Immunomodulatory effects of OX40Ig gene-modified adipose tissue-derived mesenchymal stem cells on rat kidney transplantation

Liu,Tao; Zhang,Yue; Shen,Zhongyang; Zou,Xunfeng; Chen,Xiaobo; Chen,Li; Wang,Yuliang

doi:10.3892/ijmm.2016.2808

Immunomodulatory effects of OX40Ig gene-modified adipose tissue-derived mesenchymal stem cells on rat kidney transplantation

Authors:
- Tao Liu
- Yue Zhang
- Zhongyang Shen
- Xunfeng Zou
- Xiaobo Chen
- Li Chen
- Yuliang Wang
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Affiliations: Department of Clinical Laboratory Medicine, Tianjin First Central Hospital, Key Laboratory for Critical Care Medicine of the Ministry of Health, Tianjin 300192, P.R. China, Reproductive Center, Tianjin Central Hospital of Gynecology Obstetrics, Tianjin 300100, P.R. China, Department of Transplantation Surgery, Tianjin First Central Hospital, Tianjin 300192, P.R. China, Department of General Surgery, Tianjin First Central Hospital, Tianjin 300192, P.R. China, Union Stem and Gene Engineering Co., Ltd., Tianjin 300384, P.R. China
Published online on: November 21, 2016 https://doi.org/10.3892/ijmm.2016.2808
Pages: 144-152
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Recent studies have suggested that adipose tissue-derived mesenchymal stem cell (ADSC) therapy and OX40 costimulation blockade are two immunomodulatory strategies used to suppress the immune response to alloantigens. However, relatively little has been reported regarding the immunomodulatory potential of the abilityof these two strategies to synergize. Thus, in the present study, we aimed to investigate OX40-Ig fusion protein (OX40Ig) expression in ADSCs and to validate their more potent immunosuppressive activity in preventing renal allograft rejection. For this purpose, ADSCs from Lewis rats were transfected with the recombinant plasmid, pcDNA3.1(-)OX40Ig, by nucleofection. The ADSCs transduced with the plasmid (termed ADSCsOX40Ig) or untransduced ADSCs (termed ADSCsnative) were added to allostimulated mixed lymphocyte reaction (MLR) in vitro. In vivo, ADSCsOX40Ig, ADSCsnative, or PBS were administered to an allogeneic renal transplantation model, and the therapeutic effects, as well as the underlying mechanisms were examined. The results revealed that both the ADSCsnative and ADSCsOX40Ig significantly suppressed T cell proliferation and increased the percentage of CD4+CD25+ regulatory T cells in allogeneic MLR assays, with the ADSCsOX40Ig being more effective. Furthermore, the results from our in vivo experiments revealed that compared with the ADSCsnative or PBS group, the administration of autologous ADSCsOX40Ig markedly prolonged the mean survival time of renal grafts, reduced allograft rejection, and significantly downregulated the mRNA expression of intragraft interferon-γ (IFN-γ) , and upregulated the mRNA expression of interleukin (IL)‑10, transforming growth factor-β (TGF-β) and forkhead box protein 3 (Foxp3). The findings of our study indicate that the use of ADSCsOX40Ig is a promising strategy for preventing renal allograft rejection. This strategy provides the synergistic benefits of ADSC immune modulation and OX40-OX40L pathway blockade, and may therefore have therapeutic potential in clinical renal transplantation.

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1	Shrestha B, Haylor J and Raftery A: Historical perspectives in kidney transplantation: an updated review. Prog Transplant. 25:64–69. 762015. View Article : Google Scholar : PubMed/NCBI
2	Newell KA: Clinical transplantation tolerance. Semin Immunopathol. 33:91–104. 2011. View Article : Google Scholar : PubMed/NCBI
3	Thorp EB, Stehlik C and Ansari MJ: T-cell exhaustion in allograft rejection and tolerance. Curr Opin Organ Transplant. 20:37–42. 2015. View Article : Google Scholar : PubMed/NCBI
4	Waldmann H, Hilbrands R, Howie D and Cobbold S: Harnessing FOXP3⁺ regulatory T cells for transplantation tolerance. J Clin Invest. 124:1439–1445. 2014. View Article : Google Scholar : PubMed/NCBI
5	Kinnear G, Jones ND and Wood KJ: Costimulation blockade: current perspectives and implications for therapy. Transplantation. 95:527–535. 2013. View Article : Google Scholar :
6	Kaur D and Brightling C: OX40/OX40 ligand interactions in T-cell regulation and asthma. Chest. 141:494–499. 2012. View Article : Google Scholar : PubMed/NCBI
7	Jensen SM, Maston LD, Gough MJ, Ruby CE, Redmond WL, Crittenden M, Li Y, Puri S, Poehlein CH, Morris N, et al: Signaling through OX40 enhances antitumor immunity. Semin Oncol. 37:524–532. 2010. View Article : Google Scholar : PubMed/NCBI
8	Kotani A, Hori T, Fujita T, Kambe N, Matsumura Y, Ishikawa T, Miyachi Y, Nagai K, Tanaka Y and Uchiyama T: Involvement of OX40 ligand⁺ mast cells in chronic GVHD after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 39:373–375. 2007. View Article : Google Scholar : PubMed/NCBI
9	Zhou YB, Ye RG, Li YJ and Xie CM: Targeting the CD134⁻CD134L interaction using anti-CD134 and/or rhCD134 fusion protein as a possible strategy to prevent lupus nephritis. Rheumatol Int. 29:417–425. 2009. View Article : Google Scholar
10	Wang YL, Li G, Fu YX, Wang H and Shen ZY: Blockade of OX40/OX40 ligand to decrease cytokine messenger RNA expression in acute renal allograft rejection in vitro. Transplant Proc. 45:2565–2568. 2013. View Article : Google Scholar : PubMed/NCBI
11	Casiraghi F, Remuzzi G and Perico N: Mesenchymal stromal cells to promote kidney transplantation tolerance. Curr Opin Organ Transplant. 19:47–53. 2014. View Article : Google Scholar
12	Marx C, Silveira MD and Beyer Nardi N: Adipose-derived stem cells in veterinary medicine: characterization and therapeutic applications. Stem Cells Dev. 24:803–813. 2015. View Article : Google Scholar : PubMed/NCBI
13	Alipour F, Parham A, Kazemi Mehrjerdi H and Dehghani H: Equine adipose-derived mesenchymal stem cells: phenotype and growth characteristics, gene expression profile and differentiation potentials. Cell J. 16:456–465. 2015.PubMed/NCBI
14	Minteer DM, Marra KG and Rubin JP: Adipose stem cells: biology, safety, regulation, and regenerative potential. Clin Plast Surg. 42:169–179. 2015. View Article : Google Scholar : PubMed/NCBI
15	Takahashi T, Tibell A, Ljung K, Saito Y, Gronlund A, Osterholm C, Holgersson J, Lundgren T, Ericzon BG, Corbascio M, Kumagai-Braesch M, et al: Multipotent mesenchymal stromal cells synergize with costimulation blockade in the inhibition of immune responses and the induction of Foxp3⁺ regulatory T cells. Stem Cells Transl Med. 3:1484–1494. 2014. View Article : Google Scholar : PubMed/NCBI
16	Clark JD, Gebhart GF, Gonder JC, Keeling ME and Kohn DF: Special Report: the 1996 guide for the care and use of laboratory animals. ILAR J. 38:41–48. 1997. View Article : Google Scholar : PubMed/NCBI
17	Wang YL, Li G, Zou XF, Chen XB, Liu T and Shen ZY: Effect of autologous adipose-derived stem cells in renal cold ischemia and reperfusion injury. Transplant Proc. 45:3198–3202. 2013. View Article : Google Scholar : PubMed/NCBI
18	Redmond WL, Triplett T, Floyd K and Weinberg AD: Dual anti-OX40/IL-2 therapy augments tumor immunotherapy via IL-2R-mediated regulation of OX40 expression. PLoS One. 7:e344672012. View Article : Google Scholar : PubMed/NCBI
19	Seifert M, Stolk M, Polenz D and Volk HD: Detrimental effects of rat mesenchymal stromal cell pre-treatment in a model of acute kidney rejection. Front Immunol. 3:2022012. View Article : Google Scholar : PubMed/NCBI
20	Wu H, Ye Z and Mahato RI: Genetically modified mesenchymal stem cells for improved islet transplantation. Mol Pharm. 8:1458–1470. 2011. View Article : Google Scholar : PubMed/NCBI
21	Li J, Ezzelarab MB, Ayares D and Cooper DK: The potential role of genetically-modified pig mesenchymal stromal cells in xenotransplantation. Stem Cell Rev. 10:79–85. 2014. View Article : Google Scholar :
22	Stiehler M, Duch M, Mygind T, Li H, Ulrich-Vinther M, Modin C, Baatrup A, Lind M, Pedersen FS and Bünger CE: Optimizing viral and non-viral gene transfer methods for genetic modification of porcine mesenchymal stem cells. Adv Exp Med Biol. 585:31–48. 2006. View Article : Google Scholar : PubMed/NCBI
23	Fülbier A, Schnabel R, Michael S, Vogt PM, Strauß S, Reimers K and Radtke C: Successful nucleofection of rat adipose-derived stroma cells with ambystoma mexicanum epidermal lipoxygenase (AmbLOXe). Stem Cell Res Ther. 5:1132014. View Article : Google Scholar : PubMed/NCBI
24	Fakiruddin KS, Baharuddin P, Lim MN, Fakharuzi NA, Yusof NA and Zakaria Z: Nucleofection optimization and in vitro anti-tumourigenic effect of TRAIL-expressing human adipose-derived mesenchymal stromal cells. Cancer Cell Int. 14:1222014. View Article : Google Scholar : PubMed/NCBI
25	Copland IB, Qayed M, Garcia MA, Galipeau J and Waller EK: Bone marrow mesenchymal stromal cells from patients with acute and chronic graft-versus-host disease deploy normal phenotype, differentiation plasticity, and immune-suppressive activity. Biol Blood Marrow Transplant. 21:934–940. 2015. View Article : Google Scholar : PubMed/NCBI
26	Wang Q, Qian S, Li J, Che N, Gu L, Wang Q, Liu Y and Mei H: Combined transplantation of autologous hematopoietic stem cells and allogenic mesenchymal stem cells increases T regulatory cells in systemic lupus erythematosus with refractory lupus nephritis and leukopenia. Lupus. 24:1221–1226. 2015. View Article : Google Scholar : PubMed/NCBI
27	De Bari C: Are mesenchymal stem cells in rheumatoid arthritis the good or bad guys? Arthritis Res Ther. 17:1132015. View Article : Google Scholar : PubMed/NCBI
28	Xiao J, Yang R, Biswas S, Qin X, Zhang M and Deng W: Mesenchymal stem cells and induced pluripotent stem cells as therapies for multiple sclerosis. Int J Mol Sci. 16:9283–9302. 2015. View Article : Google Scholar : PubMed/NCBI
29	Kong D, Zhuang X, Wang D, Qu H, Jiang Y, Li X, Wu W, Xiao J, Liu X, Liu J, et al: Umbilical cord mesenchymal stem cell transfusion ameliorated hyperglycemia in patients with type 2 diabetes mellitus. Clin Lab. 60:1969–1976. 2014.
30	Chullikana A, Majumdar AS, Gottipamula S, Krishnamurthy S, Kumar AS, Prakash VS and Gupta PK: Randomized, double-blind, phase I/II study of intravenous allogeneic mesenchymal stromal cells in acute myocardial infarction. Cytotherapy. 17:250–261. 2015. View Article : Google Scholar
31	Suksuphew S and Noisa P: Neural stem cells could serve as a therapeutic material for age-related neurodegenerative diseases. World J Stem Cells. 7:502–511. 2015. View Article : Google Scholar : PubMed/NCBI
32	Lim MH, Ong WK and Sugii S: The current landscape of adipose-derived stem cells in clinical applications. Expert Rev Mol Med. 16:e82014. View Article : Google Scholar : PubMed/NCBI
33	Perico N, Casiraghi F, Introna M, Gotti E, Todeschini M, Cavinato RA, Capelli C, Rambaldi A, Cassis P, Rizzo P, et al: Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clin J Am Soc Nephrol. 6:412–422. 2011. View Article : Google Scholar :
34	Perico N, Casiraghi F, Gotti E, Introna M, Todeschini M, Cavinato RA, Capelli C, Rambaldi A, Cassis P, Rizzo P, et al: Mesenchymal stromal cells and kidney transplantation: pretransplant infusion protects from graft dysfunction while fostering immunoregulation. Transpl Int. 26:867–878. 2013. View Article : Google Scholar : PubMed/NCBI
35	Peng Y, Ke M, Xu L, Liu L, Chen X, Xia W, Li X, Chen Z, Ma J, Liao D, et al: Donor-derived mesenchymal stem cells combined with low-dose tacrolimus prevent acute rejection after renal transplantation: a clinical pilot study. Transplantation. 95:161–168. 2013. View Article : Google Scholar
36	Reinders ME, de Fijter JW, Roelofs H, Bajema IM, de Vries DK, Schaapherder AF, Claas FH, van Miert PP, Roelen DL, van Kooten C, et al: Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. Stem Cells Transl Med. 2:107–111. 2013. View Article : Google Scholar : PubMed/NCBI
37	Tan J, Wu W, Xu X, Liao L, Zheng F, Messinger S, Sun X, Chen J, Yang S, Cai J, et al: Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA. 307:1169–1177. 2012. View Article : Google Scholar : PubMed/NCBI
38	Casiraghi F, Azzollini N, Todeschini M, Cavinato RA, Cassis P, Solini S, Rota C, Morigi M, Introna M, Maranta R, et al: Localization of mesenchymal stromal cells dictates their immune or proinflammatory effects in kidney transplantation. Am J Transplant. 12:2373–2383. 2012. View Article : Google Scholar : PubMed/NCBI
39	Inoue S, Popp FC, Koehl GE, Piso P, Schlitt HJ, Geissler EK and Dahlke MH: Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model. Transplantation. 81:1589–1595. 2006. View Article : Google Scholar : PubMed/NCBI
40	Popp FC, Eggenhofer E, Renner P, Slowik P, Lang SA, Kaspar H, Geissler EK, Piso P, Schlitt HJ and Dahlke MH: Mesenchymal stem cells can induce long-term acceptance of solid organ allografts in synergy with low-dose mycophenolate. Transpl Immunol. 20:55–60. 2008. View Article : Google Scholar : PubMed/NCBI
41	Kato T, Okumi M, Tanemura M, Yazawa K, Kakuta Y, Yamanaka K, Tsutahara K, Doki Y, Mori M, Takahara S and Nonomura N: Adipose tissue-derived stem cells suppress acute cellular rejection by TSG-6 and CD44 interaction in rat kidney transplantation. Transplantation. 98:277–284. 2014. View Article : Google Scholar : PubMed/NCBI
42	Yang D, Wang LP, Zhou H, Cheng H, Bao XC, Xu S, Zhang WP and Wang JM: Inducible costimulator gene-transduced bone marrow-derived mesenchymal stem cells attenuate the severity of acute graft-versus-host disease in mouse models. Cell Transplant. 24:1717–31. 2015. View Article : Google Scholar
43	Wang YL, Tang ZQ, Gao W, Jiang Y, Zhang XH and Peng L: Influence of Th1, Th2, and Th3 cytokines during the early phase after liver transplantation. Transplant Proc. 35:3024–3025. 2003. View Article : Google Scholar : PubMed/NCBI
44	Lee JH, Jeon EJ, Kim N, Nam YS, Im KI, Lim JY, Kim EJ, Cho ML, Han KT and Cho SG: The synergistic immunoregulatory effects of culture-expanded mesenchymal stromal cells and CD4(+)25(+)Foxp3+ regulatory T cells on skin allograft rejection. PLoS One. 8:e709682013. View Article : Google Scholar : PubMed/NCBI