Analysis of Immunological Biomarkers Associated With Rejection After Uterus Transplantation in Human.
Journal
Transplantation
ISSN: 1534-6080
Titre abrégé: Transplantation
Pays: United States
ID NLM: 0132144
Informations de publication
Date de publication:
18 Jul 2024
18 Jul 2024
Historique:
medline:
18
7
2024
pubmed:
18
7
2024
entrez:
18
7
2024
Statut:
aheadofprint
Résumé
Uterus transplantation (UTx) is an emerging therapy for women with uterine infertility. However, critical questions remain with this procedure including the mechanisms involved in graft rejection. In this study, we analyzed the immune profile of ectocervical biopsies from 5 patients after UTx before and during their first episode of rejection using RNA sequencing, quantitative polymerase chain reaction, and imaging mass cytometry. We identified 530 upregulated and 207 downregulated genes associated with graft rejection. Enrichment databases revealed abnormalities of skin-associated genes and the immune system, in particular activation of T and B lymphocytes, and macrophages. Imaging mass cytometry confirmed these observations; in cervical biopsies of 3 women, rejection was associated with the presence of B-cell structures linked to tertiary lymphoid structures, and 2 biopsies from 1 woman with severe rejection episodes and poor prognosis of graft function (repeated miscarriage and implantation failures) were associated with an accumulation of HLA-DR- macrophages, producing granzyme B at the surface of the epithelium. We showed that rejection of a UTx graft was associated with major alterations of immune markers including the involvement of tertiary lymphoid structures, the most organized of which may be a sign of chronic rejection, and with an increase in HLA-DR- macrophages expressing granzyme B in the case of grade 3 rejection episodes according Mölne's classification. We identified potential emerging biomarkers to predict or diagnose graft rejection (Keratin 1 granzyme B, IL1β). These findings could lead to development of improved strategies for the identification, prevention, and/or treatment of uterus graft rejection.
Sections du résumé
BACKGROUND
BACKGROUND
Uterus transplantation (UTx) is an emerging therapy for women with uterine infertility. However, critical questions remain with this procedure including the mechanisms involved in graft rejection.
METHODS
METHODS
In this study, we analyzed the immune profile of ectocervical biopsies from 5 patients after UTx before and during their first episode of rejection using RNA sequencing, quantitative polymerase chain reaction, and imaging mass cytometry.
RESULTS
RESULTS
We identified 530 upregulated and 207 downregulated genes associated with graft rejection. Enrichment databases revealed abnormalities of skin-associated genes and the immune system, in particular activation of T and B lymphocytes, and macrophages. Imaging mass cytometry confirmed these observations; in cervical biopsies of 3 women, rejection was associated with the presence of B-cell structures linked to tertiary lymphoid structures, and 2 biopsies from 1 woman with severe rejection episodes and poor prognosis of graft function (repeated miscarriage and implantation failures) were associated with an accumulation of HLA-DR- macrophages, producing granzyme B at the surface of the epithelium.
CONCLUSIONS
CONCLUSIONS
We showed that rejection of a UTx graft was associated with major alterations of immune markers including the involvement of tertiary lymphoid structures, the most organized of which may be a sign of chronic rejection, and with an increase in HLA-DR- macrophages expressing granzyme B in the case of grade 3 rejection episodes according Mölne's classification. We identified potential emerging biomarkers to predict or diagnose graft rejection (Keratin 1 granzyme B, IL1β). These findings could lead to development of improved strategies for the identification, prevention, and/or treatment of uterus graft rejection.
Identifiants
pubmed: 39020469
doi: 10.1097/TP.0000000000005126
pii: 00007890-990000000-00821
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
The authors declare no conflicts of interest.
Références
Sieunarine K, Zakaria FB, Boyle DC, et al. Possibilities for fertility restoration: a new surgical technique. Int Surg. 2005;90:249–256.
Brannstrom M, Johannesson L, Bokstrom H, et al. Livebirth after uterus transplantation. Lancet. 2015;385:607–616.
Ayoubi JM, Carbonnel M, Racowsky C, et al. Evolving clinical challenges in uterus transplantation. Reprod Biomed Online. 2022;45:947–960.
Brannstrom M, Racowsky C, Carbonnel M, et al. Uterus transplantation: from research, through human trials and into the future. Hum Reprod Update. 2023;29:521–544.
D’Amico G, Del Prete L, Eghtesad B, et al. Immunosuppression in uterus transplantation: from transplant to delivery. Expert Opin Pharmacother. 2023;24:29–35.
Mölne J, Broecker V, Ekberg J, et al. Monitoring of human uterus transplantation with cervical biopsies: a provisional scoring system for rejection. Am J Transplant. 2017;17:1628–1636.
Agarwal A, Johannesson L, Findeis SK, et al. Clinicopathological analysis of uterine allografts including proposed scoring of ischemia reperfusion injury and t-cell-mediated rejection-Dallas UtErus transplant study: a pilot study. Transplantation. 2022;106:167–177.
Flyckt R, Falcone T, Quintini C, et al. First birth from a deceased donor uterus in the United States: from severe graft rejection to successful cesarean delivery. Am J Obstet Gynecol. 2020;223:143–151.
Cendales LC, Kanitakis J, Schneeberger S, et al. The Banff 2007 working classification of skin-containing composite tissue allograft pathology. Am J Transplant. 2008;8:1396–1400.
Karlsson CC, Dahm-Kahler P, Kvarnstrom N, et al. Hysterectomy after uterus transplantation and detailed analyses of graft failures. Acta Obstet Gynecol Scand. 2022;101:355–363.
Brannstrom M, Dahm-Kahler P, Kvarnstrom N, et al. Reproductive, obstetric, and long-term health outcome after uterus transplantation: results of the first clinical trial. Fertil Steril. 2022;118:576–585.
FastQC. A quality control tool for high throughput sequence data. Available at http://www.bioinformatics.babraham.ac.uk/projects/fastqc/. Accessed January 10, 2015.
Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30:2114–2120.
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–140.
Liberzon AA. Description of the Molecular Signatures Database (MSigDB) web site. Methods Mol Biol. 2014;1150:153–160.
Kanehisa M, Sato Y, Kawashima M, et al. KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res. 2016;44:D457–D462.
Lo DJ, Kaplan B, Kirk AD. Biomarkers for kidney transplant rejection. Nat Rev Nephrol. 2014;10:215–225.
Shadeo A, Chari R, Vatcher G, et al. Comprehensive serial analysis of gene expression of the cervical transcriptome. BMC Genomics. 2007;8:142.
Ijsselsteijn ME, van der Breggen R, Farina Sarasqueta A, et al. A 40-marker panel for high dimensional characterization of cancer immune microenvironments by imaging mass cytometry. Front Immunol. 2019;10:2534.
Wang YJ, Traum D, Schug J, et al.; HPAP Consortium. Multiplexed in situ imaging mass cytometry analysis of the human endocrine pancreas and immune system in type 1 diabetes. Cell Metab. 2019;29:769–783.e4.
Elaldi R, Hemon P, Petti L, et al. High dimensional imaging mass cytometry panel to visualize the tumor immune microenvironment contexture. Front Immunol. 2021;12:666233.
Hoeltzenbein M, Elefant E, Vial T, et al. Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Am J Med Genet A. 2012;158A:588–596.
Pitzalis C, Jones GW, Bombardieri M, et al. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat Rev Immunol. 2014;14:447–462.
Nova-Lamperti E, Chana P, Mobillo P, et al.; GAMBIT Study. Increased CD40 ligation and reduced BCR signalling leads to higher IL-10 production in B cells from tolerant kidney transplant patients. Transplantation. 2017;101:541–547.
Lu Y, Li B, Shen Q, et al. Effects of CD20+ B-cell infiltration into allografts on kidney transplantation outcomes: a systematic review and meta-analysis. Oncotarget. 2017;8:37935–37941.
Thaunat O. Pathophysiologic significance of B-cell clusters in chronically rejected grafts. Transplantation. 2011;92:121–126.
Hautz T, Zelger BG, Nasr IW, et al. Lymphoid neogenesis in skin of human hand, nonhuman primate, and rat vascularized composite allografts. Transpl Int. 2014;27:966–976.
Brown K, Sacks SH, Wong W. Tertiary lymphoid organs in renal allografts can be associated with donor-specific tolerance rather than rejection. Eur J Immunol. 2011;41:89–96.
Le Texier L, Thebault P, Lavault A, et al. Long-term allograft tolerance is characterized by the accumulation of B cells exhibiting an inhibited profile. Am J Transplant. 2011;11:429–438.
Hasegawa T, Iacono A, Yousem SA. The significance of bronchus-associated lymphoid tissue in human lung transplantation: is there an association with acute and chronic rejection? Transplantation. 1999;67:381–385.
Lee YH, Sato Y, Saito M, et al. Advanced tertiary lymphoid tissues in protocol biopsies are associated with progressive graft dysfunction in kidney transplant recipients. J Am Soc Nephrol. 2022;33:186–200.
Thaunat O, Patey N, Caligiuri G, et al. Chronic rejection triggers the development of an aggressive intragraft immune response through recapitulation of lymphoid organogenesis. J Immunol. 2010;185:717–728.
Thaunat O, Patey N, Gautreau C, et al. B cell survival in intragraft tertiary lymphoid organs after rituximab therapy. Transplantation. 2008;85:1648–1653.
Nowocin AK, Meader L, Brown K, et al. Characterizing the B-cell and humoral response in tertiary lymphoid organs in kidney allografts. Exp Clin Transplant. 2019;17:330–338.
Lewis EL, Xu R, Beltra JC, et al. NFAT-dependent and -independent exhaustion circuits program maternal CD8 T cell hypofunction in pregnancy. J Exp Med. 2022;219:e20201599.
Pollard JM, Chong AS. Semiallogeneic pregnancy: a paradigm change for T-cell transplantation tolerance. Transplantation. 2022;106:1098–1100.
Garaud S, Dieu-Nosjean MC, Willard-Gallo K. T follicular helper and B cell crosstalk in tertiary lymphoid structures and cancer immunotherapy. Nat Commun. 2022;13:2259.
Li J, Li C, Zhuang Q, et al. The evolving roles of macrophages in organ transplantation. J Immunol Res. 2019;2019:5763430.
Tian H, Wu J, Ma M. Implications of macrophage polarization in corneal transplantation rejection. Transpl Immunol. 2021;64:101353.
Baba T, Ishizu A, Iwasaki S, et al. CD4+/CD8+ macrophages infiltrating at inflammatory sites: a population of monocytes/macrophages with a cytotoxic phenotype. Blood. 2006;107:2004–2012.
Basu R, Whitlock BM, Husson J, et al. Cytotoxic T cells use mechanical force to potentiate target cell killing. Cell. 2016;165:100–110.
Zaki MA, Wada N, Ikeda J, et al. Prognostic implication of types of tumor-associated macrophages in Hodgkin lymphoma. Virchows Arch. 2011;459:361–366.
Monneret G, Finck ME, Venet F, et al. The anti-inflammatory response dominates after septic shock: association of low monocyte HLA-DR expression and high interleukin-10 concentration. Immunol Lett. 2004;95:193–198.
Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–969.
Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11:723–737.
van den Bosch TP, Caliskan K, Kraaij MD, et al. CD16+ monocytes and skewed macrophage polarization toward m2 type hallmark heart transplant acute cellular rejection. Front Immunol. 2017;8:346.
Vazquez-Torres A, Xu Y, Jones-Carson J, et al. Salmonella pathogenicity island 2-dependent evasion of the phagocyte NADPH oxidase. Science. 2000;287:1655–1658.
Brannstrom M, Tullius SG, Brucker S, et al. Registry of the International Society of Uterus Transplantation: first report. Transplantation. 2023;107:10–17.
Ozkan O, Ozkan O, Dogan NU, et al. Birth of a healthy baby 9 years after a surgically successful deceased donor uterus transplant. Ann Surg. 2022;275:825–832.
Jones BP, Saso S, L’Heveder A, et al. The vaginal microbiome in uterine transplantation. BJOG. 2020;127:230–238.
Morelon E, Petruzzo P, Kanitakis J. Chronic rejection in vascularized composite allotransplantation. Curr Opin Organ Transplant. 2018;23:582–591.
Black AP, Ardern-Jones MR, Kasprowicz V, et al. Human keratinocyte induction of rapid effector function in antigen-specific memory CD4+ and CD8+ T cells. Eur J Immunol. 2007;37:1485–1493.
Guo X, Hu J, Luo W, et al. Analysis of sera of recipients with allograft rejection indicates that keratin 1 is the target of anti-endothelial antibodies. J Immunol Res. 2017;2017:8679841.