Combined Immunotherapy With Belatacept and BTLA Overexpression Attenuates Acute Rejection Following Kidney Transplantation

Zhang, Hengcheng; Wang, Zijie; Zhang, Jiayi; Gui, Zeping; Han, Ze‐Guang; Tao, Jun; Chen, Hao; Sun, Lingyun; Shuang, Fei; Yang, Haiwei; Tan, Ruoyun; Chandraker, Anil; Gu, Min

doi:10.3389/fimmu.2021.618737

Cited by 13 publications

(17 citation statements)

References 52 publications

(49 reference statements)

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“…50 Th1 cells can drive the proliferation of activated CD4 + and CD8 + effector T cells and enhance the cytotoxicity of natural killer cells by secreting inflammatory cytokines IL-2 and IFN-γ. 51,52 Th2 cells secreting IL-4 and IL-10 are involved in the induction of immune tolerance. 29,51 Studies have shown that the content of cytokine can also significantly affect the expression of PD-1/PD-L1 53 and regulate the therapeutic effect of immunosuppressive drugs in the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Aryl Hydrocarbon Receptor Ameliorates Acute Rejection of Rat Liver Transplantation by Regulating Treg Proliferation and PD-1 Expression

Cao

et al. 2022

Transplantation

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Background. Aryl hydrocarbon receptor (AhR) plays important roles in modulating immune responses. However, the role of AhR in rat liver transplantation (LT) has not been explored. Methods. Safety and side effects of N-(3,4-dimethoxycinnamonyl) anthranilic acid (3,4-DAA) and 2-methyl-2H-pyrazole-3-carboxylic acid amide (CH223191) were evaluated. We used optimal doses of 2 drugs, 3,4-DAA, a drug used for mediating AhR activation, and CH223191, antagonist of AhR (3,4-DAA, CH223191, and 3,4-DAA + CH223191), intraperitoneally administered to recipients daily to investigate the role of AhR in the rat LT model. The recipient livers were used to observe the pathological changes, the cells infiltrating the graft, and changes of AhR and programmed death-1 (PD-1) by Western blot, real-time polymerase chain reaction, and immunofluorescence assays. The contents of Foxp3+ and PD-1+ T cells in the recipient spleen and peripheral blood mononuclear cells were evaluated by flow cytometry. In vitro, after isolating CD4+ T cells, they were treated with different AhR ligands to observe the differentiation direction and PD-1 expression level. Results. The activation of AhR by 3,4-DAA prolonged survival time and ameliorated graft rejection, which were associated with increased expression of AhR and PD-1 in the livers and increased Foxp3+ T cells and PD-1+ T cells in recipient spleens, livers, and peripheral blood mononuclear cells. In vitro, primary T cells incubated with 3,4-DAA mediated increased proportion of Treg and PD-1+ T cells. However, the suppression of AhR with CH223191 reverses these effects, both in the LT model and in vitro. Conclusions. Our results indicated that AhR activation might reduce the occurrence of rat acute rejection by increasing the proportion of Treg and the expression of PD-1.

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Section: Discussionmentioning

confidence: 99%

Activation of the Aryl Hydrocarbon Receptor Ameliorates Acute Rejection of Rat Liver Transplantation by Regulating Treg Proliferation and PD-1 Expression

Cao

et al. 2022

Transplantation

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“…The activation and differentiation of T cells depend on the selection of costimulatory molecules and the composition of cytokines in the environment ( 74 ). On the one hand, cytokines secreted by Th1 cells, such as IFN-γ, TNF-α, and IL-2, can adversely affect the graft by recruiting and activating effector T cells ( 16 , 17 , 75 ). On the other hand, immunomodulatory cytokines secreted by Th2 cells, such as IL-4 and IL-10, can induce tolerance to liver allografts ( 16 , 39 , 76 ).…”

Section: Discussionmentioning

confidence: 99%

“…On the one hand, cytokines secreted by Th1 cells, such as IFN-γ, TNF-α, and IL-2, can adversely affect the graft by recruiting and activating effector T cells ( 16 , 17 , 75 ). On the other hand, immunomodulatory cytokines secreted by Th2 cells, such as IL-4 and IL-10, can induce tolerance to liver allografts ( 16 , 39 , 76 ). Our results showed that TNF-α, IFN-γ, and IL-2 increased in allograft recipients, while IL-4 decreased.…”

Section: Discussionmentioning

confidence: 99%

“…Although most results of these trials are optimistic, many experimental and clinical unanswered questions are slowing the progression of this new therapeutic alternative ( 15 ). In addition, cytokines with pro-inflammatory and regulatory properties are also considered as potential therapeutic targets for inhibiting or enhancing the immune response of recipients ( 16 – 18 ). These results suggest that the content of cytokines, proliferation, and differentiation of T cell subsets, and inhibition of costimulatory molecules are essential for the formation of immune tolerance.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomic analysis of graft liver provides insight into the immune response of rat liver transplantation

Cao

et al. 2022

Front. Immunol.

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BackgroundAs an “immune-privileged organ”, the liver has higher rates of both spontaneous tolerance and operational tolerance after being transplanted compared with other solid organs. Also, a large number of patients still need to take long-term immunosuppression regimens. Liver transplantation (LT) rejection involves varieties of pathophysiological processes and cell types, and a deeper understanding of LT immune response is urgently needed.MethodsHomogenic and allogeneic rat LT models were established, and recipient tissue was collected on postoperative day 7. The degree of LT rejection was evaluated by liver pathological changes and liver function. Differentially expressed genes (DEGs) were detected by transcriptome sequencing and confirmed by reverse transcription-polymerase chain reaction. The functional properties of DEGs were characterized by the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway analyses. The cells infiltrating the graft and recipient spleen and peripheral blood were evaluated by immunofluorescence and flow cytometry.ResultA total of 1,465 DEGs were screened, including 1,177 up-regulated genes and 288 down-regulated genes. GO enrichment and KEGG pathway analysis indicated that DEGs were involved in several immunobiological processes, including T cell activation, Th1, Th2 and Th17 cell differentiation, cytokine-cytokine receptor interaction and other immune processes. Reactome results showed that PD-1 signaling was enriched. Further research confirmed that mRNA expression of multiple immune cell markers increased and markers of T cell exhaustion significantly changed. Flow cytometry showed that the proportion of Treg decreased, and that of PD-1+CD4+ T cells and PD-1+CD8+ T cells increased in the allogeneic group.ConclusionUsing an omic approach, we revealed that the development of LT rejection involved multiple immune cells, activation of various immune pathways, and specific alterations of immune checkpoints, which would benefit risk assessment in the clinic and understanding of pathogenesis regarding LT tolerance. Further clinical validations are warranted for our findings.

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“…Kidney transplantation (KTx) is the most effective treatment for end-stage renal disease (1 , 2 ). The development of immunosuppressant therapies has greatly improved organ and recipient survival (3)(4)(5). However, acute rejection (AR) and delayed graft function (DGF) remain treatment obstacles that impair KTx outcomes, especially in the current era of donation after circulatory death (DCD) (6,7).…”

Section: Introductionmentioning

confidence: 99%

Porcine anti-human lymphocyte immunoglobulin depletes the lymphocyte population to promote successful kidney transplantation

Zhang

Zou

et al. 2023

Front. Immunol.

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IntroductionPorcine anti-human lymphocyte immunoglobulin (pALG) has been used in kidney transplantation, but its impacts on the lymphocyte cell pool remain unclear.MethodsWe retrospectively analyzed 12 kidney transplant recipients receiving pALG, and additional recipients receiving rabbit anti-human thymocyte immunoglobulin (rATG), basiliximab, or no induction therapy as a comparison group.ResultspALG showed high binding affinity to peripheral blood mononuclear cells (PBMCs) after administration, immediately depleting blood lymphocytes; an effect that was weaker than rATG but stronger than basiliximab. Single-cell sequencing analysis showed that pALG mainly influenced T cells and innate immune cells (mononuclear phagocytes and neutrophils). By analyzing immune cell subsets, we found that pALG moderately depleted CD4+T cells, CD8+T cells, regulatory T cells, and NKT cells and mildly inhibited dendritic cells. Serum inflammatory cytokines (IL-2, IL-6) were only moderately increased compared with rATG, which might be beneficial in terms of reducing the risk of untoward immune activation. During 3 months of follow-up, we found that all recipients and transplanted kidneys survived and showed good organ function recovery; there were no cases of rejection and a low rate of complications.DiscussionIn conclusion, pALG acts mainly by moderately depleting T cells and is thus a good candidate for induction therapy for kidney transplant recipients. The immunological features of pALG should be exploited for the development of individually-optimized induction therapies based on the needs of the transplant and the immune status of the patient, which is appropriate for non-high-risk recipients.

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Combined Immunotherapy With Belatacept and BTLA Overexpression Attenuates Acute Rejection Following Kidney Transplantation

Cited by 13 publications

References 52 publications

Activation of the Aryl Hydrocarbon Receptor Ameliorates Acute Rejection of Rat Liver Transplantation by Regulating Treg Proliferation and PD-1 Expression

Activation of the Aryl Hydrocarbon Receptor Ameliorates Acute Rejection of Rat Liver Transplantation by Regulating Treg Proliferation and PD-1 Expression

Transcriptomic analysis of graft liver provides insight into the immune response of rat liver transplantation

Porcine anti-human lymphocyte immunoglobulin depletes the lymphocyte population to promote successful kidney transplantation

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