Posttransplant Interleukin-4 Treatment Converts Rat Liver Allograft Tolerance to Rejection

Wang, Chuanmin; Li, Jian; Cordoba, Shaun; McLeod, Duncan; Tran, Giang; Hodgkinson, S.; Hall, Bruce M.; McCaughan, Geoffrey W.; Bishop, G. Alex

doi:10.1097/01.tp.0000161249.20922.16

Cited by 13 publications

(9 citation statements)

References 27 publications

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“…We found a relative up-regulation of C1q and C3 in the male skin grafts in the tolerized recipients compared with the female grafts. This observation is similar to the finding that C3 is up-regulated in tolerated liver grafts in a rat model 28. Interestingly, local levels of IFN-γ were also found to be higher in the tolerated male skin graft compared to the adjacent female skin graft.…”

Section: Discussionsupporting

confidence: 88%

“…In support of the hypothesis that different experimental models underlie the differences, a requirement for C3 in the induction of tolerance has also been reported in some models. An up-regulation of C3 has been noted in the transplanted rat liver following induction of tolerance 28. Also, C3 has been shown to be involved in the suppression of a delayed type-hypersensitivity response to antigen injected into the anterior chamber of the eye 4.…”

Section: Discussionmentioning

confidence: 99%

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Mice lacking C1q or C3 show accelerated rejection of minor H disparate skin grafts and resistance to induction of tolerance

et al. 2010

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Complement activation is known to have deleterious effects on organ transplantation. On the other hand, the complement system is also known to have an important role in regulating immune responses. The balance between these two opposing effects is critical in the context of transplantation. Here, we report that female mice deficient in C1q (C1qa−/−) or C3 (C3−/−) reject male syngeneic grafts (HY incompatible) at an accelerated rate compared with WT mice. Intranasal HY peptide administration, which induces tolerance to syngeneic male grafts in WT mice, fails to induce tolerance in C1qa−/− or C3−/− mice. The rejection of the male grafts correlated with the presence of HY DbUty-specific CD8+ T cells. Consistent with this, peptide-treated C1qa−/− and C3−/− female mice rejecting male grafts exhibited more antigen-specific CD8+IFN-γ+ and CD8+IL-10+ cells compared with WT females. This suggests that accumulation of IFN-γ- and IL-10-producing T cells may play a key role in mediating the ongoing inflammatory process and graft rejection. Interestingly, within the tolerized male skin grafts of peptide-treated WT mice, IFN-γ, C1q and C3 mRNA levels were higher compared to control female grafts. These results suggest that C1q and C3 facilitate the induction of intranasal tolerance.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Mice lacking C1q or C3 show accelerated rejection of minor H disparate skin grafts and resistance to induction of tolerance

et al. 2010

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“…Furthermore, C3 was shown to be required for UV immunosuppression of contact antigen,39 and in vivo, C3 was shown to inhibit Th2 cytokine secretion by activated T‐cells through its contact with antigen presenting cells 40. These findings, taken together with the finding that the Th2 cytokine IL‐4 is increased in REJ versus TOL41 and that administration of IL‐4 converts rat liver tolerance to rejection42 suggest that pharmacological inhibitors of C3 might reverse liver transplant tolerance. The functional role of C3 in liver transplant tolerance should be further examined using C3‐deficient or knockout models, or C3 inhibitors and inducers.…”

Section: Discussionmentioning

confidence: 92%

Gene array analysis of a rat model of liver transplant tolerance identifies increased complement C3 and the STAT-1/IRF-1 pathway during tolerance induction

et al. 2006

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This study aimed to define the molecular mechanism during induction of spontaneous liver transplant tolerance using microarrays and to focus on molecular pathways associated with tolerance by meta-analysis with published studies. The differences in the early immune response between PVG to DA liver transplant recipients that are spontaneously tolerant (TOL) and PVG to Lewis liver transplants that reject (REJ) were examined. Spleens from TOL and REJ on days 1 and 3 were compared by 2 color microarray. Forty-six of 199 genes differentially expressed between TOL and REJ had an immunological function. More immune genes were increased in TOL vs. REJ on day 1, including STAT-1, IRF-1 and complement C3. Differential expression of selected genes was confirmed by quantitative RT-PCR. The results were compared to two published high-throughput studies of rat liver transplant tolerance and showed that C3 was increased in all three models, while STAT-1 and IRF-1 were increased in two models. The early increases in immune genes in TOL confirmed previous reports of an active early immune response in TOL. In conclusion, the increase in STAT-1, IRF-1 and complement component C3 in several models of liver transplant tolerance suggests that the STAT-1/IRF-1 apoptotic pathway and C3 may be involved in the tolerogenic mechanism. Liver Transpl 12: [636][637][638][639][640][641][642][643] 2006 Despite their ability to prevent acute rejection episodes, conventional immunosuppressive drugs are less successful for control of chronic rejection, increase susceptibility to infections and carcinoma, and have been linked to post-transplant diabetes and renal tubular atrophy. These limitations, along with their expense, have driven development of new drug-free or drug-minimizing specific immune tolerance therapies. One approach is to study animal models of transplant tolerance. Perhaps the most powerful of these is the rat liver model, in which livers transplanted across complete MHC barriers are accepted long-term by the recipient without the requirement for immunosuppression and rapidly induce tolerance to subsequent donor-strain skin grafts.

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“…Intrahepatic IL-4 transcripts were significantly lower in tolerated rat liver allografts compared to rejected allografts, however, no significant differences were observed for other cytokines (including IL-1α, IL-2, IL-6, IL-10, TNF-α, TNF-β, and transforming growth factor β (TGF-β) (109). IL-4 injection after rat liver transplantation converts allograft tolerance to rejection partially through a graftspecific antibody response (110). In the murine tolerant liver allograft, expression of miRNA-146a, 15b, 223, 23a, 27a, 34a, and 451 is upregulated compared to syngeneic grafts, suggesting a role for miRNA in tolerance induction (111).…”

Section: Understanding the Mechanisms Of Experimental Liver Transplanmentioning

confidence: 91%

Transplant Tolerance Induction: Insights From the Liver

2020

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A comparison of pre-clinical transplant models and of solid organs transplanted in routine clinical practice demonstrates that the liver is most amenable to the development of immunological tolerance. This phenomenon arises in the absence of stringent conditioning regimens that accompany published tolerizing protocols for other organs, particularly the kidney. The unique immunologic properties of the liver have assisted our understanding of the alloimmune response and how it can be manipulated to improve graft function and survival. This review will address important findings following liver transplantation in both animals and humans, and how these have driven the understanding and development of therapeutic immunosuppressive options. We will discuss the liver's unique system of immune and non-immune cells that regulate immunity, yet maintain effective responses to pathogens, as well as mechanisms of liver transplant tolerance in pre-clinical models and humans, including current immunosuppressive drug withdrawal trials and biomarkers of tolerance. In addition, we will address innovative therapeutic strategies, including mesenchymal stem cell, regulatory T cell, and regulatory dendritic cell therapy to promote liver allograft tolerance or minimization of immunosuppression in the clinic.

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Posttransplant Interleukin-4 Treatment Converts Rat Liver Allograft Tolerance to Rejection

Cited by 13 publications

References 27 publications

Mice lacking C1q or C3 show accelerated rejection of minor H disparate skin grafts and resistance to induction of tolerance

Mice lacking C1q or C3 show accelerated rejection of minor H disparate skin grafts and resistance to induction of tolerance

Gene array analysis of a rat model of liver transplant tolerance identifies increased complement C3 and the STAT-1/IRF-1 pathway during tolerance induction

Transplant Tolerance Induction: Insights From the Liver

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