المؤلفون: Siemionow, Maria^{Aff1, Aff2, IDs1201502310608z_cor1}, Cwykiel, Joanna, Brodowska, Sonia, Chambily, Lucile

المصدر: Stem Cell Reviews and Reports. 19(8):2741-2755

المؤلفون: Isabel Arenas Hoyos, Anja Helmer, Anaïs Yerly, Ioana Lese, Stefanie Hirsiger, Lei Zhang, Daniela Casoni, Luisana Garcia, MariaFrancesca Petrucci, Sabine E. Hammer, Tereza Duckova, Yara Banz, Matteo Montani, Mihai Constantinescu, Esther Vögelin, Gregor Bordon, Simone Aleandri, Jean-Christophe Prost, Adriano Taddeo, Paola Luciani, Robert Rieben, Nicoletta Sorvillo, Radu Olariu

المصدر: Frontiers in Immunology, Vol 15 (2024)

مصطلحات موضوعية: vascularized composite allotransplantation (VCA), transplantation immunology, tacrolimus, local immunosuppression, calcineurin inhibitors (CNIs), drug delivery systems (DDSs), Immunologic diseases. Allergy, RC581-607

الوصف: IntroductionThe standard treatment for preventing rejection in vascularized composite allotransplantation (VCA) currently relies on systemic immunosuppression, which exposes the host to well-known side effects. Locally administered immunosuppression strategies have shown promising results to bypass this hurdle. Nevertheless, their progress has been slow, partially attributed to a limited understanding of the essential mechanisms underlying graft rejection. Recent discoveries highlight the crucial involvement of innate immune components, such as neutrophil extracellular traps (NETs), in organ transplantation. Here we aimed to prolong graft survival through a tacrolimus-based drug delivery system and to understand the role of NETs in VCA graft rejection.MethodsTo prevent off-target toxicity and promote graft survival, we tested a locally administered tacrolimus-loaded on-demand drug delivery system (TGMS-TAC) in a multiple MHC-mismatched porcine VCA model. Off-target toxicity was assessed in tissue and blood. Graft rejection was evaluated macroscopically while the complement system, T cells, neutrophils and NETs were analyzed in graft tissues by immunofluorescence and/or western blot. Plasmatic levels of inflammatory cytokines were measured using a Luminex magnetic-bead porcine panel, and NETs were measured in plasma and tissue using DNA-MPO ELISA. Lastly, to evaluate the effect of tacrolimus on NET formation, NETs were induced in-vitro in porcine and human peripheral neutrophils following incubation with tacrolimus.ResultsRepeated intra-graft administrations of TGMS-TAC minimized systemic toxicity and prolonged graft survival. Nevertheless, signs of rejection were observed at endpoint. Systemically, there were no increases in cytokine levels, complement anaphylatoxins, T-cell subpopulations, or neutrophils during rejection. Yet, tissue analysis showed local infiltration of T cells and neutrophils, together with neutrophil extracellular traps (NETs) in rejected grafts. Interestingly, intra-graft administration of tacrolimus contributed to a reduction in both T-cellular infiltration and NETs. In fact, in-vitro NETosis assessment showed a 62–84% reduction in NETs after stimulated neutrophils were treated with tacrolimus.ConclusionOur data indicate that the proposed local delivery of immunosuppression avoids off-target toxicity while prolonging graft survival in a multiple MHC-mismatch VCA model. Furthermore, NETs are found to play a role in graft rejection and could therefore be a potential innovative therapeutic target.

وصف الملف: electronic resource

Relation: https://www.frontiersin.org/articles/10.3389/fimmu.2024.1387945/full; https://doaj.org/toc/1664-3224

URL الوصول: https://doaj.org/article/3e407b5b4cfb452a91c1f1944aded4ad

المؤلفون: Lei Zhang, Isabel Arenas Hoyos, Anja Helmer, Yara Banz, Cédric Zubler, Ioana Lese, Stefanie Hirsiger, Mihai Constantinescu, Robert Rieben, Mitra Gultom, Radu Olariu

المصدر: Frontiers in Immunology, Vol 15 (2024)

مصطلحات موضوعية: vascularized composite allotransplantation (VCA), immune rejection, transcriptome profiling, RNA sequencing, bioinformatics analysis, large animal model, Immunologic diseases. Allergy, RC581-607

الوصف: BackgroundVascularized composite allotransplantation (VCA) offers the potential for a biological, functional reconstruction in individuals with limb loss or facial disfigurement. Yet, it faces substantial challenges due to heightened immune rejection rates compared to solid organ transplants. A deep understanding of the genetic and immunological drivers of VCA rejection is essential to improve VCA outcomesMethodsHeterotopic porcine hindlimb VCA models were established and followed until reaching the endpoint. Skin and muscle samples were obtained from VCA transplant recipient pigs for histological assessments and RNA sequencing analysis. The rejection groups included recipients with moderate pathological rejection, treated locally with tacrolimus encapsulated in triglycerol-monostearate gel (TGMS-TAC), as well as recipients with severe end-stage rejection presenting evident necrosis. Healthy donor tissue served as controls. Bioinformatics analysis, immunofluorescence, and electron microscopy were utilized to examine gene expression patterns and the expression of immune response markers.ResultsOur comprehensive analyses encompassed differentially expressed genes, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathways, spanning various composite tissues including skin and muscle, in comparison to the healthy control group. The analysis revealed a consistency and reproducibility in alignment with the pathological rejection grading. Genes and pathways associated with innate immunity, notably pattern recognition receptors (PRRs), damage-associated molecular patterns (DAMPs), and antigen processing and presentation pathways, exhibited upregulation in the VCA rejection groups compared to the healthy controls. Our investigation identified significant shifts in gene expression related to cytokines, chemokines, complement pathways, and diverse immune cell types, with CD8 T cells and macrophages notably enriched in the VCA rejection tissues. Mechanisms of cell death, such as apoptosis, necroptosis and ferroptosis were observed and coexisted in rejected tissues.ConclusionOur study provides insights into the genetic profile of tissue rejection in the porcine VCA model. We comprehensively analyze the molecular landscape of immune rejection mechanisms, from innate immunity activation to critical stages such as antigen recognition, cytotoxic rejection, and cell death. This research advances our understanding of graft rejection mechanisms and offers potential for improving diagnostic and therapeutic strategies to enhance the long-term success of VCA.

وصف الملف: electronic resource

Relation: https://www.frontiersin.org/articles/10.3389/fimmu.2024.1390163/full; https://doaj.org/toc/1664-3224

URL الوصول: https://doaj.org/article/9ff07474364446e08b2ca0c1527c091d

المؤلفون: Aycart, Mario A.^Aff5, Kinsley, Sarah E.^Aff5, Riella, Leonardo V.^Aff6, Talbot, Simon G.^{Aff7, Aff8}

المساهمون: Gurunian, Raffi, editor^Aff1, Rampazzo, Antonio, editor^Aff2, Papay, Frank, editor^Aff3, Bassiri Gharb, Bahar, editor^Aff4

المصدر: Reconstructive Transplantation. :247-257

المؤلفون: Jiqiang He, Umar Zeb Khan, Liming Qing, Panfeng Wu, Juyu Tang

المصدر: Frontiers in Immunology, Vol 13 (2022)

مصطلحات موضوعية: ischemia-reperfusion injury (IRI), vascularized composite allotransplantation (VCA), tissue damage, transplant rejection, innate immunity, adaptive immunity, Immunologic diseases. Allergy, RC581-607

الوصف: Long-time ischemia worsening transplant outcomes in vascularized composite allotransplantation (VCA) is often neglected. Ischemia-reperfusion injury (IRI) is an inevitable event that follows reperfusion after a period of cold static storage. The pathophysiological mechanism activates local inflammation, which is a barrier to allograft long-term immune tolerance. The previous publications have not clearly described the relationship between the tissue damage and ischemia time, nor the rejection grade. In this review, we found that the rejection episodes and rejection grade are usually related to the ischemia time, both in clinical and experimental aspects. Moreover, we summarized the potential therapeutic measures to mitigate the ischemia-reperfusion injury. Compare to static preservation, machine perfusion is a promising method that can keep VCA tissue viability and extend preservation time, which is especially beneficial for the expansion of the donor pool and better MHC-matching.

وصف الملف: electronic resource

Relation: https://www.frontiersin.org/articles/10.3389/fimmu.2022.998952/full; https://doaj.org/toc/1664-3224

URL الوصول: https://doaj.org/article/52c0c2b4b9eb421eabc3af823a60b5f2

المؤلفون: James Benedict

المصدر: Frontiers in Psychology, Vol 13 (2022)

مصطلحات موضوعية: vascularized composite allotransplantation (VCA), patient advocacy, vulnerability, ethics, special protections, Psychology, BF1-990

وصف الملف: electronic resource

Relation: https://www.frontiersin.org/articles/10.3389/fpsyg.2022.943393/full; https://doaj.org/toc/1664-1078

URL الوصول: https://doaj.org/article/799bbaefebe34ab59f7fd3698bba9972

المؤلفون: Alexandre G. Lellouch, Alec R. Andrews, Gaelle Saviane, Zhi Yang Ng, Ilse M. Schol, Marion Goutard, Amon-Ra Gama, Ivy A. Rosales, Robert B. Colvin, Laurent A. Lantieri, Mark A. Randolph, Gilles Benichou, Curtis L. Cetrulo

المصدر: Frontiers in Immunology, Vol 13 (2022)

مصطلحات موضوعية: Vascularized composite allotransplantation (VCA), bone marrow transplantation, mixed chimerism, co-stimulatory blockade, skin tolerance, MHC class I, Immunologic diseases. Allergy, RC581-607

الوصف: BackgroundVascularized composite allografts (VCAs) allow reconstruction of devastating injuries and amputations, yet require lifelong immunosuppression that is associated with significant morbidity. Induction of immune tolerance of VCAs would permit widespread use of these procedures. VCAs are acquired from deceased donors most likely to be fully-MHC-mismatched (in contrast to living-related renal transplant donor-recipient pairs matched at one MHC haplotype). After achieving VCA tolerance in a swine model equivalent to clinical living-related renal transplants (single-haplotype MHC mismatches: e.g., “mother-daughter”/haploidentical), we tested our protocol in MHC class I, class II, and fully-MHC-mismatched pairs. Although class II mismatched swine demonstrated similar results as the haploidentical scenario (stable mixed chimerism and tolerance), our protocol failed to prevent rejection of class I and full mismatch VCAs. Here, we describe a new adapted conditioning protocol that successfully achieved tolerance across MHC class-I-mismatch barriers in swine.MethodsSwine were treated with non-myeloablative total body and thymic irradiation two days prior to infusion of bone marrow cells from an MHC class I-mismatched donor. They also received a short-term treatment with CTLA4-Ig (Belatacept®) and anti-IL6R mAb (Tociluzimab®) and were transplanted with an osteomyocutaneous VCA from the same donor.ResultsStable mixed chimerism and tolerance of MHC class-I-mismatched VCAs was achieved in 3 recipients. Allograft tolerance was associated with a sustained lack of anti-donor T cell response and a concomitant expansion of double negative CD4-CD8- T cells producing IL-10.ConclusionsThis study demonstrates the first successful mixed chimerism-induced VCA tolerance in a large animal model across a MHC class-I-mismatch. Future studies aimed at fully-mismatched donor-recipient pairs are under investigation with this protocol.

وصف الملف: electronic resource

Relation: https://www.frontiersin.org/articles/10.3389/fimmu.2022.829406/full; https://doaj.org/toc/1664-3224

URL الوصول: https://doaj.org/article/9edd525b71754b0d840e1d03aaddef28

المؤلفون: Kuo, Yur-Ren^{Aff6, Aff7, Aff8}

المساهمون: Kazi, Rehan, Series Editor^Aff1, Dwivedi, Raghav C., Series Editor^Aff2, Cheng, Ming-Huei, editor^Aff3, Chang, Kai-Ping, editor^Aff4, Kao, Huang-Kai, editor^Aff5

المصدر: Resection and Reconstruction of Head & Neck Cancers. :165-177

المؤلفون: Feibo Zheng, author^{1, 3}, Andy Tully, author^{1, 2}, Kyle M Koss, author¹, Xiaomin Zhang, author¹, Longhui Qiu, author¹, Jiao-Jing Wang, author¹, Bilal A Naved, author^{1, 4}, David Z Ivancic, author¹, James M Mathew, author¹, Jason A Wertheim, author¹, Zheng Jenny Zhang, author¹

المصدر: Journal of Visualized Experiments. (162)

الإتاحة: http://www.jove.com/video/60777

المؤلفون: Andreea Grosu-Bularda, Ioan Lascăr, Răzvan Nicolae Teodoreanu

المصدر: Romanian Journal of Medical Practice, Vol 14, Iss 3, Pp 267-276 (2019)

مصطلحات موضوعية: transplantation, vascularized composite allotransplantation (vca), hand transplantation, face transplantation, immunosuppression, Medicine, Medicine (General), R5-920

الوصف: Introduction. The field of composite tissue allotransplatation became a clinical reality since first hand transplant performed in 1998 at Lyon, France and has been progressing over the past two decades. Vascularized composite allotransplantation (VCA) is now performed for life enhancing indications in a selected group of patients under institutional protocols. Aim. This paper is an attempt to review the outcomes of VCA to date. Method. Analysis of relevant publications of composite tissue allotransplantation was performed, including the International Registry on Hand and Composite Tissue Transplantation (IRHCTT). Results and discussion. To date, there are more than 200 composite tissue allograft transplants performed worldwide, including upper limb, face, larynx, trachea, abdominal wall, lower limb, penis, and uterus. The technical aspects of VCA are no longer the factors limiting the widespread application of this treatment modality in the clinical setting. The feasibility of the procedure has been established, and the functional outcomes have been very good so far. The major challenge is at the immunologic level, long-term goal being to promote donor-specific tolerance and to avoid the toxicity of immunosuppression. Conclusions. Vascularized composite allografts transplatation is a viable treatment option well on the way of becoming a standard of care for those who have lost extremities and suffered large tissue defects. The initial ethical dilemmas and concerns of safety and feasibility have been overcome recently and with further standardized surgical and immunological protocols the field is likely to grow significantly in the future.

وصف الملف: electronic resource

Relation: https://revistemedicale.amaltea.ro/Romanian_Journal_of_MEDICAL_PRACTICE/Practica_medicala-2019-Nr.3/RJMP_2019_3_Art-11.pdf; https://doaj.org/toc/1842-8258; https://doaj.org/toc/2069-6108

URL الوصول: https://doaj.org/article/d1b05924e71e4165a9d8738ba7c1706f