Transplant rejection remains a challenge especially in the field of vascularized composite allotransplantation (VCA). To blunt the alloreactive immune response' stable levels of maintenance immunosupression are required. However' the need for lifelong immunosuppression poses the risk of severe side effects, such as increased risk of infection, metabolic complications, and malignancies. To balance therapeutic efficacy and medication side effects, immunotolerance promoting immune cells (especially regulatory T cells [Treg]) have become of great scientific interest. This approach leverages immune system mechanisms that usually ensure immunotolerance toward self-antigens and prevent autoimmunopathies. Treg can be bioengineered to express a chimeric antigen receptor or a T-cell receptor. Such bioengineered Treg can target specific antigens and thereby reduce unwanted off-target effects. Treg have demonstrated beneficial clinical effects in solid organ transplantation and promising in vivo data in VCAs. In this review, we summarize the functional, phenotypic, and immunometabolic characteristics of Treg and outline recent advancements and current developments regarding Treg in the field of VCA and solid organ transplantation.
Transplant rejection remains a challenge especially in the field of vascularized composite allotransplantation (VCA). To blunt the alloreactive immune response' stable levels of maintenance immunosupression are required. However' the need for lifelong immunosuppression poses the risk of severe side effects, such as increased risk of infection, metabolic complications, and malignancies. To balance therapeutic efficacy and medication side effects, immunotolerance promoting immune cells (especially regulatory T cells [Treg]) have become of great scientific interest. This approach leverages immune system mechanisms that usually ensure immunotolerance toward self-antigens and prevent autoimmunopathies. Treg can be bioengineered to express a chimeric antigen receptor or a T-cell receptor. Such bioengineered Treg can target specific antigens and thereby reduce unwanted off-target effects. Treg have demonstrated beneficial clinical effects in solid organ transplantation and promising in vivo data in VCAs. In this review, we summarize the functional, phenotypic, and immunometabolic characteristics of Treg and outline recent advancements and current developments regarding Treg in the field of VCA and solid organ transplantation.
- MeSH
- antigeny virové MeSH
- COVID-19 * MeSH
- lidé MeSH
- pandemie prevence a kontrola MeSH
- virus Epsteinův-Barrové MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Facial vascularized composite allotransplantation (fVCA) represents a reconstructive approach that enables superior improvements in functional and esthetic restoration compared with conventional craniomaxillofacial reconstruction. Outcome reports of fVCA are usually limited to short-term follow-up or single-center experiences. We merge scientific literature on reported long-term outcome data to better define the risks and benefits of fVCA. METHODS: We conducted a systematic review of PubMed/MEDLINE databases in accordance with PRISMA guidelines. English full-text articles providing data on at least 1 unique fVCA patient, with ≥3 years follow-up, were included. RESULTS: The search yielded 1812 articles, of which 28 were ultimately included. We retrieved data on 23 fVCA patients with mean follow-up of 5.3 years. More than half of the patients showed improved quality of life, eating, speech, and motor and sensory function following fVCA. On average, the patients had 1 acute cell-mediated rejection and infectious episode per year. The incidence rates of acute rejection and infectious complications were high within first-year posttransplant but declined thereafter. Sixty-five percent of the patients developed at least 1 neoplastic or metabolic complication after transplantation. Chronic vascular rejection was confirmed in 2 patients, leading to allograft loss after 8 and 9 years. Two patient deaths occurred 3.5 and 10.5 years after transplant due to suicide and lung cancer, respectively. CONCLUSIONS: Allograft functionality and improvements in quality of life suggest a positive risk-benefit ratio for fVCA. Recurrent acute rejection episodes, chronic rejection, immunosuppression-related complications, and heterogeneity in outcome reporting present ongoing challenges in this field.
- MeSH
- dospělí MeSH
- homologní transplantace MeSH
- imunosupresiva terapeutické užití MeSH
- infekce etiologie MeSH
- kvalita života MeSH
- lidé středního věku MeSH
- lidé MeSH
- rejekce štěpu MeSH
- transplantace obličeje škodlivé účinky psychologie MeSH
- výzkumný projekt MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- systematický přehled MeSH
BACKGROUND: Long-term outcomes after face transplantation are rarely reported in the scientific literature. Here we present outcome data of a partial face allograft recipient 10 years after transplantation. METHODS: Medical records were reviewed for functional and psychosocial outcomes as well as complications. Histopathologic analyses of autopsy tissues and characterization of skin immune cells were performed. RESULTS: The patient retained long-term motor and sensory function, though with a noticeable drop in sensory function after year 5. Social reintegration of the patient was marked by reconnection with his family and participation in public social activities. Immunosuppressive therapy consisted of tacrolimus (target levels 6-8 ng/mL after the first year), mycophenolate, and prednisone, while steroids were completely weaned between years 1 and 7. One acute cellular rejection episode of grade II or higher occurred on average per year and led to chronic skin changes (papillary dermal sclerosis with superficial hyalinization, epidermal thinning with loss of rete ridges, perieccrine fibrosis), but the allograft vessels, muscles, adipose tissue, and bone were spared. Allograft skin was characterized by increased number of CD4+ TNF-α/IL17A producing T-cells as compared with native skin. Long-term kidney function was maintained at 60 mL/min estimated glomerular filtration rate. Unfortunately, the preexisting hepatitis C virus infection with liver cirrhosis was resistant to 3 treatments with new direct-acting antivirals and eventually hepatocellular carcinoma developed, causing the patient's death 10 years after transplantation. CONCLUSION: This report suggests that face transplants can maintain their function for at least 10 years. Chronic skin changes can occur independently of allograft vasculopathy.
- MeSH
- alografty MeSH
- antigeny CD4 metabolismus MeSH
- chronická hepatitida C komplikace MeSH
- hepatocelulární karcinom virologie MeSH
- hodnoty glomerulární filtrace MeSH
- imunosupresiva terapeutické užití MeSH
- interleukin-17 metabolismus MeSH
- kůže metabolismus patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory jater virologie MeSH
- následné studie MeSH
- příjemce transplantátu * MeSH
- T-lymfocyty metabolismus MeSH
- TNF-alfa metabolismus MeSH
- transplantace obličeje * MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- MeSH
- alely MeSH
- biologické markery krev MeSH
- dárci tkání MeSH
- hlavní histokompatibilní komplex genetika MeSH
- lidé MeSH
- paže transplantace MeSH
- příjemce transplantátu MeSH
- prospektivní studie MeSH
- rejekce štěpu krev diagnóza MeSH
- transplantace obličeje škodlivé účinky MeSH
- volné cirkulující nukleové kyseliny krev MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
BACKGROUND: Facial vascularized composite allotransplantation (fVCA) presents an established approach to restore form and function of patients with catastrophic facial defects. Skin is one of the target tissues of the rejection process, and due to its easy accessibility has become the gold standard in the diagnosis of rejection. Mucosal rejection frequently occurs; however, the added value of mucosal rejection assessment for patient management is unknown. METHODS: We conducted a systematic review of manuscripts listed in the MEDLINE/PubMed and GoogleScholar databases to identify articles that provide data on mucosal rejection following fVCA. For inclusion, papers had to be available as full-text and written in English. Non-VCA studies and animal studies were excluded. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: We included 17 articles that described changes in allotransplanted mucosa of fVCAs. These articles yielded data on 168 BANFF graded biopsies of corresponding skin and mucosa biopsies. Rejection grades were consistently higher in mucosal biopsies. Concordance between allograft skin and mucosa biopsy grades increased with an increasing skin-BANFF grade. Mucosa rejection grades were on average lower in the early stages of the posttransplant period (
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Machine perfusion (MP) has evolved as a promising approach for the ex situ preservation in organ transplantation. However, the literature on the use of MP in human vascularized composite allografts is scarce. The aim of this study was to evaluate the effects of hypothermic MP with an acellular perfusate in human upper extremities and compare with the current gold standard of static cold storage (SCS). METHODS: Six upper extremities were assigned to either MP (n = 3) or SCS (n = 3) conditions for 24 h. MP-extremities were perfused with oxygenated Steen solution at a constant pressure of 30 mm Hg and 10°C. RESULTS: Median total ischemia time was 213 min (range, 127-222 min). Myoglobin, creatine-kinase (CK) showed increased levels at the start of MP (medians: myoglobin: 4377 ng/mL, CK: 1442 U/L), peaking 6 h after perfusate exchange (medians: myoglobin: 9206 ng/mL, CK: 3995 U/L) at timepoint 24. Lactate levels decreased from a median of 6.9-2.8 mmol/L over time. Expression of hypoxia-inducible factor 1-alpha peaked in the SCS-group after 8 h, followed by a decrease. Increased hypoxia-inducible factor 1-alpha expression in the MP group was delayed until 20 h. Perfusion pressure, temperature, and circuit flow were maintained at median of 30.88 mm Hg, 9.77°C, and 31.13 mL/min, respectively. Weight increased 1.4% in the SCS group and 4.3% in the MP group over 24 h. CONCLUSIONS: Hypothermic ex situ perfusion with an oxygenated acellular Steen solution may extend the allowable extracorporeal preservation time by a factor of 4-6 compared to SCS and holds promise to be beneficial for vascularized composite allograft recipients and victims of traumatic major limb amputation.
- MeSH
- alografty MeSH
- cytokiny analýza MeSH
- dospělí MeSH
- končetiny krevní zásobení chirurgie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nízká teplota MeSH
- perfuze metody MeSH
- replantace metody MeSH
- roztoky pro uchovávání orgánů MeSH
- teplá ischemie MeSH
- uchovávání orgánů metody MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Ischemia-reperfusion injury remains the major limiting factor for limb replantation and transplantation. Static cold storage (SCS) on ice currently represents the standard mode of preservation but is limited to 6 h of duration. Ex vivo machine perfusion has evolved as a potential alternative to safely extend the duration of ex vivo preservation by providing continuous supply of oxygen and nutrients. This study aims to evaluate underlying molecular mechanisms of both preservation modalities. METHODS: We assessed molecular changes in amputated porcine forelimbs stored on ice at 4°C for 2 h (n = 2) and limbs perfused with Perfadex solution at 10°C for 2 h (n = 3) or 12 h (n = 3) before replantation. Muscle biopsies were examined for histological changes and gene expression levels using H&E staining and a hypoxia-related PCR gene array, respectively. RESULTS: Histology revealed only minor differences between the ice (SCS) and perfusion groups after 2 h of preservation, with decreased muscle fiber disruption in the perfusion groups compared with the ice (SCS) group. Perfused limbs demonstrated downregulation of genes coding for glycolytic pathways and glucose transporters after 2 h and 12 h when compared with SCS after 2 h. Similarly, genes that induce angiogenesis and those that are activated on DNA damage were downregulated in both perfusion groups as compared with SCS. CONCLUSIONS: Perfusion of porcine limbs resulted in less activation of hypoxia-related gene families when compared with SCS. This may indicate a state more closely resembling physiological conditions during perfusion and potentially limiting ischemic injury. Our study confirms ex vivo perfusion for up to 12 h as a viable alternative for preservation of vascularized composite tissues.
- Publikační typ
- časopisecké články MeSH
Severe injuries of the face and limbs remain a major challenge in today's reconstructive surgery. Vascularized composite allotransplantation (VCA) has emerged as a promising approach to restore these defects. Yet, there are major obstacles preventing VCA from broad clinical application. Two key restrictions are (1) the graft's limited possible ischemia time, keeping the potential donor radius extremely small, and (2) the graft's immunogenicity, making extensive lifelong monitoring and immunosuppressive treatment mandatory. Machine perfusion systems have demonstrated clinical success addressing these issues in solid organ transplantation by extending possible ischemia times and decreasing immunogenicity. Despite many recent promising preclinical trials, machine perfusion has not yet been utilized in clinical VCA. This review presents latest perfusion strategies in clinical solid organ transplantation and experimental VCA in light of the specific requirements by the vascularized composite allograft's unique tissue composition. It discusses optimal settings for temperature, oxygenation, and flow types, as well as perfusion solutions and the most promising additives. Moreover, it highlights the implications for the utility of VCA as therapeutic measure in plastic surgery, if machine perfusion can be successfully introduced in a clinical setting.
- Publikační typ
- časopisecké články MeSH
