Combination of C-X-C motif chemokine 9 and C-X-C motif chemokine 10 antibodies with FTY720 prolongs the survival of cardiac retransplantation allografts in a mouse model

Ma,Teng; Xu,Jiacheng; Zhuang,Jiawei; Zhou,Xiaobiao; Lin,Lianfeng; Shan,Zhonggui; Qi,Zhongquan

doi:10.3892/etm.2015.2204

Combination of C-X-C motif chemokine 9 and C-X-C motif chemokine 10 antibodies with FTY720 prolongs the survival of cardiac retransplantation allografts in a mouse model

Authors:
- Teng Ma
- Jiacheng Xu
- Jiawei Zhuang
- Xiaobiao Zhou
- Lianfeng Lin
- Zhonggui Shan
- Zhongquan Qi
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Affiliations: Department of Cardiac Surgery, The First Affiliated Hospital, Xiamen University, Xiamen, Fujian 361003, P.R. China, Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian 361005, P.R. China
Published online on: January 22, 2015 https://doi.org/10.3892/etm.2015.2204
Pages: 1006-1012

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Abstract

The upregulation of chemokine genes and the subsequent T‑lymphocyte recruitment to the graft are early events in the development of acute cardiac transplant rejection or cardiac allograft vasculopathy. In the present study, a combined immunosuppressive regimen of C-X-C motif chemokine 9 (CXCL9) antibody (Ab), CXCL10 Ab and FTY720 was used in order to reduce the infiltration of memory T lymphocytes and prolong graft survival in a retransplantation murine model. BALB/c donor hearts were transplanted heterotopically into C57BL/6 mice at day 28 after skin transplantation. The mice were divided into four groups: i) Control (normal saline), ii) CXCL9 Ab and CXCL10 Ab [150 µg; once daily (qd); intraperitoneal (ip)], iii) FTY720 (0.2 mg/day; qd; ip) and iv) combined (2 mg/kg/day; qd; ip). Measurements of the median survival time of the cardiac grafts, histological examination, reverse transcription‑quantitative polymerase chain reaction analysis, enzyme‑linked immunosorbent assay and a mixed lymphocyte reaction were performed. The median graft survival time of the combined group was prolonged (9.3 days) compared with that of the control group (3.5 days) (P<0.001). Histological examination revealed that the combined treatment group graft rejection pathological score was 0.50, while the control group score was 3.62 (P<0.001). In addition, the gene expression level of interleukin (IL)‑2 was significantly lower and the levels of IL‑10 and transforming growth factor‑β (TGF‑β) were significantly higher in the combined group compared with those in the control group (P<0.001). Furthermore, the serum concentration levels of IL‑2 and interferon‑γ (IFN‑γ) were significantly lower (P<0.001) and the concentration of IL‑10 was significantly higher (P<0.05) in the combined group compared with those in the control group. In the mixed lymphocyte reaction, T‑cell proliferation was found to be significantly lower in the combined treatment group than that in the control group (P<0.001). In conclusion, treatment with CXCL9 Ab and CXCL10 Ab or FTY720 reduced the graft infiltration of inflammatory cells, inhibited T‑cell proliferation and prolonged graft survival. The combined treatment regimen of CXCL9 Ab, CXCL10 Ab and FTY720 was found to significantly reduce the infiltration of inflammatory cells in the graft and prolong graft survival.

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1	Taylor DO, Edwards LB, et al: Registry of the International Society for Heart and Lung Transplantation: twenty-third official adult heart transplantation report - 2006. J Heart Lung Transplant. 25:869–879. 2006. View Article : Google Scholar : PubMed/NCBI
2	Pour-Reza-Gholi F, Nafar M, Saeedinia A, Farrokhi F, Firouzan A, Simforoosh N, Basiri A and Einollahi B: Kidney retransplantation in comparison with first kidney transplantation. Transplant Proc. 37:2962–2964. 2005. View Article : Google Scholar : PubMed/NCBI
3	Amir AL, D’Orsogna LJ, Roelen DL, van Loenen MM, Hagedoorn RS, de Boer R, van der Hoorn MA, Kester MG, Doxiadis II, Falkenburg JH, et al: Allo-HLA reactivity of virus-specific memory T cells is common. Blood. 115:3146–3157. 2010. View Article : Google Scholar : PubMed/NCBI
4	Bingaman AW and Farber DL: Memory T cells in transplantation: generation, function, and potential role in rejection. Am J Transplant. 4:846–852. 2004. View Article : Google Scholar : PubMed/NCBI
5	Valujskikh A and Li XC: Frontiers in nephrology: T cell memory as a barrier to transplant tolerance. J Am Soc Nephrol. 18:2252–2261. 2007. View Article : Google Scholar : PubMed/NCBI
6	Yun JJ, Whiting D, Fischbein MP, Banerji A, Irie Y, Stein D, Fishbein MC, Proudfoot AE, Laks H, Berliner JA and Ardehali A: Combined blockade of the chemokine receptors CCR1 and CCR5 attenuates chronic rejection. Circulation. 109:932–937. 2004. View Article : Google Scholar : PubMed/NCBI
7	Iida S, Suzuki T, Tanabe K, Valujskikh A, Fairchild RL and Abe R: Transient lymphopenia breaks costimulatory blockade-based peripheral tolerance and initiates cardiac allograft rejection. Am J Transplant. 13:2268–2279. 2013. View Article : Google Scholar : PubMed/NCBI
8	Wang H, Zhang Z, Tian W, Liu T, Han H, Garcia B, Li XC and Du C: Memory T cells mediate cardiac allograft vasculopathy and are inactivated by anti-OX40L monoclonal antibody. Cardiovasc Drugs Ther. 28:115–122. 2014. View Article : Google Scholar
9	Liang H, Liao C, Qi Z, Sha C, Xie B, Chen J, Xia J, Wang Y, Yao Q and Zhao Y: Rapamycin or tacrolimus alone fails to resist cardiac allograft accelerated rejection mediated by alloreactive CD4(+) memory T cells in mice. Transpl Immunol. 22:128–136. 2010. View Article : Google Scholar
10	Larsen CP, Knechtle SJ, Adams A, Pearson T and Kirk AD: A new look at blockade of T-cell costimulation: a therapeutic strategy for long-term maintenance immunosuppression. Am J Transplant. 6:876–883. 2006. View Article : Google Scholar : PubMed/NCBI
11	Sallusto F, Schaerli P, Loetscher P, Schaniel C, Lenig D, Mackay CR, Qin S and Lanzavecchia A: Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol. 28:2760–2769. 1998. View Article : Google Scholar : PubMed/NCBI
12	Zhai Y, Wang Y, Wu Z and Kupiec-Weglinski JW: Defective alloreactive CD8 T cell function and memory response in allograft recipients in the absence of CD4 help. J Immunol. 179:4529–4534. 2007. View Article : Google Scholar : PubMed/NCBI
13	Rosenblum JM, Shimoda N, Schenk AD, Zhang H, Kish DD, Keslar K, Farber JM and Fairchild RL: CXC chemokine ligand (CXCL) 9 and CXCL10 are antagonistic costimulation molecules during the priming of alloreactive T cell effectors. J Immunol. 184:3450–3460. 2010. View Article : Google Scholar : PubMed/NCBI
14	Zhou X, Shan Z, Liang H, et al: Role of regulated upon activation normal T-cell expressed and secreted in a model of retransplantation acute rejection mediated by alloreactive memory CD4+T cells. Transplant Proc. 45:546–551. 2013. View Article : Google Scholar : PubMed/NCBI
15	Chen ZH: A technique of cervical heterotopic heart transplantation in mice. Transplantation. 52:1099–1101. 1991. View Article : Google Scholar : PubMed/NCBI
16	Billingham ME, Cary NR, Hammond ME, et al: A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant. 9:587–593. 1990.PubMed/NCBI
17	Winters GL, Marboe CC and Billingham ME: The International Society for Heart and Lung Transplantation grading system for heart transplant biopsy specimens: clarification and commentary. J Heart Lung Transplant. 17:754–760. 1998.PubMed/NCBI
18	Salom RN, Maguire JA and Hancock WW: Endothelial activation and cytokine expression in human acute cardiac allograft rejection. Pathology. 30:24–29. 1998. View Article : Google Scholar : PubMed/NCBI
19	Setoguchi K, Hattori Y, Iida S, Baldwin WM III and Fairchild RL: Endogenous memory CD8 T cells are activated within cardiac allografts without mediating rejection. Am J Transplant. 13:2293–2307. 2013. View Article : Google Scholar : PubMed/NCBI
20	Farivar AS, Mackinnon-Patterson BC, McCourtie AS, Ward PA and Mulligan MS: The role of CC and CXC chemokines in cardiac allograft rejection in rats. Exp Mol Pathol. 78:171–176. 2005. View Article : Google Scholar : PubMed/NCBI
21	Zhou X, Shan Z, Liang H, Lin Z, Qiu S, Kuang F, Zhuang J and Qi Z: Role of regulated upon activation normal T-cell expressed and secreted in a model of retransplantation acute rejection mediated by alloreactive memory CD4⁺ T cells. Transplant Proc. 45:546–551. 2013. View Article : Google Scholar : PubMed/NCBI
22	Liu Y, Jiang J, Xiao H, Wang X, et al: Topical application of FTY720 and cyclosporin A prolong corneal graft survival in mice. Mol Vis. 18:624–633. 2012.PubMed/NCBI
23	Heng Y, Ma Y, Yin H, Duan L, et al: Adoptive transfer of FTY720-treated immature BMDCs significantly prolonged cardiac allograft survival. Transpl Int. 23:1259–1270. 2010. View Article : Google Scholar : PubMed/NCBI
24	Pearl JP, Parris J, Hale DA, Hoffmann SC, Bernstein WB, McCoy KL, Swanson SJ, Mannon RB, Roederer M and Kirk AD: Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am J Transplant. 5:465–474. 2005. View Article : Google Scholar : PubMed/NCBI
25	Zhang L, Zhu T, Sun EW, Shen SQ, Min ZL and Chen ZK: Pretreatment with FTY720 alone induced long-term survival of mouse heart allograft. Transplant Proc. 35:567–568. 2003. View Article : Google Scholar : PubMed/NCBI
26	Wang ME, Tejpal N, Qu X, Yu J, Okamoto M, Stepkowski SM and Kahan BD: Immunosuppressive effects of FTY720 alone or in combination with cyclosporine and/or sirolimus. Transplantation. 65:899–905. 1998. View Article : Google Scholar : PubMed/NCBI
27	Yanagawa Y, Hoshino Y and Chiba K: The significance of timing of FTY720 administration on the immunosuppressive effect to prolong rat skin allograft survival. Int J Immunopharmacol. 22:597–602. 2000. View Article : Google Scholar : PubMed/NCBI
28	Kim MG, Lee SY, Ko YS, Lee HY, Jo SK, Cho WY and Kim HK: CD4+ CD25+ regulatory T cells partially mediate the beneficial effects of FTY720, a sphingosine-1-phosphate analogue, during ischaemia/reperfusion-induced acute kidney injury. Nephrol Dial Transplant. 26:111–24. 2011. View Article : Google Scholar