Recent Advances in Allograft Vasculopathy

Overview

Journal Curr Opin Organ Transplant

Specialty General Surgery

Date 2016 Nov 30

PMID 27898462

Citations 25

Authors

Jonathan Merola

Daniel D Jane-Wit

Jordan S Pober

Affiliations

Soon will be listed here.

Abstract

Purpose Of Review: Despite considerable advances in controlling acute rejection, the longevity of cardiac and renal allografts remains significantly limited by chronic rejection in the form of allograft vasculopathy. This review discusses recently reported mechanistic insights of allograft vasculopathy pathogenesis as well as recent clinical evaluations of new therapeutic approaches.

Recent Findings: Although adaptive immunity is the major driver of allograft vasculopathy, natural killer cells mediate vasculopathic changes in a transplanted mouse heart following treatment with donor-specific antibody (DSA). However, natural killer cells may also dampen chronic inflammatory responses by killing donor-derived tissue-resident CD4 T cells that provide help to host B cells, the source of DSA. DSA may directly contribute to vascular inflammation by inducing intracellular signaling cascades that upregulate leukocyte adhesion molecules, facilitating recruitment of neutrophils and monocytes. DSA-mediated complement activation additionally enhances endothelial alloimmunogenicity through activation of noncanonical NF-κB signaling. New clinical studies evaluating mammalian target of rapamycin and proteasome inhibitors to target these pathways have been reported.

Summary: Allograft vasculopathy is a disorder resulting from several innate and adaptive alloimmune responses. Mechanistic insights from preclinical studies have identified agents that are currently being investigated in clinical trials.

Citing Articles

Antibody ligation of HLA class II induces YAP nuclear localization and formation of cytoplasmic YAP condensates in human endothelial cells.

Lone M, Anwar T, Sinnett-Smith J, Jin Y, Reed E, Rozengurt E Immunohorizons. 2025; 9(3).

PMID: 39865973 PMC: 11841970. DOI: 10.1093/immhor/vlae008.

Apolipoprotein B-48 and late graft failure in kidney transplant recipients.

Szili-Torok T, de Borst M, Soteriou A, Post L, Bakker S, Tietge U Clin Kidney J. 2024; 17(10):sfae289.

PMID: 39430793 PMC: 11487158. DOI: 10.1093/ckj/sfae289.

Reduced Ceramides Are Associated with Acute Rejection in Liver Transplant Patients and Skin Graft and Hepatocyte Transplant Mice, Reducing Tolerogenic Dendritic Cells.

Yoo H, Yi Y, Kang Y, Kim S, Yoon Y, Tran P Mol Cells. 2023; 46(11):688-699.

PMID: 37968983 PMC: 10654454. DOI: 10.14348/molcells.2023.0104.

Hedgehog signalling in allograft vasculopathy: a new therapeutic target?.

Rowell J, Lau C, Yanez D, Zhang E, Crompton T Trends Pharmacol Sci. 2023; 44(9):558-560.

PMID: 37296035 PMC: 11569892. DOI: 10.1016/j.tips.2023.05.005.

Strategies to counteract adverse remodeling of vascular graft: A 3D view of current graft innovations.

Tan W, Boodagh P, Selvakumar P, Keyser S Front Bioeng Biotechnol. 2023; 10:1097334.

PMID: 36704297 PMC: 9871289. DOI: 10.3389/fbioe.2022.1097334.

References

Tellides G, Tereb D, Kirkiles-Smith N, Kim R, Wilson J, Schechner J . Interferon-gamma elicits arteriosclerosis in the absence of leukocytes. Nature. 2000; 403(6766):207-11. DOI: 10.1038/35003221. View

Gorbacheva V, Fan R, Fairchild R, Baldwin 3rd W, Valujskikh A . Memory CD4 T Cells Induce Antibody-Mediated Rejection of Renal Allografts. J Am Soc Nephrol. 2016; 27(11):3299-3307. PMC: 5084884. DOI: 10.1681/ASN.2015080848. View

Lin C, Plenter R, Coulombe M, Gill R . Interferon Gamma and Contact-dependent Cytotoxicity Are Each Rate Limiting for Natural Killer Cell-Mediated Antibody-dependent Chronic Rejection. Am J Transplant. 2016; 16(11):3121-3130. PMC: 5083186. DOI: 10.1111/ajt.13865. View

Zou H, Yang Y, Gao M, Zhang B, Ming B, Sun Y . HMGB1 is involved in chronic rejection of cardiac allograft via promoting inflammatory-like mDCs. Am J Transplant. 2014; 14(8):1765-77. DOI: 10.1111/ajt.12781. View

Shin S, Kim Y, Cho Y, Park Y, Han S, Choi B . Interpreting CD56+ and CD163+ infiltrates in early versus late renal transplant biopsies. Am J Nephrol. 2015; 41(4-5):362-9. DOI: 10.1159/000430473. View

Walker J, Maier C, Pober J . Cytomegalovirus-infected human endothelial cells can stimulate allogeneic CD4+ memory T cells by releasing antigenic exosomes. J Immunol. 2009; 182(3):1548-59. PMC: 2630120. DOI: 10.4049/jimmunol.182.3.1548. View

Nayak D, Zhou F, Xu M, Huang J, Tsuji M, Hachem R . Long-Term Persistence of Donor Alveolar Macrophages in Human Lung Transplant Recipients That Influences Donor-Specific Immune Responses. Am J Transplant. 2016; 16(8):2300-11. PMC: 5289407. DOI: 10.1111/ajt.13819. View

Minami E, Laflamme M, Saffitz J, Murry C . Extracardiac progenitor cells repopulate most major cell types in the transplanted human heart. Circulation. 2005; 112(19):2951-8. DOI: 10.1161/CIRCULATIONAHA.105.576017. View

Bergler T, Jung B, Bourier F, Kuhne L, Banas M, Rummele P . Infiltration of Macrophages Correlates with Severity of Allograft Rejection and Outcome in Human Kidney Transplantation. PLoS One. 2016; 11(6):e0156900. PMC: 4902310. DOI: 10.1371/journal.pone.0156900. View

10.

Chan R, Ibrahim S, Takahashi K, Kwon E, McCormack M, Ezekowitz A . The differing roles of the classical and mannose-binding lectin complement pathways in the events following skeletal muscle ischemia-reperfusion. J Immunol. 2006; 177(11):8080-5. DOI: 10.4049/jimmunol.177.11.8080. View

11.

Fantus D, Thomson A . Evolving perspectives of mTOR complexes in immunity and transplantation. Am J Transplant. 2015; 15(4):891-902. DOI: 10.1111/ajt.13151. View

12.

Arbore G, West E, Spolski R, Robertson A, Klos A, Rheinheimer C . T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4⁺ T cells. Science. 2016; 352(6292):aad1210. PMC: 5015487. DOI: 10.1126/science.aad1210. View

13.

Rodrigues-Diez R, Gonzalez-Guerrero C, Ocana-Salceda C, Rodrigues-Diez R, Egido J, Ortiz A . Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling. Sci Rep. 2016; 6:27915. PMC: 4904742. DOI: 10.1038/srep27915. View

14.

Yu L, Qin L, Zhang H, He Y, Chen H, Pober J . AIP1 prevents graft arteriosclerosis by inhibiting interferon-γ-dependent smooth muscle cell proliferation and intimal expansion. Circ Res. 2011; 109(4):418-27. PMC: 3227522. DOI: 10.1161/CIRCRESAHA.111.248245. View

15.

Habig D, Gaspari J, Lokhandwala P, Domen R, Abendroth C, Kadry Z . Donor-specific antibody to trans-encoded donor HLA-DQ heterodimer. Hum Immunol. 2015; 76(8):587-90. DOI: 10.1016/j.humimm.2015.09.004. View

16.

Pober J, Tellides G . Participation of blood vessel cells in human adaptive immune responses. Trends Immunol. 2011; 33(1):49-57. PMC: 3253953. DOI: 10.1016/j.it.2011.09.006. View

17.

Hirohashi T, Chase C, Pelle P, Sebastian D, Alessandrini A, Madsen J . A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody. Am J Transplant. 2011; 12(2):313-21. PMC: 3667648. DOI: 10.1111/j.1600-6143.2011.03836.x. View

18.

Loupy A, Toquet C, Rouvier P, Beuscart T, Bories M, Varnous S . Late Failing Heart Allografts: Pathology of Cardiac Allograft Vasculopathy and Association With Antibody-Mediated Rejection. Am J Transplant. 2015; 16(1):111-20. DOI: 10.1111/ajt.13529. View

19.

Wedel J, Hottenrott M, Bulthuis M, Huitema S, Yard B, Hillebrands J . N-octanoyl Dopamine Attenuates the Development of Transplant Vasculopathy in Rat Aortic Allografts Via Smooth Muscle Cell Protective Mechanisms. Transplantation. 2015; 100(1):80-90. DOI: 10.1097/TP.0000000000000870. View

20.

Pearl M, Nayak A, Ettenger R, Puliyanda D, Palma Diaz M, Zhang Q . Bortezomib may stabilize pediatric renal transplant recipients with antibody-mediated rejection. Pediatr Nephrol. 2016; 31(8):1341-8. PMC: 5590841. DOI: 10.1007/s00467-016-3319-3. View