CXCR4 Antagonist Reduced the Incidence of Acute Rejection and Controlled Cardiac Allograft Vasculopathy in a Swine Heart Transplant Model Receiving a Mycophenolate-based Immunosuppressive Regimen

Hsu, Wei Hsuan; Lin, Chung-Yuan; Jui, Hsiang-Yiang; Tseng, Ya-Hsuan; Shun, Chia‐Tung; Hsu, Ming‐Chu; Wu, Kenneth K.; Lee, Chi-Ming

doi:10.1097/tp.0000000000002404

Cited by 13 publications

(10 citation statements)

References 46 publications

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“…As expected, the overall survival probability of patients with higher expression of CD44, CXCR4, and PTPN6 showed worse disease consequences (Figure 4G), suggesting that these genes were HR regulators of allograft loss. It is known that antagonists of CD44 and CXCR4 can help improve outcomes in allograft rejection (56,60), which further supports our hypothesis.…”

Section: Ptpn6 Is a Novel Signaling Molecular Inducing Stat4 Signalin...supporting

confidence: 88%

T Cells With Activated STAT4 Drive the High-Risk Rejection State to Renal Allograft Failure After Kidney Transplantation

et al. 2022

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In kidney transplantation, deteriorated progression of rejection is considered to be a leading course of postoperative mortality. However, the conventional histologic diagnosis is limited in reading the rejection status at the molecular level, thereby triggering mismatched pathogenesis with clinical phenotypes. Here, by applying uniform manifold approximation and projection and Leiden algorithms to 2,611 publicly available microarray datasets of renal transplantation, we uncovered six rejection states with corresponding signature genes and revealed a high-risk (HR) state that was essential in promoting allograft loss. By identifying cell populations from single-cell RNA sequencing data that were associated with the six rejection states, we identified a T-cell population to be the pathogenesis-triggering cells associated with the HR rejection state. Additionally, by constructing gene regulatory networks, we identified that activated STAT4, as a core transcription factor that was regulated by PTPN6 in T cells, was closely linked to poor allograft function and prognosis. Taken together, our study provides a novel strategy to help with the precise diagnosis of kidney allograft rejection progression, which is powerful in investigating the underlying molecular pathogenesis, and therefore, for further clinical intervention.

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Section: Ptpn6 Is a Novel Signaling Molecular Inducing Stat4 Signalin...supporting

confidence: 88%

T Cells With Activated STAT4 Drive the High-Risk Rejection State to Renal Allograft Failure After Kidney Transplantation

et al. 2022

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“…CXCR4 leads to enhanced proliferation, migration, and invasion of tumor cells by binding to CXCL12 and activating various downstream signaling pathways ( 28 ). Some studies on the role of CXCR4 in immune rejection show that its antagonist can effectively reduce the intensity of rejection after transplantation ( 29 , 30 ). These observations are consistent with our results.…”

Section: Resultsmentioning

confidence: 99%

Single-Cell Transcriptome Analysis of Chronic Antibody-Mediated Rejection After Renal Transplantation

Kong

Zhong

et al. 2022

Front. Immunol.

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Renal transplantation is currently the most effective treatment for end-stage renal disease. However, chronic antibody-mediated rejection (cABMR) remains a serious obstacle for the long-term survival of patients with renal transplantation and a problem to be solved. At present, the role and mechanism underlying immune factors such as T- and B- cell subsets in cABMR after renal transplantation remain unclear. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood monocytes (PBMCs) from cABMR and control subjects was performed to define the transcriptomic landscape at single-cell resolution. A comprehensive scRNA-seq analysis was performed. The results indicated that most cell types in the cABMR patients exhibited an intense interferon response and release of proinflammatory cytokines. In addition, we found that the expression of MT-ND6, CXCL8, NFKBIA, NFKBIZ, and other genes were up-regulated in T- and B-cells and these genes were associated with pro-inflammatory response and immune regulation. Western blot and qRT-PCR experiments also confirmed the up-regulated expression of these genes in cABMR. GO and KEGG enrichment analyses indicated that the overexpressed genes in T- and B-cells were mainly enriched in inflammatory pathways, including the TNF, IL-17, and Toll-like receptor signaling pathways. Additionally, MAPK and NF-κB signaling pathways were also involved in the occurrence and development of cABMR. This is consistent with the experimental results of Western blot. Trajectory analysis assembled the T-cell subsets into three differentiation paths with distinctive phenotypic and functional prog rams. CD8 effector T cells and γδ T cells showed three different differentiation trajectories, while CD8_MAI T cells and naive T cells primarily had two differentiation trajectories. Cell-cell interaction analysis revealed strong T/B cells and neutrophils activation in cABMR. Thus, the study offers new insight into pathogenesis and may have implications for the identification of novel therapeutic targets for cABMR.

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“…16 Similarly, blocking Cxcr4, along with simultaneous mycophenolate mofetil, decreases vascular injury and shortterm rejection in cardiac allografts. 42 This finding is relevant for hepatic grafts because Cxcl4 (ligand for Cxcr4) is persistently expressed in allogeneic hepatocytes with mycophenolate mofetil and tacrolimus treatment. More recently, sustained Ccl22 release was shown to recruit Tregulatory cells in rodents to improve tolerance of allogeneic vascularized grafts.…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor Directs Allograft-Related Innate Responses and Its Neutralization Improves Hepatocyte Engraftment in Rats

Jaber

Sharma

Mui

et al. 2021

The American Journal of Pathology

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CXCR4 Antagonist Reduced the Incidence of Acute Rejection and Controlled Cardiac Allograft Vasculopathy in a Swine Heart Transplant Model Receiving a Mycophenolate-based Immunosuppressive Regimen

Abstract: The augmentation of conventional MMF plus corticosteroids with a CXCR4 antagonist is potentially effective in improving outcomes after heart transplantation in minipigs. Future studies are warranted into optimizing the therapeutic regimens for humans.

Cited by 13 publications

References 46 publications

T Cells With Activated STAT4 Drive the High-Risk Rejection State to Renal Allograft Failure After Kidney Transplantation

T Cells With Activated STAT4 Drive the High-Risk Rejection State to Renal Allograft Failure After Kidney Transplantation

Single-Cell Transcriptome Analysis of Chronic Antibody-Mediated Rejection After Renal Transplantation

Tumor Necrosis Factor Directs Allograft-Related Innate Responses and Its Neutralization Improves Hepatocyte Engraftment in Rats

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