces anergy by deleting effector T-cells that respond to the presented antigens. An increase in regulatory T-cells is also induced after ECP and may contribute to the allograft acceptance by the recipient. ECP has already been used for the great majority of solid organ transplantations to cure acute rejection episodes or in an attempt to prevent or cure chronic rejections.

For Starzl,^35–37 a pioneer of liver transplantation, tolerance should not be sought immediately, but should rather be a progressive approach through immunomodulation with rapid decline of anti-rejection treatment after the induction phase and adapted control of rejection. In light of his experience in transplantation of kidney and liver, he explained that in some cases, we may obtain a long-term safe treatment with low or no immunosuppression, by allowing the rejection to occur but by controlling it fast before the immune system is overwhelmed or the graft is damaged. The rejection will not only stimulate toxic T-cells but also regulatory cells. A long-term tissue chimerism should then occur even if never demonstrated in the transplanted patient. The results observed in our long-term follow-up in our team, are in favor of this hypothesis, as we have obtained a state of immunological stability, despite the strong decrease of immunosuppressive therapy.

Acute rejection is almost inevitable after the induction phase, when the rate of T-lymphocytes recovers at 3 weeks, but it is easily controlled by several boli of steroids. However, infection episodes can trigger other acute rejection episodes and need further specific treatment. Chronic rejection resulting in destruction of the graft, seen in all other transplants, has not been seen in a face transplant but is still a major threat. It seems however, that in the hand and face transplant patient with long-term follow-up, the grafts do not show any signs of degradation.

Face transplant only necessitates blood type compatibility. However, HLA matching can be a necessity in the case of patients who are sensitized, as seen in the burn patient who has received cadaver allograft, or after blood transfusion.⁴⁵ Each screened patient should have an anti-HLA serum test every 3 months during the preoperative period. HLA antibodies can appear also even in the absence of any recognized transplant, as certain viruses can mimic HLA antigens.⁴⁶ This explains the occasional apparition of these antibodies when very sensitive detection methods as Luminex⁴⁷ are used. In the case of a high level of positive HLA antibody, desensitization can be attempted but is often inefficient.⁴⁸ A virtual preoperative cross-match should be made and this has to be negative to allow transplantation, followed by postoperative real cross-match. If real cross-match is positive, then specific treatment by anti-CD20 monoclonal antibody and injection of immunoglobulin should be made to avoid humeral rejection.

Patient selection

Video1

Contrary to hand transplants, indications for a face transplant seem somewhat difficult to determine. In the hand, we are looking at organ replacement in a patient with no hand, whereas in faces, there is a patient with no face and most of the patients can benefit from reconstruction using autologous tissue. However, there are elements in the face that cannot be reconstructed, which are the orbicularis muscle (orbicularis occuli and/or orbicularis oris). The indication should then be limited to this type of destruction. These are rarely isolated and can be seen in various etiologies, such as burns, ballistic traumas, animal bites and tumors. Many classifications have been published to try to score potential candidates. In our limited experience of five transplanted patients out of an initial 12 selected patients with a potential need of transplant, none of these classifications have been useful to determine the right indication. Indication for face transplant is a combination of three elements: the defect, the patient, and the transplantation team. Various traumas lead to a large variety of defects which are difficult to classify but that can be summarized in two types of transplant, depending on the kind of muscle destruction: upper face transplant for orbicularis occuli and lower face transplant for orbicularis oris. Full face transplant is a combination of both. The transplant can be limited to the lower face when the orbicularis oris is destroyed. This can be found in ballistic trauma where the mouth and the nose are destroyed and can be transplanted but the indication is related to the destruction of the mouth, not the nose. For the upper face, bilateral eyelid destruction, e.g., can be found in burn patient; the transplant is then justified and can be combined with other elements of the face like the ears and the nose. The indication is not limited to the anatomical aspect of the defect but should be estimated in combination with the immunological aspect and the psychological aspect, as even with the same defect some patients are not suitable for transplant due to immunological or psychological contraindications. In terms of immunology, some patients can be presensitized by either blood transfusion or a cadaveric skin graft. In the case of presensitization, an evaluation can be made for potential HLA compatible donors to estimate the possibility of having an organ in a reasonable time. If, for instance, the patient is presensitized to HLA A2, which is present in 50% of potential donors, only half of the potential donors will be suitable for this recipient. The enlistment has then to be carefully evaluated with the organ procurement organization and only done if the chances of transplant are real. The psychological evaluation of the patient is, of course, a key element to enlistment. Contraindications are mostly psychological instability, borderline personalities, addiction, and more generally, any psychiatric disorder that supposedly creates a doubt in the capacity of the patient to understand or to follow a lifelong treatment. The psychological and psychiatric evaluation takes time. During that process where the patients are hospitalized for evaluation, contact with different elements of the team are made. The nurses and assistant nurses have to be integrated into this process, as they are constantly confronted with the patient and can help to have a clear view of the adaptive capacity of the patient. Interestingly, it is probably the patients who have shown initially the best adaptive capacity, who have the best outcomes. An informed consent in such extreme surgery should be obtained with a clear understanding of the patient of the risks of the surgery but also that the transplantation implies a lifelong treatment. Ethical questions are raised for patients who are children, teenagers, and for emergency cases. Until more data are collected, it is for us to go early into this field with the simple question of free will. We advocate the use of time trade off (TTO) to evaluate the motivation of the patient. This consists of asking the patient how many years of life he will be ready to give to have perfect health. However, the TTO is only a tool. We have also been using quality-of-life scales, which are all adapted for disfigured patients evaluated for face transplant. If elements concerning the defect and concerning the patient (immunology and psychology) are not contraindicated, the third element is the transplantation team. All the members have to approve the case via several staff meetings. Rehearsals are mandatory to keep the spirit of teamwork and the instruments have to be regularly checked so that no logistic problem will appear during the procedure.

Face transplant harvest

We recommend developing a reproducible and standardized technique.^49,50 The best technique is to harvest a full face transplant and to remove the unnecessary elements for the recipient. In this way, as all the elements are brought from the donor, the recipient team are confident as to what to remove on the recipient. Moreover, the reconstitution of the donor is easier. Basically, the drawing (Fig. 20.6) goes from the scalp as a coronal incision; goes behind the ears and down to the neck, where a large skin flap has to be elevated and is only limited by the tracheotomy. The dissection starts in the neck with the approach of the external jugular vein on each side (Figs 20.7, 20.8). This vein has to be dissected as low as possible to allow its use on the recipient. It is divided to have access to the deep vessels. The carotid artery and vein are isolated and followed upward. The thyrolingofacial trunk is then isolated (Figs 20.9–20.11). To have access to the different vascular branches, the hypoglossal nerve and the posterior part of the digastric muscle has to be divided (Fig. 20.12). This has to be done on both sides before proceeding to the next step. The facial nerve is approached through a parotidectomy access route. It is dissected until its bifurcation and transected at its exit from the stylomastoid foramen (Fig. 20.13). A 8-0 nylon is used to facilitate its location once on the recipient. To facilitate the approach, the external auricular conduit is transected. This way the facial nerve can be seen well and the maximum of nerve can be harvested. At that stage, several branches of the external carotid are still holding it back. The pharyngeal and lingual arteries have to be divided. One should take great care not to cut the facial artery at that stage, as it is running deep in the neck. The posterior auricular artery should be raised with the flap to allow scalp blood supply. For face transplant including the upper part and the scalp, the incision is sagittal and the flap is raised from posterior to anterior, followed by the forehead and including both ears (Figs 20.14, 20.15). The sagittal incision allows the harvest of the entire scalp. It is not necessary to harvest the occipital arteries. The dissection of these arteries is difficult and rarely reproducible, as they run very deep behind the sternocleidomastoid muscle. Our anatomical studies revealed that the superficial temporalis pedicle can perfuse at least 80% of the scalp and that the posterior auricular arteries are more important than occipital artery for scalp blood supply. The sagittal incision runs from the occipital area to the vertex. The scalp is dissected on a subperiosteal plane from backwards to forwards, as in a coronal approach. If the scalp is not necessary, a standard coronal approach is done. At that stage, the flap holds laterally by both maxillary arteries and vein just at the temporomandibular joint level. These vessels are ligated on both sides, which helps to have access to the orbital region (Figs 20.16, 20.17). On the upper part of the flap, the dissection goes down to the levator muscle, which is divided after positioning a 3-0 nylon for easier repair (Figs 20.18–20.21). The flap is then raised towards the front, following the masseter plane (beneath its aponeurosis) to the oral mucosa, along with the facial nerve, the parotid gland – including Stensen’s duct, the superficial portion, and part of the deep portion – the mental nerve, the orbicularis oris, and most of the smile muscles (including both the zygomaticus and levators). At the anterior edge of the masseter muscle, the dissection plane is subperiosteal at the level of the horizontal branch of the mandible and on the malar bone and the zygoma. The mental nerve is identified at its exit from the mental foramen and communicates with the oral cavity at the level of the cheek. The entire cheek mucosa is harvested along the parotid ostium. The buccal fat pad is left behind. On the dental part of the maxilla and mandible, the mucosa is cut at the gingival. The lateral canthus on each side is also divided after insertion of a 2-0 steel stitch, which will allow reinsertion (Fig. 20.22)

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