How Immunosuppressants in Transplant Therapy cause Blood Vessel Damage

Understanding how immunosuppressants in transplant therapy cause blood vessel damage – C4d staining in liver tissue

The study titled “Modeling antithymocyte globulin-induced microvasculopathy using human iPSC-derived vascularized liver organoids” aims to better understand the vascular side effects caused by antithymocyte globulin (ATG), a drug used in transplant medicine. Researchers created vascularized liver organoids from human induced pluripotent stem cells (iPSCs) to simulate human liver blood vessels. Using this model, they investigated how ATG induces microvasculopathy, or small blood vessel damage. This platform offers new insights into the mechanisms of ATG-related vascular injury and could help develop safer treatments to reduce side effects in transplant patients.

C4d staining in Paraffin-Embedded (FFPE) liver tissue was performed with the BIOMEDICA anti-C4d antibody.

Anti-C4d Antibody | BI-RC4D 

for the identification of human complement split product C4d in paraffin and frozen sections as well as by flow cytometry.

 Product Highlights:

 Anti-C4d Antibody  cat. no. BI-RC4D

• TRUSTED – widely cited in over 100 citations
• MULTI-USE – for immunohistochemistry on paraffin embedded tissue and frozen sections
• The C4d antibody has been utilized in kidney, heart, liver and other transplants
• working protocol

 

Anti-C4d Antibody (FITC) | BI-RC4D-FITC

• Protocol for cell- or solid-phase bound C4 and C4d split product by flow cytometry
• working protocol

-Discover our anti-C4d antibodies for IHC and FITC.

 

How Immunosuppressants in Transplant Therapy cause Blood Vessel Damage

Publication: Modeling antithymocyte globulin-induced microvasculopathy using human iPSC-derived vascularized liver organoids. Kawamura S, Yoneyama Y, Saiki N, Wu Y, Moriya C, Ohmura R, Maezawa M, Shimada Y, Wang Y, Mori K, Okada N, Onishi Y, Sanada Y, Hirata Y, Sakuma Y, Takebe T. Cell Rep Med. 2025 Nov 18;6(11):102433. doi: 10.1016/j.xcrm.2025.102433. Epub 2025 Nov 6. PMID: 41202806; PMCID: PMC12711670.

Abstract

Antithymocyte globulin (ATG) is a widely used immunosuppressive agent, yet its off-target vascular effects remain a clinical challenge in part due to a lack of relevant human models. Here, we uncover a biphasic mechanism of ATG-induced microvasculopathy using a humanized liver organoid platform derived from induced pluripotent stem cells (iPSCs). We show that ATG triggers a rapid, complement-dependent phase of injury restricted to human iPSC-derived liver sinusoidal endothelial cells (iLSECs), leading to C3 deposition and acute thrombosis specifically in human but not in mouse vessels. Transcriptomics reveals a delayed transforming growth factor β (TGF-β) pathway-driven proinflammatory program that coincides with neutrophil recruitment and degranulation, while pharmacological TGF-β blockade attenuates thrombosis and flow disturbance. Our findings reveal a pathogenic sequence of complement and TGF-β pathway activation and establish a translational platform for dissecting human liver-specific microvasculopathy in vivo.

Related literature

Anti-thymocyte globulin-induced hyperbilirubinemia in patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation. Ecsedi M, Schmohl J, Zeiser R, Drexler B, Halter J, Medinger M, Duyster J, Kanz L, Passweg J, Finke J, Bethge W, Lengerke C. Ann Hematol. 2016 Oct;95(10):1627-36. doi: 10.1007/s00277-016-2758-z. Epub 2016 Aug 2. PMID: 27480090.

Complement component 4d immunostaining in liver allografts of patients with de novo immune hepatitis. Aguilera I, Sousa JM, Gavilan F, Gomez L, Alvarez-Márquez A, Núñez-Roldán A. Liver Transpl. 2011 Jul;17(7):779-88. doi: 10.1002/lt.22302. PMID: 21425430.

Influence of preformed donor-specific antibodies and C4d on early liver allograft function. Perera MT, Silva MA, Murphy N, Briggs D, Mirza DF, Neil DA. Scand J Gastroenterol. 2013 Dec;48(12):1444-51. doi: 10.3109/00365521.2013.845795. Epub 2013 Oct 16. PMID: 24131305.