Fries, Charles Anton (2021) Targeted graft specific immunosuppression to improve outcomes in reconstructive transplantation. PhD thesis, University of Warwick.

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Abstract

Vascularized Composite Allotransplantation (VCA) refers to the transplantation of a part of the human body, from a deceased donor to a living recipient who has suffered loss or irrevocable damage of the corresponding part1. Most commonly this is of the hand or face. Such transplants are also referred to as ‘reconstructive transplants’, as they form part of the reconstructive surgeons’ armamentarium to treat functional loss. They differ to more common solid organ transplants (SOT), as multiple tissue types are transplanted. VCAs are ‘composites’ of tissue types such as skin, bone, muscle, tendons and nerves, as opposed to being a single organ of more uniform cell types. They also differ from solid organ transplantation in that they are not performed to treat life-threatening organ failure, but to improve the patients function and quality of life. Put simply; a patient with total liver failure will die without a liver transplant, however a patient with bilateral hand amputation may have a ‘normal’ life expectancy, but require around the clock support with feeding, toileting and other self-care. Thus, subjecting such a patient to lifelong immunosuppression with attendant morbidity and mortality is a complex decision. However, the concept of ‘normalcy’ with respect to life-expectancy in such patients is open to debate. The natural history of bilateral hand loss, or facial disfigurement of such severity that a face transplant might be considered, may well predispose to joblessness, social exclusion, depression, substance dependency and even suicide2. Initial challenges in VCA surgery focussed on the technical difficulties of this work. Operations required teams of surgeons from multiple specialties working for over 24 hours using microsurgical skills to reattach blood vessels, nerves and tendons as well as bony components of the facial skeleton or forearm. However, having achieved technical successes in completing the operations, determinants of long-term outcome have come to focus on the immunological suppression regimens required to prevent immunological rejection, and the psychological preparedness and adaptation of the patient themselves to prevent psychological rejection. 13 The intricacy of the human hand is a marvel of evolution that is inextricably linked with the elevation of the species itself. Described as an ‘extension of the brain’, the prehensile, sensory, aesthetic and social functions of the hand defy recreation by prosthetic alternatives3. Replacing the hand by conventional reconstructive surgical means is impossible. The use of the operating microscope to perform vascular anastomosis, the joining in continuity of two hollow viscera or vessels, in small, distal blood vessels was first described in 1960, and the first replantation of an amputated digit in 19654. The stage was thus set for the epistemological leap from replantation to transplantation of the hand, to treat patients who had suffered total hand loss. The first hand transplant of the modern era was performed in Ecuador in 1964, but with only rudimentary immunosuppression the allograft was lost in the early post-operative phase5. The first hand transplant to be performed with modern immunosuppression and achieve durable success was performed in France in 19986. Such transplantation of functional tissue composites, tissue blocks supplied by defined neurovascular territories, could in theory be extended to any area of the body. However, the requirement for lifelong immunosuppression with attendant risks of morbidity and mortality meant that such transplants could only be considered in situations where the benefits might reasonably be expected to outweigh these risks1,7–9. For example, whilst lower limb transplantation has been attempted to treat lower extremity amputation, the generally excellent rehabilitation achieved with the use of prosthetics has meant that this remains a rarely indicated and controversial procedure10. Conversely, a transplant of abdominal tissue from an identical twin was used to reconstruct her sister’s back in a case of recurrent sarcoma, the excision of which resulted in a large defect that could not otherwise be skin grafted. No immunosuppression was required due to their being identical twins, and, despite the donor sister did have to undergo the risks of surgery, she effectively received a cosmetic excision of excess abdominal tissue. The face, like the hand, defies conventional reconstruction and its functional role is so significant that allotransplantation can be considered a potential treatment. The first face transplant was performed, also in France, in 200511. Since then at least 130 upper limb and 40 craniofacial transplants have been performed, with 20-year follow-up in some cases12. Subsequently, the field has expanded to include abdominal wall, lower limb, uterus, penis, 14 scalp, neck organs, larynx, and sentinel skin flap transplants for immunologic monitoring of solid organ transplants. Assessing outcomes has been challenging, vide infra; however, the re-amputation of the first hand transplant after only two years, following psychological rejection of the limb and non-compliance with immunosuppression, is said to have set the field back by years. Conversely, the wonderful success of the world’s second hand transplant, who enjoys good function 20 years after the fact and staunchly advocates for the procedure, has been hard to replicate. To date all VCA transplants have been performed as experimental treatments under Institutional Review Board supervision, although it is argued that double hand transplantation may be considered the standard of care treatment for bilateral hand loss13.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QP Physiology Q Science > QR Microbiology > QR180 Immunology R Medicine > RD Surgery
Library of Congress Subject Headings (LCSH):	Surgery, Plastic, Transplantation of organs, tissues, etc., Transplantation immunology, Vascular grafts, Graft rejection
Official Date:	21 August 2021
Dates:	Date Event 21 August 2021 UNSPECIFIED
Institution:	University of Warwick
Theses Department:	Warwick Medical School
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Hardwicke, Joseph ; Greaves, Erin
Format of File:	pdf
Extent:	141 leaves : illustrations
Language:	eng

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