Prolongation of rat renal allograft survival by CD4+CD25‑ T cells induced by recipient dendritic cells transfected with IKK2dn

Wang,Shen; Chen,Han‑Chun; Fan,Cai‑Bin; Wen,Duan‑Gai; Hou,Jian‑Quan; Ouyang,Jun

doi:10.3892/mmr.2013.1689

Prolongation of rat renal allograft survival by CD4+CD25‑ T cells induced by recipient dendritic cells transfected with IKK2dn

Authors:
- Shen Wang
- Han‑Chun Chen
- Cai‑Bin Fan
- Duan‑Gai Wen
- Jian‑Quan Hou
- Jun Ouyang
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Affiliations: Department of Urology, The Fourth People's Hospital of Changzhou, Changzhou, Jiangsu 213032, P.R. China, Department of Neurosurgery, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu 215007, P.R. China, Department of Urology, Shaoxing County Center Hospital, Shaoxing, Zhejiang 312030, P.R. China, Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
Published online on: September 17, 2013 https://doi.org/10.3892/mmr.2013.1689
Pages: 1519-1524

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Abstract

Previous studies have demonstrated that recipient‑derived immature dendritic cells transfected by recombinant adenovirus‑mediated IKK2dn (Adv‑IKK2dn) and loaded with donor splenocyte lysate generate CD4+CD25‑ T cells (Adv‑IKK2dn‑CD4+CD25‑ T cells). These cells may inhibit T cell responses in vitro. In the present study, Lewis (LW) rats were administered with an intravenous injection of naive CD4+ T cells, empty adenovirus (Adv‑0)‑dendritic cell‑generated CD4+CD25‑ T cells (Adv‑0‑CD4+CD25‑ T cells), Adv‑IKK2dn‑CD4+CD25‑ T cells or an equal volume of normal saline, seven days prior to transplantation. The potency and the mechanism of action of Adv‑IKK2dn‑CD4+CD25‑ T cells was analyzed, as well as an investigation of their tolerogenic properties in vivo. Administration of Adv‑IKK2dn‑CD4+CD25‑ T cells in vivo to LW rats was observed to markedly prolong the survival of a kidney allograft from Brown Norway rats. Furthermore, the Adv‑IKK2dn‑CD4+CD25‑ T cell‑treated group exhibited significantly reduced levels of interleukin (Il)‑2 and interferon‑γ production and increased Il‑10 and transforming growth factor‑β (TGF‑β) secretion. The serum creatinine levels remained at low levels in the Adv‑IKK2dn‑CD4+CD25‑ T cell‑treated group. Their ability to induce allogeneic T cell proliferation was markedly reduced compared with the other groups. These observations indicated that Adv‑IKK2dn‑CD4+CD25‑ T cells induce prolongation of kidney allograft survival in vivo, which is hypothesized to be due to the high expression levels of Il‑10 and TGF‑β.

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1	van Duivenvoorde LM, van Mierlo GJ, Boonman ZF and Toes RE: Dendritic cells: vehicles for tolerance induction and prevention of autoimmune diseases. Immunobiology. 211:627–632. 2006.PubMed/NCBI
2	Moser M: Dendritic cells in immunity and tolerance-do they display opposite functions? Immunity. 19:5–8. 2003. View Article : Google Scholar : PubMed/NCBI
3	Morelli AE and Thomson AW: Dendritic cells: regulators of alloimmunity and opportunities for tolerance induction. Immunol Rev. 196:125–146. 2003. View Article : Google Scholar : PubMed/NCBI
4	Muth S, Schütze K, Schild H and Probst HC: Release of dendritic cells from cognate CD4⁺ T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity. Proc Natl Acad Sci USA. 109:9059–9064. 2012.PubMed/NCBI
5	Camirand G, Caron NJ, Turgeon NA, Rossini AA and Tremblay JP: Treatment with anti-CD154 antibody and donor-specific transfusion prevents acute rejection of myoblast transplantation. Transplantation. 73:453–461. 2002. View Article : Google Scholar : PubMed/NCBI
6	Sela U, Olds P, Park A, Schlesinger SJ and Steinman RM: Dendritic cells induce antigen-specific regulatory T cells that prevent graft versus host disease and persist in mice. J Exp Med. 208:2489–2496. 2011. View Article : Google Scholar : PubMed/NCBI
7	Karin M, Yamamoto Y and Wang QM: The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov. 3:17–26. 2004. View Article : Google Scholar : PubMed/NCBI
8	Peng H, Guerau-de-Arellano M, Mehta VB, Yang Y, Huss DJ, Papenfuss TL, Lovett-Racke AE and Racke MK: Dimethyl fumarate inhibits dendritic cell maturation via nuclear factor κB (NF-κB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress-activated kinase 1 (MSK1) signaling. J Biol Chem. 287:28017–28026. 2012.PubMed/NCBI
9	Jimenez F, Quinones MP, Martinez HG, Estrada CA, Clark K, Garavito E, Ibarra J, Melby PC and Ahuja SS: CCR2 plays a critical role in dendritic cell maturation: possible role of CCL2 and NF-kappa B. J Immunol. 184:5571–5581. 2010. View Article : Google Scholar : PubMed/NCBI
10	Cosulich SC, James NH, Needham MR, Newham PP, Bundell KR and Roberts RA: A dominant negative form of IKK2 prevents suppression of apoptosis by the peroxisome proliferator nafenopin. Carcinogenesis. 21:1757–1760. 2000. View Article : Google Scholar : PubMed/NCBI
11	Tomasoni S, Aiello S, Cassis L, Noris M, Longaretti L, Cavinato RA, Azzollini N, Pezzotta A, Remuzzi G and Benigni A: Dendritic cells genetically engineered with adenoviral vector encoding dnIKK2 induce the formation of potent CD4⁺ T-regulatory cells. Transplantation. 79:1056–1061. 2005. View Article : Google Scholar : PubMed/NCBI
12	Ouyang J, Fan C, Wen D, Hou J, Du Y, Wang Y and Shi G: Donor antigen loaded IKK2dn gene-modified dendritic cells prolong allograft survival. Scand J Immunol. 71:336–344. 2010. View Article : Google Scholar : PubMed/NCBI
13	Aiello S, Cassis P, Cassis L, Tomasoni S, Benigni A, Pezzotta A, Cavinato RA, Cuqini D, Azzollini N, Mister M, et al: DnIKK2-transfected dendritic cells induce a novel population of inducible nitric oxide synthase-expressing CD4⁺CD25⁻ cells with tolerogenic properties. Transplantation. 83:474–484. 2007.PubMed/NCBI
14	Fan CB, Zhang DX, Wen DG, Hou JQ, Ouyang J and Du KL: Screening and function identifying of CD4⁺CD25⁻ T cells induced by immature dendritic cells transfected with IKK2dn. Zhonghua Shi Yan Wai Ke Za Zhi. 29:1076–1079. 2012.
15	Du KL, Fan CB, Wen DG, Hou JQ, Ouyang J and Zhang DX: Dominant negative form of IκB kinases 2-transfected recipient immature dendritic cells induce CD4⁺CD25⁻ T cells with tolerogenic properties. Zhonghua Shi Yan Wai Ke Za Zhi. 29:2439–2441. 2012.
16	Schumacher M, Van Vliet BN and Ferrari P: Kidney transplantation in rats: an appraisal of surgical techniques and outcome. Microsurgery. 23:387–394. 2003. View Article : Google Scholar : PubMed/NCBI
17	Wood KJ and Sakaguchi S: Regulatory T cells in transplantation tolerance. Nat Rev Immunol. 3:199–210. 2003. View Article : Google Scholar
18	Yates SF, Paterson AM, Nolan KF, Cobbold SP, Saunders NJ, Waldmann H and Fairchild PJ: Induction of regulatory T cells and dominant tolerance by dendritic cells incapable of full activation. J Immunol. 179:967–976. 2007. View Article : Google Scholar : PubMed/NCBI
19	Yamazaki S, Inaba K, Tarbell KV and Steinman RM: Dendritic cells expand antigen-specific Foxp3⁺ CD25⁺CD4⁺ regulatory T cells including suppressors of alloreactivity. Immunol Rev. 212:314–329. 2006. View Article : Google Scholar : PubMed/NCBI
20	Yang H, Cheng EY, Sharma VK, Lagman M, Chang C, Song P, Ding R, Muthukumar T and Suthanthiran M: Dendritic cells with TGF-β1 and Il-2 differentiate naive CD4⁺ T cells into alloantigen-specific and allograft protective Foxp3⁺ regulatory T Cells. Transplantation. 93:580–588. 2012.
21	Brennan TV, Tang Q, Liu FC, Hoang V, Bi M, Bluestone JA and Kang SM: Requirements for prolongation of allograft survival with regulatory T cell infusion in lymphosufficient hosts. J Surg Res. 169:e69–e75. 2011. View Article : Google Scholar : PubMed/NCBI
22	Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, Del Papa B, Zei T, Ostini RI, Cecchini D, et al: Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 117:3921–3928. 2011.PubMed/NCBI
23	Sagoo P, Ali N, Garg G, Nestle FO, Lechler RI and Lombardi G: Human regulatory T cells with alloantigen specificity are more potent inhibitors of alloimmune skin graft damage than polyclonal regulatory T cells. Sci Transl Med. 3:83ra422011. View Article : Google Scholar : PubMed/NCBI
24	Wakkach A, Fournier N, Brun V, Breittmayer JP, Cottrez F and Groux H: Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo. Immunity. 18:605–617. 2003. View Article : Google Scholar : PubMed/NCBI
25	Fahlén L, Read S, Gorelik L, Hurst SD, Coffman RL, Flavell RA and Powrie F: T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med. 201:737–746. 2005.PubMed/NCBI
26	Marie JC, Letterio JJ, Gavin M and Rudensky AY: TGF-beta1 maintains suppressor function and Foxp3 expression in CD4⁺CD25⁺ regulatory T cells. J Exp Med. 201:1061–1067. 2005. View Article : Google Scholar : PubMed/NCBI
27	Kearley J, Barker JE, Robinson DS and Lloyd CM: Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4⁺ D25⁺ regulatory T cells is interleukin 10 dependent. J Exp Med. 202:1539–1547. 2005. View Article : Google Scholar : PubMed/NCBI
28	Darrah PA, Hegde ST, Patel DT, Lindsay RW, Chen L, Roederer M and Seder RA: Il-10 production differentially influences the magnitude, quality, and protective capacity of Th1 responses depending on the vaccine platform. J Exp Med. 207:1421–1433. 2010. View Article : Google Scholar : PubMed/NCBI
29	Cao Q, Wang Y, Zheng D, Sun Y, Wang Y, Lee VW, Zheng G, Tan TK, Ince J, Alexander SI and Harris DC: Il-10/TGF-beta-modified macrophages induce regulatory T cells and protect against adriamycin nephrosis. J AM Soc Nephrol. 21:933–942. 2010. View Article : Google Scholar : PubMed/NCBI
30	Jiang S, Golshayan D, Tsang J, Lombardi G and Lechler RI: In vitro expanded alloantigen-specific CD4⁺CD25⁺ regulatory T cell treatment for the induction of donor-specific transplantation tolerance. Int Immunopharmacol. 6:1879–1882. 2006.PubMed/NCBI
31	Velásquez-Lopera MM, Eaton VL, Lerret NM, Correa LA, Decresce RP, García LF and Jaramillo A: Induction of transplantation tolerance by allogeneic donor-derived CD4(+)CD25(+)Foxp3(+) regulatory T cells. Transpl Immunol. 19:127–135. 2008.
32	Zhang Y, Wang YL, Liu YW, Li Q, Yuan YH, Niu WY, Sun LY, Zhu ZJ, Shen ZY and Han RF: Change of peripheral blood mononuclear cells IFN-gamma, Il-10, and TGF-beta1 mRNA expression levels with active human cytomegalovirus infection in orthotopic liver transplantation. Transplant Proc. 41:1767–1769. 2009. View Article : Google Scholar
33	Tomasoni S, Azzollini N, Casiraghi F, Capogrossi MC, Remuzzi G and Benigni A: CTLA4Ig gene transfer prolongs survival and induces donor-specific tolerance in a rat renal allograft. J Am Soc Nephrol. 11:747–752. 2000.PubMed/NCBI
34	Kurlberg G, Haglind E, Schön K, Törnqvist H and Lycke N: Blockade of the B7-CD28 pathway by CTLA4-Ig counteracts rejection and prolongs survival in small bowel transplantation. Scand J Immunol. 51:224–230. 2000. View Article : Google Scholar : PubMed/NCBI