Reaching New Heights: A Comprehensive Study of Hand Transplantations in Korea after Institutionalization of Hand Transplantation Law.

PURPOSE: With the revision of the Organ and Transplantation Act in 2018, the hand has become legal as an area of transplantable organs in Korea. In January 2021, the first hand allotransplantation since legalization was successfully performed, and we have performed a total of three successful hand transplantation since then. By comparing and incorporating our experiences, this study aimed to provide a comprehensive reconstructive solution for hand amputation in Korea. MATERIALS AND METHODS: Recipients were selected through a structured preoperative evaluation, and hand transplantations were performed at the distal forearm level. Postoperatively, patients were treated with three-drug immunosuppressive regimen, and functional outcomes were monitored. RESULTS: The hand transplantations were performed without intraoperative complications. All patients had partial skin necrosis and underwent additional surgical procedures in 2 months after transplantation. After additional operations, no further severe complications were observed. Also, patients developed acute rejection within 3 months of surgery, but all resolved within 2 weeks after steroid pulse therapy. Motor and sensory function improved dramatically, and patients were very satisfied with the appearance and function of their transplanted hands. CONCLUSION: Hand transplantation is a viable reconstructive option, and patients have shown positive functional and psychological outcomes. Although this study has limitations, such as the small number of patients and short follow-up period, we should focus on continued recovery of hand function, and be careful not to develop side effects from immunosuppressive drugs. Through the present study, we will continue to strive for a bright future regarding hand transplantation in Korea.

Longitudinal Analysis of the T-cell Receptor Repertoire in Graft-infiltrating Lymphocytes Following Hand Transplantation.

BACKGROUND: T lymphocyte-mediated acute rejection is a significant complication following solid organ transplantation. Standard methods of monitoring for acute rejection rely on assessing histological tissue damage but do not define the immunopathogenesis. Additionally, current therapies for rejection broadly blunt cellular immunity, creating a high risk for opportunistic infections. There is, therefore, a need to better understand the process of acute cellular rejection to help develop improved prognostic tests and narrowly targeted therapies. METHODS: Through next-generation sequencing, we characterized and compared the clonal T-cell receptor (TCR) repertoires of graft-infiltrating lymphocytes (GILs) and blood-derived lymphocytes from a hand transplant recipient over 420 days following transplantation. We also tracked the TCR clonal persistence and V beta (BV) gene usage, evaluating overlap between these 2 compartments. RESULTS: TCR repertoires of blood and GIL populations remained distinct throughout the sampling period, and differential BV usage was consistently seen between these compartments. GIL TCR clones persisted over time and were seen in only limited frequency in the blood T-lymphocyte populations. CONCLUSIONS: We demonstrate that blood monitoring of TCR clones does not reveal the pathogenic process of acute cellular rejection in transplanted tissue. GILs show clonal persistence with biased BV usage, suggesting that tissue TCR clonal monitoring could be useful, although a deeper understanding is necessary to prognosticate rejection based on TCR clonal repertoires. Finally, the distinct TCR BV usage bias in GILs raises the possibility for prevention and therapy of acute cellular rejection based on targeting of specific TCR clones.

The Significance of Vascular Alterations in Acute and Chronic Rejection for Vascularized Composite Allotransplantation.

Vascularized composite allotransplantation (VCA) has emerged as a useful reconstructive option for patients suffering from major tissue defects and functional deficits. While the technical feasibility has been optimized and more than 130 VCAs have been performed during the last two decades, hurdles such as acute and chronic allograft rejection, graft deterioration, and eventual functional impairment need to be addressed. Recently, chronic graft rejection and progressive failure have been linked to vascular alterations observed in the allografts. Graft vasculopathy (GV) may play a pivotal role in long-term graft deterioration. The understanding of the underlying pathophysiological processes and their initial triggers is of utmost importance in the prevention, attenuation, and therapy of GV. While there are reports on the etiology and development of GV in solid organ transplantation, there are limited data with respect to chronic rejection and GV in the realm of VCA. Nevertheless, recent reports from long-term VCA recipients suggest that GV could truly jeopardize allografts in the follow-up evaluation. Chronic rejection and GV include different entities and might have different pathways in distinct organs. Herein, we reviewed the current literature on vascular changes during both acute and chronic allograft rejection, with a focus on their clinical and translational significance for VCA.

Clinical Significance of Alloantibodies in Hand Transplantation: A Multicenter Study.

BACKGROUND: Donor-specific antibodies (DSAs) have a strong negative correlation with long-term survival in solid organ transplantation. Although the clinical significance of DSA and antibody-mediated rejection (AMR) in upper extremity transplantation (UET) remains to be established, a growing number of single-center reports indicate their presence and potential clinical impact. METHODS: We present a multicenter study assessing the occurrence and significance of alloantibodies in UET in reference to immunological parameters and functional outcome. RESULTS: Our study revealed a high prevalence and early development of de novo DSA and non-DSA (43%, the majority detected within the first 3 postoperative y). HLA class II mismatch correlated with antibody development, which in turn significantly correlated with the incidence of acute cellular rejection. Cellular rejections preceded antibody development in almost all cases. A strong correlation between DSA and graft survival or function cannot be statistically established at this early stage but a correlation with a lesser outcome seems to emerge. CONCLUSIONS: While the phenotype and true clinical effect of AMR remain to be better defined, the high prevalence of DSA and the correlation with acute rejection highlight the need for optimizing immunosuppression, close monitoring, and the relevance of an HLA class II match in UET recipients.

Infections after upper extremity allotransplantation: a worldwide population cohort study, 1998-2017.

Risk-to-benefit analysis of upper extremity allotransplantation (UEA) warrants a careful assessment of immunosuppression-related complications. This first systematic report of infectious complications after UEA aimed to compare incidence and pattern of infections to that observed after kidney transplantation (KT). We conducted a matched cohort study among UEA and KT recipients from the International Registry on Hand and Composite Tissue Transplantation and the French transplant database DIVAT. All UEA recipients between 1998 and 2016 were matched with KT recipients (1:5) regarding age, sex, cytomegalovirus (CMV) serostatus and induction treatment. Infections were analyzed at three posttransplant periods (early: 0-6 months, intermediate: 7-12 months, late: >12 months). Sixty-one UEA recipients and 305 KT recipients were included. Incidence of infection was higher after UEA than after KT during the early period (3.27 vs. 1.95 per 1000 transplant-days, P = 0.01), but not statistically different during the intermediate (0.61 vs. 0.45/1000, P = 0.5) nor the late period (0.15 vs. 0.21/1000, P = 0.11). The distribution of infectious syndromes was significantly different, with mucocutaneous infections predominating after UEA, urinary tract infections and pneumonia predominating after KT. Incidence of infection is high during the first 6 months after UEA. After 1 year, the burden of infections is low, with favorable patterns.

A Flow Dynamic Rationale for Accelerated Vascularized Composite Allotransplant Rejection.

BACKGROUND: From 1996 to 2000, Diefenbeck et al. carried out six knee vascularized composite allotransplants. The allotransplants were composed of bone, soft tissue, and femoral vascular pedicle (25 to 40 cm). All rejected between 14 and 56 months. Failures were attributed to chronic rejection. In 2008, the Louisville team lost their fourth patient's hand transplant at 8 months. During the rejection workup, intraoperative findings noted a thickened arterial pedicle attributed to intimal hyperplasia with significant fibrotic perivascular tissue and a near "no-flow phenomenon." No cutaneous rejection was appreciated and failure was attributed to chronic rejection. METHODS: Data were collected from two teams, one in Germany and the other in Louisville, Kentucky. The population under study consisted of the six knee and one hand transplants. The factor of interest was the long donor arterial pedicle. The outcome measurements were transplant survival time and histopathologic results. RESULTS: There are only seven published vascularized composite allotransplant cases where a donor artery longer than 25 cm was used. This cohort represents a 100 percent accelerated failure rate. The cause of these losses remains unexplained. The donor arteries suffered from T-cell-mediated rejection and ischemia-induced media/adventitial necrosis. CONCLUSIONS: We hypothesize that the donor artery rejected at an accelerated rate because of ischemia caused by disruption of the external vasa vasorum in conjunction with intimal hyperplasia induced by T-cell-mediated rejection that led to disruption of the Windkessel effect. Loss of this effect presented as intimal hyperplasia accelerated by ischemia causing an expedited transplant failure. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Bone infarction of the hip after hand allotransplantation: A case report.

Vascularized composite allotransplantation represents as an emerging field in reconstructive surgery. However, some complications can be associated with the procedure. The authors describe a case of bone infarctions of the bilateral hip joints following the first hand allotransplantation in Taiwan. A 45-year-old man who experienced a traumatic amputation of the distal third of his forearm received a hand transplantation from a brain-dead donor. Immunosuppression included antithymocyte globulins, and bolus methylprednisolone (Solu-Medrol) was used for the induction. The maintenance therapy protocol included systemic tacrolimus, mycophenolate mofetil, and prednisone. The patient discontinued the systemic steroid 15 months after surgery. Two episodes of acute rejections were observed at 105 and 810 days after surgery. These signs disappeared after pulse therapy with Solu-Medrol, titration with tacrolimus, and topical immunosuppressive creams (tacrolimus and clobetasol). However, the patient felt pain in both hips after long periods of standing 30 months after the transplantation. A pelvic radiograph and magnetic resonance imaging revealed avascular necrosis (AVN) in both hip joints. Because of the progressive worsening of the pain, the patient underwent a decompression surgery on the left hip involving a fibula bone graft. The patient underwent a right hip hemi-arthroplasty with a bipolar prosthesis 3 months later. The patient remained in good health without major complications. These findings indicate that systemic steroids and tacrolimus might be the major predisposing factors for the induction of AVN after hand allotransplantation.

Transplants for non-lethal conditions: a case against hand transplantation in minors.

Human allografts for life-threatening organ failure have been demonstrated to be lifesaving and are now considered to be standard of care for many conditions. Transplantation of non-vital anatomic body parts has also been accomplished. Hand transplantation after limb loss in adults has been shown to offer some promising benefits in both functional and psychological measures in preliminary studies. It has been suggested to expand eligibility criteria to include minors, with one such operation having already been performed. With this in mind, we examine the current state of hand transplantation research in the context of available alternatives. We examine the ethics of carrying out these operations in minors, including under the protections of clinical research. We argue that children should not be considered for this surgery due to the substantial risks of immunosuppressive medication, the likelihood that the graft will need to be replaced during the patient's lifetime and the lack of significant compensatory advantages over modern prosthetics.

De novo belatacept in clinical vascularized composite allotransplantation.

Most immunosuppressive regimens used in clinical vascularized composite allotransplantation (VCA) have been calcineurin inhibitor (CNI)-based. As such, most recipients have experienced CNI-related side effects. Costimulation blockade, specifically CD28/B7 inhibition with belatacept, has emerged as a clinical replacement for CNI-based immunosuppression in kidney transplantation. We have previously shown that belatacept can be used as a centerpiece immunosuppressant for VCA in nonhuman primates, and subsequently reported successful conversion from a CNI-based regimen to a belatacept-based regimen after clinical hand transplantation. We now report on the case of a hand transplant recipient, whom we have successfully treated with a de novo belatacept-based regimen, transitioned to a CNI-free regimen. This case demonstrates that belatacept can provide sufficient prophylaxis from rejection without chronic CNI-associated side effects, a particularly important goal in nonlifesaving solid organ transplants such as VCA.

Benefits and limitations of belatacept in 4 hand-transplanted patients.

Belatacept (cytotoxic T-lymphocyte-associated protein 4 Ig) is an emerging treatment in kidney transplantation. Lack of nephrotoxicity and possibly an inhibitory effect on the development of donor-specific antibodies (DSAs) make it an interesting agent in hand transplantation. To reduce calcineurin inhibitor immunosuppression and preserve kidney function, we have added belatacept to the therapeutic regimen of 4 hand-transplanted patients at month 4 and at 6, 9, and 13 years after hand-forearm transplantation. Patients received 5 mg/kg belatacept every 2 weeks, and the dosing interval was extended to 4 weeks after 5 applications. Belatacept was initially well tolerated in all cases. Two patients were weaned to a low-dose tacrolimus monotherapy together with monthly belatacept applications. One patient is taking belatacept with lowered tacrolimus and sirolimus trough levels. A fourth patient had significant levels of DSAs at time of conversion and progressed to a severe necrotizing rejection early despite an unaltered baseline immunosuppression. Finger skin necrosis and histologic signs of severe chronic allograft vasculopathy eventually led to amputation of the graft. Implementation of belatacept can be beneficial in hand transplantation. However, our findings indicated both potential and caution and reflection of the immunologic state at the time of conversion.

Outcomes after hand and upper extremity transplantation.

Hand and upper extremity transplantation (HUET) has emerged as the most frequently performed reconstructive procedure in the burgeoning field of vascularized composite allotransplantation (VCA). VCA refers to a form of transplant with multiple tissue types that represents a viable treatment option for devastating injuries where conventional reconstruction would be unable to restore form and function. As hand transplantation becomes increasingly more common, discussions on advantages and disadvantages of the procedure seem to intensify. Despite encouraging functional outcomes, current immunosuppressive regimens with their deleterious side-effect profile remain a major concern for a life-changing but not life-saving type of transplant. In addition, a growing number of recipients with progressively longer follow-up prompt the need to investigate potential long-term sequelae, such as chronic rejection. This review will discuss the current state of HUET, summarizing outcome data on graft survival, motor and sensory function, as well as immunosuppressive treatment. The implications of these findings for VCA in terms of achievements and challenges ahead will then be discussed.

Scabies in a bilateral hand allograft recipient: An additional mimicker of acute skin rejection in vascularized composite allotransplantation.

Vascularized composite tissue allografts include skin, which frequently undergoes, in the early post-graft period, acute rejections. The diagnosis of acute rejection may be difficult as it can be mimicked by several dermatoses. We present a bilateral hand allograft recipient who developed, 16.5 years post-graft, cutaneous lesions raising suspicion about rejection. Physical examination and skin biopsy were diagnostic of scabies. This ectoparasitosis should be added in the list of dermatoses that can mimic allograft rejection in vascular composite allografts.

Capillary Thrombosis in the Skin: A Pathologic Hallmark of Severe/Chronic Rejection of Human Vascularized Composite Tissue Allografts?

BACKGROUND: Vascularized composite tissue allografts (VCA) can undergo rejection, manifesting pathologically with skin changes that form the basis of the Banff 2007 classification of VCA rejection. METHODS: We have followed 10 human VCA recipients (7 with hand allografts, 3 with face allografts) for pathological signs of rejection. All of them developed episodes of acute rejection. Two patients with hand allografts presented in some of their skin biopsies an as yet unreported pathological finding in human VCA, consisting of capillary thromboses (CT) in the upper dermis. RESULTS: Capillary thrombosis was associated with other typical changes of grade II to III VCA rejection, namely, perivascular T cell infiltrates, but not with vascular C4d deposits (in formalin-fixed tissue). Clinically, the lesions presented as red or violaceous (lichenoid) cutaneous maculopapules. The first patient had several episodes of acute rejection during the 7-year follow-up. The second patient developed donor-specific antibodies; some months after CT were first observed, he developed chronic rejection leading to partial amputation of the allograft. Pathological examination of the skin showed graft vasculopathy and occasional C4d deposits in cutaneous capillaries. CONCLUSIONS: Capillary thrombosis seems to be a novel pathologic finding associated with human VCA rejection. Although its mechanism (immunologic vs nonimmunologic) remains unclear, this finding could carry an unfavorable prognostic significance, prompting close monitoring of the patients for severe/chronic rejection.

Using Decision Analysis to Understand the Indications for Unilateral Hand Transplantation.

Background: Upper extremity transplantation has been performed to improve quality of life, the benefit which must be traded off for the risk created by life-long immunosuppression. We believe the process of decision analysis is well suited to improve our understanding of these trade-offs. Method: We created a decision tree to include a branch point to illustrate the expected recovery of useful function in the transplant, using the best estimates for utility and probability that exist. Results: Our model revealed that when the probability of achieving a good result, graded as Chen level one or two is greater than 73%, transplantation is preferred over no transplantation. The decision is sensitive to the probability of major complications and the utility of a transplanted limb with minimal function. Conclusions: The results of this analysis show that under some circumstances given a high probability of satisfactory functional recovery, unilateral hand transplantation can be justified.

Allogeneic hand transplantation and rehabilitation of hand function: a 10-year follow-up study.

The purpose of this study is to present the long-term outcomes of allogenic hand transplantations performed at our centre. Between January 2001 and October 2002, five allogeneic limb transplantations were performed in three patients (two bilateral forearm and one left hand transplantation). Donors and recipients were matched for blood types (ABO/Rh) and had at least two human leukocyte antigen (HLA) matches. A comprehensive rehabilitation plan integrating preoperative, intraoperative and postoperative management was developed for each patient. After 10 years, all transplantations were performed successfully without complications. As of 2014, all grafts were viable. The transplanted hands showed palmate morphology, perceived superficial pain and tactile sensations, and the static two-point discrimination ranged from 2·5 to 4·0 mm. Chronic rejection at 4 years after surgery reduced hand function in case 2. Grip strength ranged from 3 kg (case 2) to 16-18 kg (case 1) to 41-43 kg for case 3. Lifting strength ranged from 3 kg (case 2) to 21-23 kg (case 1) to 47-51 kg for case 3. They lead a completely independent life. In summary, hand function following allogeneic limb transplantation allows the ability to perform tasks of daily living.

Is Duplex-Ultrasound a useful tool in defining rejection episodes in composite tissue allograft transplants?

Immunologic reactions in transplanted organs are in more or less all allograft patients detectable: clear parameters exist as e.g. in renal transplants where the clearance power reduces by rejection. On the contrary, in composite tissue allografts clear and objective indicators stating a rejection episode lack. We present the case of a hand-transplanted subject with signs of acute transplant rejection diagnosed by means of Duplex Ultrasound and confirmed by biopsy.

Clonal CD8+ T Cell Persistence and Variable Gene Usage Bias in a Human Transplanted Hand.

Immune prophylaxis and treatment of transplanted tissue rejection act indiscriminately, risking serious infections and malignancies. Although animal data suggest that cellular immune responses causing rejection may be rather narrow and predictable based on genetic background, there are only limited data regarding the clonal breadth of anti-donor responses in humans after allogeneic organ transplantation. We evaluated the graft-infiltrating CD8+ T lymphocytes in skin punch biopsies of a transplanted hand over 178 days. Profiling of T cell receptor (TCR) variable gene usage and size distribution of the infiltrating cells revealed marked skewing of the TCR repertoire indicating oligoclonality, but relatively normal distributions in the blood. Although sampling limitation prevented complete assessment of the TCR repertoire, sequencing further identified 11 TCR clonal expansions that persisted through varying degrees of clinical rejection and immunosuppressive therapy. These 11 clones were limited to three TCR beta chain variable (BV) gene families. Overall, these data indicate significant oligoclonality and likely restricted BV gene usage of alloreactive CD8+ T lymphocytes, and suggest that changes in rejection status are more due to varying regulation of their activity or number rather than shifts in the clonal populations in the transplanted organ. Given that controlled animal models produce predictable BV usage in T lymphocytes mediating rejection, understanding the determinants of TCR gene usage associated with rejection in humans may have application in specifically targeted immunotherapy.