{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T19:44:00Z","timestamp":1791834240699,"version":"4.3.4"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Vascularized composite allotransplantation (VCA) of the face and limbs restores form and function after devastating injury but, as in other transplant settings, remains limited by the precision of its diagnostic tools. Current surveillance relies on skin biopsy histology, which addresses acute cellular but not antibody-mediated or chronic rejection. More than a decade of clinical experience has revealed persistent diagnostic gaps, including sampling bias and interobserver variability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Published studies describing histopathologic, molecular, and imaging approaches in human VCA were reviewed to summarize diagnostic advances and identify emerging tools.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The Banff 2022 revision introduced vascular modifiers to capture chronic vascular injury. Comparative work indicates that mucosal rejection may occur earlier or more severely than cutaneous rejection. Molecular assays such as donor-derived cell-free DNA, miRNA profiling, and proteomic and transcriptomic panels show promise for early and minimally invasive detection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Key challenges in VCA diagnostics include variability in biopsy interpretation across centers, absence of validated molecular and biomarker criteria, and limited integration of multimodal data into clinical workflows. Coordinated multicenter efforts are needed to standardize evaluation and improve early, accurate diagnosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1804957","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T04:55:05Z","timestamp":1779944105000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Diagnostic modalities in vascularized composite allotransplantation: from histopathology to multimodal strategies"],"prefix":"10.3389","volume":"17","author":[{"given":"William J.","family":"Crisler","sequence":"first","affiliation":[{"name":"Department of Dermatology, Brigham and Women\u2019s Hospital, Harvard Medical School","place":["Boston, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix J.","family":"Klimitz","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Plastic Surgery, Yale School of Medicine","place":["New Haven, CT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel J.","family":"Steuart","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Brigham and Women\u2019s Hospital, Harvard Medical School","place":["Boston, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine J.","family":"Ko","sequence":"additional","affiliation":[{"name":"Departments of Dermatology and Pathology, Yale School of Medicine","place":["New Haven, CT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael A.","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Brigham and Women\u2019s Hospital, Harvard Medical School","place":["Boston, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bohdan","family":"Pomahac","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Plastic Surgery, Yale School of Medicine","place":["New Haven, CT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Kauke-Navarro","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Plastic Surgery, Yale School of Medicine","place":["New Haven, CT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2008.02243.x","article-title":"The Banff 2007 working classification of skin-containing composite tissue allograft pathology","volume":"8","author":"Cendales","year":"2008","journal-title":"Am J Transplant"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1562024","article-title":"A comparative analysis of lesional skin, sentinel flap, and mucosal biopsies in assessing acute face transplant rejection","volume":"16","author":"Kauke-Navarro","year":"2025","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1179355","article-title":"Cellular activation pathways and interaction networks in vascularized composite allotransplantation","volume":"14","author":"Knoedler","year":"2023","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/tp.0000000000003171","article-title":"Mucosa and rejection in facial vascularized composite allotransplantation: A systematic review","volume":"104","author":"Kauke","year":"2020","journal-title":"Transplantation"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajt.2025.01.013","article-title":"B-cell infiltration distinguishes mucosal from skin patterns of rejection in facial vascularized composite allografts","volume":"25","author":"Kauke-Navarro","year":"2025","journal-title":"Am J Transplant"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1097\/gox.0000000000004831","article-title":"Immunohistochemical analysis of lymphocyte populations in acute skin rejection: The University Health Network addition to the Banff classification","volume":"11","author":"Haykal","year":"2023","journal-title":"Plast Reconstr Surg Glob Open"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2139\/ssrn.4449819","article-title":"Banff 2022 vascularized composite allotransplantation meeting report: Diagnostic criteria for vascular changes","volume":"24","author":"Cendales","year":"2024","journal-title":"Am J Transplant"},{"key":"B8","doi-asserted-by":"publisher","first-page":"86","DOI":"10.4103\/jomfp.jomfp_195_16","article-title":"Pathophysiology of keratinization","volume":"22","author":"Deo","year":"2018","journal-title":"J Oral Maxillofac Pathol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.12379","article-title":"A four-year pathology review of the near total face transplant","volume":"13","author":"Bergfeld","year":"2013","journal-title":"Am J Transplant"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1097\/01.tp.0000248780.55263.33","article-title":"Clinicopathologic monitoring of the skin and oral mucosa of the first human face allograft: Report on the first eight months","volume":"82","author":"Kanitakis","year":"2006","journal-title":"Transplantation"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/wrr.12072","article-title":"Detrimental dermal wound healing: what can we learn from the oral mucosa","volume":"21","author":"Glim","year":"2013","journal-title":"Wound Repair Regener"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.682143","article-title":"A scarless healing tale: Comparing homeostasis and wound healing of oral mucosa with skin and oesophagus","volume":"9","author":"Pereira","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.3390\/biom11081165","article-title":"The bigger picture: Why oral mucosa heals better than skin","volume":"11","author":"Waasdorp","year":"2021","journal-title":"Biomolecules"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1097\/prs.0000000000000797","article-title":"Utility of sentinel flaps in assessing facial allograft rejection","volume":"135","author":"Kueckelhaus","year":"2015","journal-title":"Plast Reconstr Surg"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0b013e31823d4af6","article-title":"First human face transplantation: 5 years outcomes","volume":"93","author":"Petruzzo","year":"2012","journal-title":"Transplantation"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2013.249","article-title":"Biomarker evaluation of face transplant rejection: association of donor T cells with target cell injury","volume":"27","author":"Lian","year":"2014","journal-title":"Mod Pathol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1097\/tp.0000000000005450","article-title":"Clinical manifestation, mechanisms, and potential targets of intervention for chronic rejection in vascularized composite allotransplantation","author":"Brandacher","year":"2025","journal-title":"Transplantation"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1097\/mot.0000000000000571","article-title":"Chronic rejection in human vascularized composite allotransplantation (Hand and face recipients): An update","volume":"100","author":"Kanitakis","year":"2016","journal-title":"Transplantation"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.15143","article-title":"Chronic rejection of human face allografts","volume":"19","author":"Krezdorn","year":"2019","journal-title":"Am J Transplant"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0235266","article-title":"A chronic rejection model and potential biomarkers for vascularized composite allotransplantation","volume":"15","author":"Puscz","year":"2020","journal-title":"PloS One"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1672754","article-title":"Differentiation of acute versus chronic skin rejection in a rodent model of vascularized composite allotransplantation","volume":"16","author":"Thom\u00e9","year":"2025","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajt.2023.04.008","article-title":"Insights from immunoproteomic profiling of a rejected full-face transplant","volume":"23","author":"Lee","year":"2023","journal-title":"Am J Transplant"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e135166","DOI":"10.1172\/jci135166","article-title":"Immunoregulatory and lipid presentation pathways are upregulated in human face transplant rejection","volume":"131","author":"Win","year":"2021","journal-title":"J Clin Invest"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00406","article-title":"A critical analysis of rejection in vascularized composite allotransplantation: clinical, cellular and molecular aspects, current challenges, and novel concepts","volume":"4","author":"Sarhane","year":"2013","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0b013e31824728b8","article-title":"Immunological issues in clinical composite tissue allotransplantation: where do we stand today","volume":"93","author":"Morelon","year":"2012","journal-title":"Transplantation"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1097\/prs.0000000000005436","article-title":"Is skin the most allogenic tissue in vascularized composite allotransplantation and a valid monitor of the deeper tissues","volume":"143","author":"Robbins","year":"2019","journal-title":"Plast Reconstr Surg"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000000882","article-title":"Capillary thrombosis in the skin: A pathologic hallmark of severe\/chronic rejection of human vascularized composite tissue allografts","volume":"100","author":"Kanitakis","year":"2016","journal-title":"Transplantation"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2011.03915.x","article-title":"Graft vasculopathy in clinical hand transplantation","volume":"12","author":"Kaufman","year":"2012","journal-title":"Am J Transplant"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajt.2025.12.009","article-title":"Sentinel flaps reflect key inflammatory aspects of human face transplant rejection","volume":"26","author":"Crisler","year":"2025","journal-title":"Am J Transplant"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.bjps.2025.01.028","article-title":"The prognostic relevance of donor-specific antibodies in facial transplantation \u2013 a retrospective cohort study","volume":"103","author":"Huelsboemer","year":"2025","journal-title":"J Plast Reconstr Aesthet Surg"},{"key":"B31","doi-asserted-by":"publisher","first-page":"14108","DOI":"10.1016\/j.ajt.2025.07.692","article-title":"Thermal rejection assessment: New strategies for early detection","volume":"38","author":"Filz von Reiterdank","year":"2025","journal-title":"Transpl Int"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.bjps.2020.11.022","article-title":"Biomarker and surrogate development in vascularised composite allograft transplantation: Current progress and future challenges","volume":"74","author":"Honeyman","year":"2021","journal-title":"J Plast Reconstr Aesthet Surg"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1111\/tri.12652","article-title":"Vascularized composite allotransplantation: current standards and novel approaches to prevent acute rejection and chronic allograft deterioration","volume":"29","author":"Kueckelhaus","year":"2016","journal-title":"Transpl Int"},{"key":"B34","doi-asserted-by":"publisher","first-page":"241ra77","DOI":"10.1126\/scitranslmed.3007803","article-title":"Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection","volume":"6","author":"De Vlaminck","year":"2014","journal-title":"Sci Transl Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1013924108","article-title":"Universal noninvasive detection of solid organ transplant rejection","volume":"108","author":"Snyder","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2009.129072","article-title":"Cell-free DNA as a noninvasive acute rejection marker in renal transplantation","volume":"55","author":"Garc\u00eda Moreira","year":"2009","journal-title":"Clin Chem"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1681\/asn.2016091034","article-title":"Cell-free DNA and active rejection in kidney allografts","volume":"28","author":"Bloom","year":"2017","journal-title":"J Am Soc Nephrol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03087-3","article-title":"Cell-free DNA for the detection of kidney allograft rejection","volume":"30","author":"Aubert","year":"2024","journal-title":"Nat Med"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfae282","article-title":"Donor-derived cell-free DNA monitoring for early diagnosis of antibody-mediated rejection after kidney transplantation: a randomized trial","volume":"40","author":"Akifova","year":"2025","journal-title":"Nephrol Dial Transplant"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajt.2025.07.2470","article-title":"Associations between donor-derived cell-free DNA dynamics and clinical outcomes after kidney allograft rejection: A prospective, multicenter study","volume":"25","author":"Bunnapradist","year":"2025","journal-title":"Am J Transplant"},{"key":"B41","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1186\/s12967-024-05964-4","article-title":"Advancements in noninvasive techniques for transplant rejection: from biomarker detection to molecular imaging","volume":"23","author":"Song","year":"2025","journal-title":"J Transl Med"},{"key":"B42","doi-asserted-by":"publisher","first-page":"3908","DOI":"10.3390\/ijms24043908","article-title":"Monitoring of serological, cellular and genomic biomarkers in transplantation, computational prediction models and role of cell-free DNA in transplant outcome","volume":"24","author":"Jimenez-Coll","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813121106","article-title":"MicroRNA expression profiles predictive of human renal allograft status","volume":"106","author":"Anglicheau","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.trim.2016.09.001","article-title":"Free microRNA levels in plasma distinguish T-cell mediated rejection from stable graft function after kidney transplantation","volume":"39","author":"Matz","year":"2016","journal-title":"Transpl Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.31083\/j.fbl2710279","article-title":"Expression and predictive functional profiles of microRNAs data in vascularized composite allotransplantation acute rejection","volume":"27","author":"Fang","year":"2022","journal-title":"Front Biosci (Landmark Ed)"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1490472","article-title":"Current and emerging tools for simultaneous assessment of infection and rejection risk in transplantation","volume":"15","author":"Tharmaraj","year":"2024","journal-title":"Front Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.labinv.2023.100304","article-title":"Development and validation of a multiclass model defining molecular archetypes of kidney transplant rejection: A large cohort study of the Banff human organ transplant gene expression panel","volume":"104","author":"Zhang","year":"2024","journal-title":"Lab Invest"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.16059","article-title":"Banff 2019 meeting report: Molecular diagnostics in solid organ transplantation-consensus for the Banff human organ transplant (B-HOT) gene panel and open source multicenter validation","volume":"20","author":"Mengel","year":"2020","journal-title":"Am J Transplant"},{"key":"B49","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1186\/s12967-023-04379-x","article-title":"Methods of ex vivo analysis of tissue status in vascularized composite allografts","volume":"21","author":"Ton","year":"2023","journal-title":"J Transl Med"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1161\/cir.0000000000000708","article-title":"Perfusion assessment in critical limb ischemia: Principles for understanding and the development of evidence and evaluation of devices: A scientific statement from the American Heart Association","volume":"140","author":"Misra","year":"2019","journal-title":"Circulation"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1111\/tri.12150","article-title":"Near-infrared lymphography as a minimally invasive modality for imaging lymphatic reconstitution in a rat orthotopic hind limb transplantation model","volume":"26","author":"Buretta","year":"2013","journal-title":"Transpl Int"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijom.2019.05.003","article-title":"Role of flow magnetic resonance imaging in the monitoring of facial allotransplantations: preliminary results on graft vasculopathy","volume":"49","author":"Bettoni","year":"2020","journal-title":"Int J Oral Maxillofac Surg"},{"key":"B53","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.3390\/bioengineering10091041","article-title":"Artificial intelligence advances in transplant pathology","volume":"10","author":"Rahman","year":"2023","journal-title":"Bioengineering (Basel)"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2024.08.011","article-title":"Towards accurate and efficient diagnoses in nephropathology: An AI-based approach for assessing kidney transplant rejection","volume":"24","author":"Fayzullin","year":"2024","journal-title":"Comput Struct Biotechnol J"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.trre.2023.100790","article-title":"Minimally and non-invasive approaches to rejection identification in vascularized composite allotransplantation","volume":"37","author":"Stead","year":"2023","journal-title":"Transplant Rev (Orlando)"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2024.07.007","article-title":"C-reactive protein orchestrates acute allograft rejection in vascularized composite allotransplantation via selective activation of monocyte subsets","volume":"72","author":"Kiefer","year":"2025","journal-title":"J Adv Res"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.bjps.2023.04.050","article-title":"Correlation between facial vascularized composite allotransplantation rejection and laboratory markers: Insights from a retrospective study of eight patients","volume":"83","author":"Kauke-Navarro","year":"2023","journal-title":"J Plast Reconstr Aesthet Surg"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02771","article-title":"MMP3 is a non-invasive biomarker of rejection in skin-bearing vascularized composite allotransplantation: A multicenter validation study","volume":"10","author":"Kollar","year":"2019","journal-title":"Front Immunol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1097\/gox.0000000000006598","article-title":"New paradigms in rejection monitoring: Lymphocyte subsets as noninvasive graft markers in vascularized composite allotransplantation","volume":"13","author":"Chinta","year":"2025","journal-title":"Plast Reconstr Surg Glob Open"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1804957\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T04:55:13Z","timestamp":1779944113000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1804957\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,28]]},"references-count":59,"alternative-id":["10.3389\/fimmu.2026.1804957"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1804957","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,28]]},"article-number":"1804957"}}