Dataset Information

Overexpression of fibrinogen-like protein 2 alleviates acute rejection in rat models of liver transplantation.

ABSTRACT:

Background

The role of cluster of differentiation (CD)8+ regulatory T cells (Tregs) has previously been elucidated in tolerance models. Fibrinogen-like protein 2 (FGL2), that is secreted by Treg cells, which exhibited immunosuppressive functions, may alleviate acute rejection (AR). However, the precise role of CD8+ Tregs and FGL2 in the AR of rat liver transplantation remains unknown. Our previous study found that CD8+CD45RClow Tregs played crucial roles in maintaining immune tolerance. Here, we elucidated the role of CD8+ CD45RClowTreg and FGL2 in AR of rat liver transplantation.

Methods

A rat non-materialized AR of liver transplantation model was established using donors infected with no-load adeno-associated virus and adeno-associated virus expressing FGL2.

Results

There was an accumulation of tolerogenic CD8+CD45RClow in allografts compared with blank groups. Moreover, the proportion of CD8+CD45RClow Tregs was increased with longer survival time. Furthermore, we detected higher levels of FGL2 in the allografts infected with AAV-FGL2 in rats with AR of liver transplantation. We found that FGL2 could alleviate AR, and the survival time was prolonged in the recipients of donors infected with AAV-FGL2.

Conclusions

Our data suggest that CD8+CD45RClow Tregs was accumulated in allografts. The presence of FGL2 alleviated AR and prolonged survival time in the AR of liver transplantation rat model, suggesting that FGL2 and CD8+CD45RClow Tregs may serves as novel therapeutic targets for AR in liver transplantation.

SUBMITTER: Zhang X

PROVIDER: S-EPMC8033335 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

Overexpression of fibrinogen-like protein 2 alleviates acute rejection in rat models of liver transplantation.

Zhang Xinxue X Ma Jun J Li Han H Zhou Lin L Liu Zhe Z Lyu Shaocheng S He Qiang Q Li Xianliang X

Annals of translational medicine 20210301 5

<h4>Background</h4>The role of cluster of differentiation (CD)8+ regulatory T cells (Tregs) has previously been elucidated in tolerance models. Fibrinogen-like protein 2 (FGL2), that is secreted by Treg cells, which exhibited immunosuppressive functions, may alleviate acute rejection (AR). However, the precise role of CD8+ Tregs and FGL2 in the AR of rat liver transplantation remains unknown. Our previous study found that CD8+CD45RClow Tregs played crucial roles in maintaining immune tolerance. ...[more]

PMID: 33842629

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Project description:BackgroundTo establish an animal model of pre-sensitization following liver transplantation either with or without immunosuppressors. To study whether accelerated liver rejection or acute antibody-mediated rejection (AMR) occurred and study the characteristics and potential mechanism in the animal model.MethodsLewis (LEW) rats were subjected to liver [liver graft of Brown Norway (BN) rat] transplantation 2 weeks after lymphocyte injection (lymphocytes of BN rat; pre-sensitization). At 2 weeks after transplantation, serum samples of recipients were collected for antibody analysis to identify donor-specific alloantibody (DSA) level. The recipients were treated with or without a low dose of immunosuppressor (2 mg/kg). The liver grafts of each group were analyzed by hematoxylin and eosin (HE) stain, Masson stain, CK19, C4d, and CD20 immunohistochemical (IHC) stain, CD3, CD68, and CD86 immunofluorescence and transmission electron microscope (TEM) to study the characteristics of liver rejection. Moreover, cytotoxin-associated genes, M1 macrophages conversion-related proteins, and interleukin-6 (IL-6) signaling pathway proteins were detected by western blotting.ResultsHigh level of DSA and accelerated liver rejection occurred in the pre-sensitized rat models following liver transplant. Accelerated liver graft rejection occurred in the pre-sensitized, post liver transplant rats regardless of whether a low dose immunosuppressor had been applied. Severe injury of the interlobular bile ducts and accelerated fibrosis could be observed. Moreover, evidence of endothelial injury, such as capillary inflammation, was found in the pre-sensitized, post-transplant rats. In addition, C4d deposition and M1 macrophages recruitment were also found in this sensitized followed transplant model, indicating that complement activation might occur in this model. The levels of IL-6, JAK1, STAT3, SHP2, and ERK1-2 were increased in the pre-sensitized, post-transplant rats.ConclusionsPre-sensitized post liver transplant rats might be potential AMR models for further study.

Project description:BackgroundCostimulatory blockade provides new therapeutic opportunities for ensuring the long-term survival of kidney grafts. The adoption of the novel immunosuppressant Belatacept has been limited, partly due to concerns regarding higher rates and grades of acute rejection in clinical trials. In this study, we hypothesized that a combined therapy, Belatacept combined with BTLA overexpression, may effectively attenuate acute rejection after kidney transplantation.Materials and methodsThe rat kidney transplantation model was used to investigate graft rejection in single and combined therapy. Graft function was analyzed by detecting serum creatinine. Pathological staining was used to observe histological changes in grafts. The expression of T cells was observed by immunohistochemistry and flow cytometry. In vitro, we constructed an antigen-stimulated immune response by mixed lymphocyte culture, treated with or without Belatacept and BTLA-overexpression adenovirus, to observe the proliferation of receptor cells and the expression of cytokines. In addition, western blot and qRT-PCR analyses were performed to evaluate the expression of CTLA-4 and BTLA at various time points during the immune response.ResultsIn rat models, combined therapy reduced the serum creatinine levels and prolonged graft survival compared to single therapy and control groups. Mixed acute rejection was shown in the allogeneic group and inhibited by combination treatment. Belatacept reduced the production of DSA and the deposition of C4d in grafts. Belatacept combined with BTLA overexpression downregulated the secretion of IL-2 and IFN-γ, as well as increasing IL-4 and IL-10 expression. We also found that Belatacept combined with BTLA overexpression inhibited the proliferation of spleen lymphocytes. The duration of the elevated expression levels of CTLA-4 and BTLA differentially affected the immune response.ConclusionBelatacept combined with BTLA overexpression attenuated acute rejection after kidney transplantation and prolonged kidney graft survival, which suggests a new approach for the optimization of early immunosuppression after kidney transplantation.

Dataset Information

Overexpression of fibrinogen-like protein 2 alleviates acute rejection in rat models of liver transplantation.

Background

Methods

Results

Conclusions

Publications

Overexpression of fibrinogen-like protein 2 alleviates acute rejection in rat models of liver transplantation.

Similar Datasets

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