Rapamycin or tacrolimus alone fails to resist cardiac allograft accelerated rejection mediated by alloreactive CD4+ memory T cells in mice

Liang, Hua; Liao, Chenxi; Qi, Zhongquan; Sha, Chuang; Xie, Binbin; Chen, Jibing; Xia, Junjie; Wang, Yongzhi; Yao, Qing; Zhao, Yongxiang

doi:10.1016/j.trim.2009.09.003

Cited by 20 publications

(10 citation statements)

References 24 publications

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“…As stated previously, T M cells are not sensitive to conventional immunosuppressive regimens (24). A number of studies have demonstrated that the use of anti-CXCL9 and anti-CXCL10 antibodies can prolong allograft survival time (25,26).…”

Section: Discussionmentioning

confidence: 72%

CXCL9 and CXCL10 accelerate acute transplant rejection mediated by alloreactive memory T cells in a mouse retransplantation model

Zhuang

Zhang

et al. 2014

Experimental and Therapeutic Medicine

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C-X-C motif chemokine ligand (CXCL) 9 and CXCL10 play key roles in the initiation and development of acute transplant rejection. Previously, higher levels of RANTES expression and secretion were demonstrated in retransplantation or T-cell memory-transfer models. In the present study, the effect of the chemokines, CXCL9 and CXCL10, were investigated in a mouse retransplantation model. BALB/c mice were used as donors, while C57BL/6 mice were used as recipients. In the experimental groups, a heterotopic heart transplantation was performed six weeks following skin grafting. In the control groups, a heterotopic heart transplantation was performed without skin grafting. Untreated mice served as blank controls. The mean graft survival time of the heterotopic heart transplantations was 7.7 days in the experimental group (n=6), as compared with 3.25 days in the control group (n=6; P<0.001). On day three following cardiac transplantation, histological evaluation of the grafts revealed a higher International Society for Heart & Lung Transplantation grade in the experimental group as compared with the control group. In addition, gene expression and serum concentrations of CXCL9, CXCL10, interferon-γ, and interleukin-2 were markedly higher in the experimental group when compared with the control group. Differences between the levels of CXCL9 and CXCL10 in the pre- and post-transplant mice indicated that the chemokines may serve as possible biomarkers to predict acute rejection. The results of the present study demonstrated that CXCL9 and CXCL10 play a critical role in transplantation and retransplantation. High levels of these cytokines during the pre-transplant period may lead to extensive acute rejection. Thus, the observations enhance the understanding of the mechanism underlying the increased expression and secretion of CXCL9 and CXCL10 by alloreactive memory T cells.

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Section: Discussionmentioning

confidence: 72%

CXCL9 and CXCL10 accelerate acute transplant rejection mediated by alloreactive memory T cells in a mouse retransplantation model

Zhuang

Zhang

et al. 2014

Experimental and Therapeutic Medicine

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“…Various studies have indicated that Tm cells confer resistance to traditional immunosuppression, are difficult to eliminate by depletion therapies and have limited dependence on co-stimulatory blockage strategies (32,33). Hence, the present study adopted a strategy of applying anti-CXCL10 antibodies alone.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of C‑X‑C motif chemokine 10 reduces graft loss mediated by memory CD8+ T cells in a rat cardiac re‑transplant model

Deng

et al. 2017

Exp Ther Med

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Abstract. The interaction of chemokine (C-X-C motif) ligand 10 (CXCL10) with its receptor (CXCR3) is a critical process in recruiting donor reactive T cells to a graft and alloantigen-specific memory T (Tm) cells exert a principal function in promoting graft dysfunction during accelerated cardiac rejection. However, whether CXCL10 chemokine exerts any effects on acute accelerated rejection mediated by CD8 + Tm cells in a re-transplant model has remained elusive. The present study established a cardiac transplant model by advanced microsurgery technology and improved organ storage. A novel rat model of cardiac re-transplantation was established at 40 days following primary heart transplant. The experiment included two parts, and when models were established, the rats were divided into two groups: Primary cardiac transplant (HTx) and re-transplantation without treatment (HRTx). In part 1, recipients from part 2, including re-transplantation without treatment (HRTx+NS) and re-transplantation treated with anti-CXCL10 antibodies (500 µg every other day by intraperitoneal injection; HRTx+CXCL10 Abs group). The graft survival time was observed and graft infiltration by inflammatory cells was assessed via histology of cardiac graft sections; in addition, the gene expression and the serum concentration of CXCL10 in each group was assessed. Indexes such as rejection-associated cytokines were assayed by reverse-transcription quantitative PCR and ELISA kits, and flow cytometry of splenocytes was used to detect Tm cells in the re-transplantation groups. The results demonstrated that level of CXCL10 was significantly increased and the graft mean survival time was shortened accompanied with aggravated lymphocyte cell infiltration in the HRTx group when compared that in the HTx group; in addition, the serum levels and mRNA expression of interleukin (IL)-2 and interferon (IFN)-γ were increased, while transforming growth factor (TGF)-β was decreased in the HRTx group. Furthermore, neutralization of CXCL10 prolonged the graft mean survival time and delayed accelerated rejection. Compared with that in the HRTx+NS group, serum levels and graft tissue mRNA expression of IFN-γ and IL-2 were decreased in the HRTx+CXCL10 Abs group, while TGF-β mRNA was significantly increased but the serum concentration was not significantly affected. In addition, there was no difference in IL-10 between the two groups, while delayed accelerated rejection paralleled with inflammatory cell infiltration decreased and the proliferation and differentiation of CD8 + Tm cells in secondary lymphoid organs were reduced in the HRTx+CXCL10 Abs group vs. those in the HRTx+NS group. The present study demonstrated that CXCL10 had a crucial role in cardiac transplantation and re-transplantation, and that treatment with CXCL10 antibodies delays accelerated acute rejection mediated by Tm cells in a rat model of cardiac re-transplantation. IntroductionA multidisciplinary program has been initiated to better establish transplantation for prolonging survival time of cardi...

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“…5 Here we hypothesized that the 3435C.T SNP in the ABCB1 gene can modulate the immunosuppressive activity of tacrolimus by altering the activity of the pump. [18][19][20] The T cells with the highest ABCB1 efflux activity are memory CD4 + and CD8 + T cells, 9,21 a population with low susceptibility to tacrolimus 22 and important in the transplantation setting because they are pivotal for alloreactivity. 2).…”

Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms in ABCB1 Influence the Pharmacodynamics of Tacrolimus

Vafadari

Bouamar

Hesselink

et al. 2013

Therapeutic Drug Monitoring

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Rapamycin or tacrolimus alone fails to resist cardiac allograft accelerated rejection mediated by alloreactive CD4+ memory T cells in mice

Cited by 20 publications

References 24 publications

CXCL9 and CXCL10 accelerate acute transplant rejection mediated by alloreactive memory T cells in a mouse retransplantation model

CXCL9 and CXCL10 accelerate acute transplant rejection mediated by alloreactive memory T cells in a mouse retransplantation model

Inhibition of C‑X‑C motif chemokine 10 reduces graft loss mediated by memory CD8+ T cells in a rat cardiac re‑transplant model

Genetic Polymorphisms in ABCB1 Influence the Pharmacodynamics of Tacrolimus

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