WP Andrew Lee

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (16)35.86 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Broader clinical application of reconstructive hand and face transplantation is hindered by the need for lifelong immunosuppression for allograft maintenance. In this review, we summarize various cell-based approaches to tolerance induction currently under investigation in both clinical and pre-clinical models to alleviate the need for chronic immunosuppression. These include strategies to induce mixed hematopoietic chimerism, therapy with T and B regulatory cells, regulatory macrophages, tolerogenic dendritic cells, and mesenchymal stem cells. The vascularized, intragraft bone components inherent to reconstructive transplants serve as a continuous source of donor-derived hematopoietic cells, and make hand and face transplants uniquely well suited for cell-based approaches to tolerance that may ultimately tilt the risk-benefit balance for these life-changing, but not life-saving, procedures.
    Expert Review of Clinical Immunology 08/2015; 11(11):1-16. DOI:10.1586/1744666X.2015.1078729 · 2.48 Impact Factor
  • Jaimie T Shores · Gerald Brandacher · Wp Andrew Lee ·
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    ABSTRACT: Background: Hand/upper extremity transplantation is the most common form of vascularized composite allotransplantation performed to date. An Update of worldwide outcomes is reported. Methods: The authors summarize the international experience with 107 known transplanted hand/upper extremities in 72 patients. Data from published medical literature, national and international meetings, lay press reports, and personal communications were utilized to provide the most up-to-date summary. Results: Although 24 losses (including four mortalities) are known, three of the four reported mortalities and eight of 24 limb losses were caused by multiple type vascularized composite allotransplantations (combined upper and lower limb or upper limb and face). Seven more losses were attributable to 15 patients in the early experience in China. In the United States and Western Europe, only three other non-acute graft losses have been reported, resulting in a patient survival rate for unilateral or bilateral hand transplantation in isolation of 98.5 percent and an overall graft survival rate of 83.1 percent. Conclusions: Published functional outcomes continue to demonstrate improvement in function and quality of life. The international experience supports the idea that, for properly selected individuals, hand and upper extremity transplantation should be considered an important treatment option.
    Plastic &amp Reconstructive Surgery 11/2014; 135(2). DOI:10.1097/PRS.0000000000000892 · 2.99 Impact Factor
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    ABSTRACT: Transplantation tolerance remains an elusive goal, partly due to limitations in our understanding of the interplay between inflammatory mediators and their role in the activation and regulation of T lymphocytes. Although multiple mechanisms acting both centrally and peripherally are responsible for tolerance induction, the signaling pathways leading to activation or regulation of adaptive immunity are often complex, branched, redundant and modulated by the microenvironment's inflammatory milieu. Accumulating evidence clearly indicates that inflammatory cytokines limit the tolerogenic potential of immunomodulatory protocols by supporting priming of the immune system and counteracting regulatory mechanisms, ultimately promoting rejection. In this review, we summarize recent progress in the development of novel therapeutics to manipulate this inflammatory environment and achievements in targeted inhibition of inflammatory cytokine signaling. Ultimately, robust transplant tolerance induction will probably require a multifaceted, holistic approach that integrates the various mechanisms of tolerance induction, incorporates the dynamic alterations in costimulatory requirements of alloreactive T cells, while maintaining endogenous mechanisms of immune regulation.
    Immunotherapy 05/2014; 6(5):637-653. DOI:10.2217/imt.14.25 · 2.07 Impact Factor
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    ABSTRACT: The mechanisms of skin rejection in vascularized composite allotransplantation (VCA) remain incompletely understood. The formation of tertiary lymphoid organs (TLO) in hand transplantation has been recently described. We assess this phenomenon in experimental and clinical VCA rejection. Skin biopsies of human (n=187), nonhuman primate (n=11) and rat (n=15) VCAs were analyzed for presence of TLO. A comprehensive immunohistochemical assessment (characterization of the cell infiltrate, expression of adhesion molecules) including staining for peripheral node addressin (PNAd) was performed and correlated with rejection and time post-transplantation. TLO were identified in human, nonhuman primate and rat skin samples. Expression of PNAd was increased in the endothelium of vessels upon rejection in human skin (p=0.003) and correlated with B- and T-lymphocyte numbers and LFA-1 expression. PNAd expression was observed at all time-points after transplantation and increased significantly after year 5. In nonhuman primate skin PNAd expression was found during inflammatory conditions early and late after transplantation. In rat skin PNAd expression was strongly associated with acute rejection and time post-transplantation. Lymphoid neogenesis and TLO formation can be uniformly found in experimental and human VCA. PNAd expression in vascular endothelium correlates with skin rejection and T- and B-cell infiltration.This article is protected by copyright. All rights reserved.
    Transplant International 05/2014; 27(9). DOI:10.1111/tri.12358 · 2.60 Impact Factor

  • American Association of Plastic Surgeons 93rd Annual Meeting, Miami, FL; 04/2014

  • Plastic &amp Reconstructive Surgery 04/2014; 133:1041-1042. DOI:10.1097/01.prs.0000445871.81297.78 · 2.99 Impact Factor
  • Article: Abstract 9

    Plastic &amp Reconstructive Surgery 03/2014; 133:16-17. DOI:10.1097/01.prs.0000444952.84840.10 · 2.99 Impact Factor
  • Article: Abstract 11

    Plastic &amp Reconstructive Surgery 03/2014; 133:21. DOI:10.1097/01.prs.0000444974.27904.cd · 2.99 Impact Factor
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    ABSTRACT: Vascular and microvascular anastomosis are critical components of reconstructive microsurgery, vascular surgery and transplant surgery. Imaging modality that provides immediate, real-time in-depth view and 3D structure and flow information of the surgical site can be a great valuable tool for the surgeon to evaluate surgical outcome following both conventional and innovative anastomosis techniques, thus potentially increase the surgical success rate. Microvascular anastomosis for vessels with outer diameter smaller than 1.0 mm is extremely challenging and effective evaluation of the outcome is very difficult if not impossible using computed tomography (CT) angiograms, magnetic resonance (MR) angiograms and ultrasound Doppler. Optical coherence tomography (OCT) is a non-invasive high-resolution (micron level), high-speed, 3D imaging modality that has been adopted widely in biomedical and clinical applications. Phaseresolved Doppler OCT that explores the phase information of OCT signals has been shown to be capable of characterizing dynamic blood flow clinically. In this work, we explore the capability of Fourier domain Doppler OCT as an evaluation tool to detect commonly encountered post-operative complications that will cause surgical failure and to confirm positive result with surgeon's observation. Both suture and cuff based techniques were evaluated on the femoral artery and vein in the rodent model.
    Proceedings of SPIE - The International Society for Optical Engineering 02/2014; 8934. DOI:10.1117/12.2041975 · 0.20 Impact Factor
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    ABSTRACT: Anastomosis is one of the most commonly performed procedure in the clinical environment that involves tubular structures, such as blood vessel, lymphatic vessel, seminal duct and ureter. Suture based anastomosis is still the foundation for most basic surgical training and clinical operation, although alternate techniques have been developed and under development. For those tubular-structure-anastomosis, immediate real-time post-operative evaluation of the surgical outcome is critical to the success of surgery. Previously evaluation is mostly based on surgeons' experience. Fourier-domain optical coherence tomography is high-speed, high-resolution noninvasive 3D imaging modality that has been widely used in the biomedical research and clinical study. In this study we used Fourier-domain optical coherence tomography as an evaluation tool for anastomosis of lymphatic vessels, ureter and seminal duct in rodent model. Immediate post-operative and long term surgical site data were collected and analyzed. Critical clinical parameters such as lumen patency, anastomosed site narrowing and suture error detection are provided to surgeons.
    Proceedings of SPIE - The International Society for Optical Engineering 01/2014; 8935. DOI:10.1117/12.2040093 · 0.20 Impact Factor
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    ABSTRACT: Le Fort-based, maxillofacial allotransplantation is a reconstructive alternative gaining clinical acceptance. However, the vast majority of single-jaw transplant recipients demonstrate less-than-ideal skeletal and dental relationships with suboptimal aesthetic harmony. The purpose of this study was to investigate reproducible cephalometric landmarks in a large animal model, where refinement of computer-assisted planning, intra-operative navigational guidance, translational bone osteotomies, and comparative surgical techniques could be performed. Cephalometric landmarks that could be translated into the human craniomaxillofacial skeleton, and would remain reliable following maxillofacial osteotomies with mid-facial alloflap inset, were sought on six miniature swine. Le Fort I- and Le Fort III-based alloflaps were harvested in swine with osteotomies, and all alloflaps were either auto-replanted or transplanted. Cephalometric analyses were performed on lateral cephalograms pre- and post-operatively. Critical cephalometric data sets were identified with the assistance of surgical planning and virtual prediction software, and evaluated for reliability and translational predictability. Several pertinent landmarks and human analogues were identified including pronasale (PRN), zygion (Zy), parietale (PA), gonion (GO), gnathion (GN), lower incisior base (LIB), and alveolare (ALV). PA-PRN-ALV and PA-PRN-LIB were found to be reliable correlates of SNA and SNB measurements in humans, respectively. There is a set of reliable cephalometric landmarks and measurement angles pertinent for utilization within a translational large animal model. These craniomaxillofacial landmarks will allow us to develop novel navigational software technology, improve our cutting guide designs, and explore new avenues for investigation and collaboration.Level of Evidence: N/A (Large Animal Study).
    Plastic and Reconstructive Surgery 01/2014; 133(5). DOI:10.1097/PRS.0000000000000110 · 2.99 Impact Factor
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    ABSTRACT: For many devastating injuries and tissue defects where conventional reconstruction is not possible, reconstructive transplantation such as hand and face transplantation has become a viable alternative. This novel approach allows for improved restoration of appearance, anatomy and function not feasible by other available treatment options. However, clinical management of these injuries prior to transplantation frequently requires multiple blood transfusion or skin grafts resulting in the formation of alloantibodies (anti-HLA IgG Abs) and a high degree of sensitization. The role of donor-specific antibodies (DSA) and mechanisms of antibody-mediated rejection (AMR) in reconstructive transplantation are still largely unknown. Thus there is an imminent need to develop a better understanding of the mechanisms related to DSA and AMR after reconstructive transplantation. In this review, we will define the role of DSA and mechanisms of AMR in reconstructive transplantation and compare them to established measures and treatment concepts in solid organ transplantation.
    Expert Review of Clinical Immunology 09/2013; 9(9):835-44. DOI:10.1586/1744666X.2013.824667 · 2.48 Impact Factor
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    ABSTRACT: Kv1.3-channels are critically involved in activation and function of effector memory T cells. Blocking Kv1.3-channels was investigated for its effect on skin rejection in a rat limb-transplantation-model. Animals received the Kv1.3-blocker correolide C systemically or locally as intra-graft-treatment in combination with tacrolimus. Systemic (intraperitoneal) administration of correolide C resulted in slight, but significant prolongation of allograft survival compared with untreated and placebo treated controls. In 4/6 correolide C treated animals, histology showed an intact epidermis and a mild infiltrate by day 10. High correolide C plasma trough levels correlated with prolonged allograft survival. A decrease in CD4+ and CD8+ effector memory T cells was observed in allograft skin, peripheral blood and the spleen on day 5. When applied subcutaneously in combination with systemic tacrolimus (30 days+/-anti-lymphocyte serum) detectable, but insignificant prolongation of graft survival was achieved. 2/5 animals showed an intact epidermis and a mild infiltrate until day 45. Tapering systemic tacrolimus and weaning on day 50 resulted in rejection by day 55, regardless of local correolide C treatment. Subcutaneous injection did not lead to systemic plasma levels. The Kv1.3-channel is a potential drug target worth exploring in more detail for immunosuppression in vascularized composite allotransplantation.
    Transplant International 03/2013; 26(5). DOI:10.1111/tri.12080 · 2.60 Impact Factor
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    Plastic &amp Reconstructive Surgery 01/2013; 131:173. DOI:10.1097/01.prs.0000430183.71201.be · 2.99 Impact Factor
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    Gerald Brandacher · Wp Andrew Lee · Stefan Schneeberger ·
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    ABSTRACT: Hand transplantation, despite all initial skepticism, has developed from myth to reality over the past decade and has shown highly encouraging immunological and functional outcomes. However, the requirement of life-long, multidrug immunosuppression bearing the risk of serious side effects still remains the limiting factor for widespread clinical application of this novel reconstructive modality. Recent advances in immunosuppressive drug development and the design of novel cell-based therapeutic strategies that take into consideration the unique immunological and biological aspects of vascularized composite allografts have shown favorable results with regard to minimization of immunosuppressive medication and tolerance induction in both translational animal studies and first clinical trials in reconstructive transplantation. This review provides an overview of the current available conventional treatment protocols and novel immunosuppression minimization concepts for hand transplantation, which ultimately could significantly favor the risk-benefit ratio for this life-changing type of transplant.
    Expert Review of Clinical Immunology 09/2012; 8(7):673-84. DOI:10.1586/eci.12.54 · 2.48 Impact Factor
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    ABSTRACT: AIMS: Vertebral bone marrow is a rich and easily accessible source of hematopoietic and mesenchymal stem cells that has been used to promote chimerism and transplantation tolerance in connection with cadaveric organ transplantation. The purpose of this study is to provide a detailed account of the procedure used to prepare the first five vertebral bone marrow products for infusion in conjunction with the first hand/hand-forelimb transplants performed at the University of Pittsburgh (PA, USA). MATERIALS & METHODS: The cell separation and release testing were performed at the University of Pittsburgh Cancer Institute's Hematopoietic Stem Cell Laboratory, a Good Manufacturing Practice-compliant facility accredited for clinical cell processing by the Foundation for Accreditation of Cellular Therapy (FACT) and for clinical flow cytometry by the College of American Pathologists (CAP).
    Regenerative Medicine 11/2011; 6(6):701-6. DOI:10.2217/rme.11.89 · 2.79 Impact Factor