The dynamic changes of Th17/Treg cytokines in rat liver transplant rejection and tolerance

Li, Jinzheng; Lai, Xiaorong; Liao, Wang-Yang; He, Yong; Liu, Yiming; Gong, Jianping

doi:10.1016/j.intimp.2011.02.010

Cited by 34 publications

(17 citation statements)

References 37 publications

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“…Foxp3 + Tregs possess immune-regulatory functions by producing the anti-inflammatory cytokines IL-10 and TGF-β1 [47], [48]. Similar to our data, Li et al recently reported the induction of Foxp3 and IL-10 in liver allografts at the rejection phase after OLT in BN-to-LEW combinations [49]. The gene expression of Foxp3 and IL-10 in the rejected livers (day 7) was higher than those in the tolerant livers (>day 60), while the protein expression of Foxp3 and IL-10 was opposite fashion.…”

Section: Discussionsupporting

confidence: 90%

Immunological and Regenerative Aspects of Hepatic Mast Cells in Liver Allograft Rejection and Tolerance

et al. 2012

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The precise roles of mast cells in liver allograft rejection and tolerance are still unknown. This study aimed to explore the roles of mast cells in immune regulation and liver regeneration for tolerance induction by using rat models of orthotopic liver transplantation (OLT). Stem cell factor (SCF) and its receptor c-Kit, which are critical to the migration and development of not only stem cells but also mast cells, significantly increased in the tolerogenic livers as compared with rejected livers. The significant elevation of mast cell tryptase, high-affinity IgE receptor, and histamine suggested the activation of mast cells in liver allografts at the tolerogenic phase after OLT. Immunohistochemical analysis using confocal microscope clearly showed colocalization of mast cells, Foxp3+ Tregs, γδ T cells, and recipient-derived hepatic progenitor cells with higher expression of SCF, IL-9, IL-10, TGF-β1, and IL-17 related to immunoregulation and liver regeneration in the donor grafts of a tolerogenic OLT model. Cross-talk among mast cells and other cells was evaluated by in vitro studies demonstrating that syngeneic bone marrow−derived mast cells (BMMCs) co-cultured with naïve splenocytes or primary hepatocytes significantly increased the population of splenic γδ T cells by mitogen stimulation or by mast cell degranulation, and also significantly induced the hepatocyte proliferation, respectively. Our results suggested that mast cells in the donor grafts may play important roles in the induction/maintenance of immune tolerance and liver regeneration resulting in the replacement of hepatic cells from donor to recipient.

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Section: Discussionsupporting

confidence: 90%

Immunological and Regenerative Aspects of Hepatic Mast Cells in Liver Allograft Rejection and Tolerance

et al. 2012

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“…However, we also found an increase in the IL-23 expression in the skin graft, confirming the presence of Th17 cells. In agreement with our data, Li et al (39) found both Treg and Th17 cells in mouse liver transplants. They showed a time-dependent and significant increase in Th17-related cytokines (IL-17, IL-6 and IL-23), whereas the expression of Treg-related cytokines (IL-10, TGF-β1) was markedly low in the liver of transplanted mice prior to graft rejection.…”

Section: Discussionsupporting

confidence: 94%

The imbalance between Treg and Th17 cells caused by FTY720 treatment in skin allograft rejection

Commodaro¹,

Pedregosa²,

Peron³

et al. 2012

Clinics

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OBJECTIVES:FTY720 modulates CD4+T cells by the augmentation of regulatory T cell activity, secretion of suppressive cytokines and suppression of IL-17 secretion by Th17 cells. To further understand the process of graft rejection/acceptance, we evaluated skin allograft survival and associated events after FTY720 treatment.METHODS:F1 mice (C57BL/6xBALB/c) and C57BL/6 mice were used as donors for and recipients of skin transplantation, respectively. The recipients were transplanted and either not treated or treated with FTY720 by gavage for 21 days to evaluate the allograft survival. In another set of experiments, the immunological evaluation was performed five days post-transplantation. The spleens, axillary lymph nodes and skin allografts of the recipient mice were harvested for phenotyping (flow cytometry), gene expression (real-time PCR) and cytokine (Bio-Plex) analysis.RESULTS:The FTY720 treatment significantly increased skin allograft survival, reduced the number of cells in the lymph nodes and decreased the percentage of Tregs at this site in the C57BL/6 recipients. Moreover, the treatment reduced the number of graft-infiltrating cells and the percentage of CD4+ graft-infiltrating cells. The cytokine analysis (splenocytes) showed decreased levels of IL-10, IL-6 and IL-17 in the FTY720-treated mice. We also observed a decrease in the IL-10, IL-6 and IL-23 mRNA levels, as well as an increase in the IL-27 mRNA levels, in the splenocytes of the treated group. The FTY720-treated mice exhibited increased mRNA levels of IL-10, IL-27 and IL-23 in the skin graft.CONCLUSIONS:Our results demonstrated prolonged but not indefinite skin allograft survival by FTY720 treatment. This finding indicates that the drug did not prevent the imbalance between Tr1 and Th17 cells in the graft that led to rejection.

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“…The levels of T h 17 effector cytokines (IL‐17, IL‐6, and IL‐23) and a transcription factor retinoid acid receptor–related orphan receptor γt (RORγt) were significantly increased in the rejection group, whereas the levels of Treg effector cytokines (IL‐10 and TGF‐β) and the transcription factor Foxp3 were reduced in comparison with the levels in day‐matched tolerant groups 3 days after transplantation. The results of this study suggest that there is a functional imbalance between T h 17 cells and Tregs in tolerance and rejection groups 41…”

Section: Role Of Tregs In Experimental Models Of Liver Transplant Tolmentioning

confidence: 64%

“…The balance of T helper 17 (T h 17) cells and Tregs was examined in tolerant and rejection groups with a rat model of liver transplantation 41. The levels of T h 17 effector cytokines (IL‐17, IL‐6, and IL‐23) and a transcription factor retinoid acid receptor–related orphan receptor γt (RORγt) were significantly increased in the rejection group, whereas the levels of Treg effector cytokines (IL‐10 and TGF‐β) and the transcription factor Foxp3 were reduced in comparison with the levels in day‐matched tolerant groups 3 days after transplantation.…”

Section: Role Of Tregs In Experimental Models Of Liver Transplant Tolmentioning

confidence: 99%

Role of regulatory T cells in the promotion of transplant tolerance

et al. 2012

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Liver transplantation is now recognized as the most effective therapy for patients with end-stage acute and chronic liver failure. Despite outstanding short-term graft and patient survival, liver transplantation continues to face several major challenges, including poor long-term graft survival due to chronic rejection and major side effects of long-term immunosuppressive therapy (which is required for the prevention of rejection). The ability to produce a state of tolerance after transplantation would potentially obviate long-term immunosuppression. Self-tolerance and immune homeostasis involve both central and peripheral immunoregulatory mechanisms. To date, studies have shown that many subsets of regulatory T cells (Tregs) control immune responses to foreign and alloantigens. The identification of Tregs that are positive for CD4, CD25, and the transcription factor forkhead box (Foxp3) has resulted in major advances in our understanding of the immunology of rejection and the development of transplant tolerance. In this article, we focus on the importance of Tregs in tolerance induction in experimental models of liver transplantation. Furthermore, we discuss the therapeutic potential of Tregs for the promotion of tolerance in transplant patients and highlight recent clinical trials of Treg-based therapies. Liver

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The dynamic changes of Th17/Treg cytokines in rat liver transplant rejection and tolerance

Cited by 34 publications

References 37 publications

Immunological and Regenerative Aspects of Hepatic Mast Cells in Liver Allograft Rejection and Tolerance

Immunological and Regenerative Aspects of Hepatic Mast Cells in Liver Allograft Rejection and Tolerance

The imbalance between Treg and Th17 cells caused by FTY720 treatment in skin allograft rejection

Role of regulatory T cells in the promotion of transplant tolerance

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