Improving allogeneic islet transplantation by suppressing Th17 and enhancing Treg with histone deacetylase inhibitors
2014; Springer Science+Business Media; Volume: 27; Issue: 4 Linguagem: Inglês
10.1111/tri.12265
ISSN1432-2277
AutoresKoji Sugimoto, Takeshi Itoh, Morihito Takita, Masayuki Shimoda, Daisuke Chujo, Jeffrey A. SoRelle, Bashoo Naziruddin, Marlon F. Levy, Mitsuo Shimada, Shinichi Matsumoto,
Tópico(s)Diabetes and associated disorders
ResumoTransplant InternationalVolume 27, Issue 4 p. 408-415 Original ArticleFree Access Improving allogeneic islet transplantation by suppressing Th17 and enhancing Treg with histone deacetylase inhibitors Koji Sugimoto, Corresponding Author Koji Sugimoto Baylor Research Institute Fort Worth Campus, Fort Worth, TX, USA The Departments of Surgery, Tokushima University, Tokushima, Japan Correspondence Dr Koji Sugimoto, 3-18-15 Kuramoto cho, Tokushima 7708503, Japan. Tel.: +81 88 633 3179; fax: +81 88 631 9698; e-mail: ko2moto23@hotmail.comSearch for more papers by this authorTakeshi Itoh, Takeshi Itoh Baylor Research Institute Fort Worth Campus, Fort Worth, TX, USASearch for more papers by this authorMorihito Takita, Morihito Takita Baylor Research Institute Fort Worth Campus, Fort Worth, TX, USA Baylor Regional Transplant Institute, Dallas, TX, USASearch for more papers by this authorMasayuki Shimoda, Masayuki Shimoda Division of Cardiology, Department of Internal Medicine, Baylor University Medical Center, Baylor Heart and Vascular Institute, Dallas, TX, USASearch for more papers by this authorDaisuke Chujo, Daisuke Chujo Baylor Institute for Immunology Research, Dallas, TX, USASearch for more papers by this authorJeff A. SoRelle, Jeff A. SoRelle Institute of Biomedical Studies, Baylor University, Waco, TX, USASearch for more papers by this authorBashoo Naziruddin, Bashoo Naziruddin Baylor Regional Transplant Institute, Dallas, TX, USASearch for more papers by this authorMarlon F. Levy, Marlon F. Levy Baylor Research Institute Fort Worth Campus, Fort Worth, TX, USA Baylor Regional Transplant Institute, Dallas, TX, USASearch for more papers by this authorMitsuo Shimada, Mitsuo Shimada The Departments of Surgery, Tokushima University, Tokushima, JapanSearch for more papers by this authorShinichi Matsumoto, Shinichi Matsumoto Baylor Research Institute Fort Worth Campus, Fort Worth, TX, USASearch for more papers by this author Koji Sugimoto, Corresponding Author Koji Sugimoto Baylor Research Institute Fort Worth Campus, Fort Worth, TX, USA The Departments of Surgery, Tokushima University, Tokushima, Japan Correspondence Dr Koji Sugimoto, 3-18-15 Kuramoto cho, Tokushima 7708503, Japan. Tel.: +81 88 633 3179; fax: +81 88 631 9698; e-mail: ko2moto23@hotmail.comSearch for more papers by this authorTakeshi Itoh, Takeshi Itoh Baylor Research Institute Fort Worth Campus, Fort Worth, TX, USASearch for more papers by this authorMorihito Takita, Morihito Takita Baylor Research Institute Fort Worth Campus, Fort Worth, TX, USA Baylor Regional Transplant Institute, Dallas, TX, USASearch for more papers by this authorMasayuki Shimoda, Masayuki Shimoda Division of Cardiology, Department of Internal Medicine, Baylor University Medical Center, Baylor Heart and Vascular Institute, Dallas, TX, USASearch for more papers by this authorDaisuke Chujo, Daisuke Chujo Baylor Institute for Immunology Research, Dallas, TX, USASearch for more papers by this authorJeff A. SoRelle, Jeff A. SoRelle Institute of Biomedical Studies, Baylor University, Waco, TX, USASearch for more papers by this authorBashoo Naziruddin, Bashoo Naziruddin Baylor Regional Transplant Institute, Dallas, TX, USASearch for more papers by this authorMarlon F. Levy, Marlon F. Levy Baylor Research Institute Fort Worth Campus, Fort Worth, TX, USA Baylor Regional Transplant Institute, Dallas, TX, USASearch for more papers by this authorMitsuo Shimada, Mitsuo Shimada The Departments of Surgery, Tokushima University, Tokushima, JapanSearch for more papers by this authorShinichi Matsumoto, Shinichi Matsumoto Baylor Research Institute Fort Worth Campus, Fort Worth, TX, USASearch for more papers by this author First published: 10 January 2014 https://doi.org/10.1111/tri.12265Citations: 16 Conflicts of interest: The authors of this manuscript have no conflict of interests. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Summary Islet transplantation is a new treatment for achieving insulin independence for patients with severe diabetes. However, major drawbacks of this treatment are the long graft survival, the necessity for immunosuppressive drugs, and the efficacy of transplantation. Donor-specific transfusion (DST) has been shown to reduce rejection after organ transplantation, potentially through enhanced regulatory T-cell (Treg) activity. However, recent findings have shown that activated Treg can be converted into Th17 cells. We focused on histone deacetylase inhibitors (HDACi) because it was reported that inhibition of HDAC activity prevented Treg differentiation into IL17-producing cells. We therefore sought to enhance Treg while suppressing Th17 cells using DST with HDACi to prolong graft survival. To stimulate Treg by DST, we used donor splenocytes. In DST with HDACi group, Foxp3 mRNA expression and Treg population increased in the thymus and spleen, whereas Th17 population decreased. qPCR analysis of lymphocyte mRNA indicated that Foxp3, IL-10, and TGF-b expression increased. However, interleukin 17a, Stat3 (Th17), and IFN-g expression decreased in DST + HDACi group, relative to DST alone. Moreover, DST treated with HDACi prolonged graft survival relative to controls in mice islet transplantation. DST with HDACi may therefore have utility in islet transplantation. Introduction Beneficial effects and unsolved issues of islet transplantation The Edmonton protocol of 2000 opened a new age of clinical islet transplantation research for the treatment of type 1 diabetes. In their report, seven patients with type 1 diabetes became insulin independent after islet transplantation with glucocorticoid-free immunosuppression 1. Approximately 80% of study subjects had islet function as indicated by the presence of C-peptide at 5-year follow-up, although only 10% of patients maintained insulin independence 2. That study demonstrated that while there are several issues to be solved, islet transplantation holds promise as a treatment for severe diabetes. Islet transplantation still faces several challenges, including the requirement for immunosuppressants to prevent rejection. Immunosuppressants cause side effects and hinder beta cell regeneration, and incomplete immunosuppression can lead to autoimmune recurrence or allorejection 3. Eliminating the need for immunosuppressants is therefore a major goal for islet transplantation and would significantly improve its efficacy. Donor-specific blood transfusion for immunological tolerance Donor-specific blood transfusion (DST) has been shown to reduce rejection after organ transplantation 4. A possible mechanism of DST is stimulation of regulatory T cells that have potent immunosuppressive effects. It has also been shown that the simultaneous infusion of islets and regulatory T cells reduces the rejection and prolongs islet survival in a mouse model 5. Histone deacetylase inhibitors (HDACi) for enhancing Treg We focused on HDACi for promoting the generation of Treg 6-8. Histone deacetylases (HDACs), in conjunction with histone acetyltransferases, control the level of acetylation on lysine residues in histones. Treatment of cells with HDACi, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), leads to hyperacetylation of histones, resulting in a more open chromatin architecture and increased access for transcription factors 9. HDACi regulates gene expression as well as the functions of more than 50 transcription factors and nonhistone proteins 10. Treg is a target of HDACi. Studies on Foxp3, a key gene of Treg, reveal that histone H4 is hyperacetylated when the gene is activated 11. Another study revealed that acetylated Foxp3 is upregulated in CD4+ CD25+ Treg cells 12. Moreover, TSA induced Treg production from naïve CD4+ CD25-T-cell populations following epigenetic modification 13. These results suggest that HDACi treatments altered CpG island methylation sites that allow FOXP3 to enter the space between DNA and histone proteins, allowing transcription. Both methylated and acetylated FOXP3 within CD4+ CD25-T cells induced Treg phenotypes in vitro. To summarize, HDACi treatment may enhance Treg expression by methylation and acetylation of Foxp3. HDACi for anti-Th17 effect Studies suggest that activated Treg promotes Th17 cell differentiation from CD4 T cells, through production of TGF-b. In addition, transfer of Treg enhanced IL17 production in a mouse model, and enhanced IL17 is associated with systemic autoimmune disease 14. Therefore, expansion of Th17 cells may disrupt Treg and immunological tolerance. Importantly, treatment of HDACi may help address this problem. Interestingly, differentiation of Treg into IL17-producing cells depended on HDAC activity, and inhibition of HDAC activity prevented differentiation into IL17-producing cells, yet sustained Foxp3 expression 15. Based on these data, we hypothesized that HDACi could be critical for increasing Treg growth and preventing Treg from becoming Th17 cells. Materials and method In vitro experiments Balb/c mice were used as donors, and C57BL/6 mice were used as recipients. To stimulate Treg by DST, we used donor splenocytes. Splenocytes (1.0 × 108 cells) derived from Balb/c mice were injected into C57BL/6 mice (day 0, i.v.). TSA, a HDACi, was also injected (1.0 mg/kg/day, day 0–6, i.p.). On day 7, thymic and splenic lymphocytes were isolated and analyzed by flow cytometry (CD4, CD25, Foxp3, and IL17a) as in vitro experiments. In addition, mRNA expressions in thymic and splenic lymphocytes were analyzed by qPCR (Foxp3, TGF-b, IL-6, IL-10, IL-17a, IL-21, Stat3, and IFN-g) (SABiosciences, Frederick, MD, USA) as in vitro experiments. In vivo experiments Streptozotocin (180 mg/kg, i.v.)-induced diabetic C57BL/6 mice were used as recipients. Donor splenocytes (1.0 × 108 cells, day 0, i.v.) and TSA (1.0 mg/kg/day, day 0–6, i.p.) were injected, and on day 7, 400 islets from donor mice were transplanted into the left renal capsule of recipient mice as in vivo experiments. Graft survival was observed by checking the blood glucose level three times a week. Immunohistochemistry Frozen sections were made with Cryostat (CM 3050S, Leica, Wetzlar, Germany) from the left renal capsule of DST + TSA recipient mice 60 days after islet transplantation and control recipient mice after graft rejection. Sections were stained with anti-mouse insulin antibody (Abcam, Cambridge, MA, USA). Statistics Statistical significance was determined by one-way anova and Tukey/Kramer post hoc test. All statistical analyses were performed using statview 5.0 (SAS Institute Inc, Cary, NC, USA). Differences were considered significant if P < 0.05. Results DST and HDACi induced Treg expression In in vitro and in vivo models, mice were divided into four groups (n = 5): (i) control, (ii) DST, (iii) TSA (HDACi), and (iv) DST + TSA. In preliminary data, we observed that Treg did not significantly increase on day 3 after DST. However, Treg significantly increased on day 7 after DST. So we analyzed the immune response on day 7. In in vitro model, we made the four groups, and on day 7, Foxp3 mRNA expression in thymus was significantly increased in DST, TSA, and DST + TSA, relative to controls. Moreover, Foxp3 mRNA expression in DST + TSA was significantly higher than DST or TSA alone (Fig. 1a). On the other hand, splenic Foxp3 mRNA expression was significantly increased in DST, TSA, and DST + TSA relative to controls. However, there was no significant difference between the DST and DST + TSA groups (Fig. 1b). As determined by FACS analysis, the fold change of Treg in thymus was significantly higher in DST, TSA, and DST + TSA than in controls. Moreover, the Treg increase observed for DST + TSA treatment was significantly higher than that observed in DST-only treatment (Fig. 1e). In spleen, the fold increase in Treg was significantly higher for DST, TSA, and DST + TSA against controls. However, the Treg increase in DST + TSA group tended to be higher than that for DST treatment (P = 0.09) (Fig. 1f). The representative data of FACS analysis of lymphocytes in thymus and spleen are shown in Fig. 1c and d. Figure 1Open in figure viewerPowerPoint Donor-specific transfusion (DST) and HDACi induced Treg expression. (a) Foxp3 mRNA expression in thymus (day 7). Foxp3 mRNA expression following DST + TSA treatment is significantly higher than with DST or TSA alone (P < 0.05). (b) Foxp3 mRNA expression in spleen (day 7). There is no significant difference between DST and DST + TSA groups. (c) Flow cytometry chart of CD4+ CD25+ Foxp3+ T cells in thymus (day 7). The representative data of FACS analysis in thymus were shown. (d) Flow cytometry chart of CD4+ CD25+ Foxp3+ T cells in spleen (day 7). The representative data of FACS analysis in spleen were shown. (e) FACS analysis of the fold change in Treg in thymus. The fold change of Treg in DST + TSA was significantly higher than that in the DST group (P < 0.05). (f) FACS analysis of the fold change of Treg in spleen. Treg increase observed for DST + TSA tended to be higher than that in the DST group (P = 0.09). TSA, trichostatin A. HDACi decreased Th17 expression We next focused on Th17 expression. In in vitro model, we used four groups (n = 5): (i) control, (ii) DST, (iii) TSA (HDACi), and (iv) DST + TSA. We made the four groups, and on day 7, splenocytes were taken and analyzed for mRNA expression and flow cytometry. IL-17, a major Th17 cytokine, increased (not significantly) mRNA expression when treated with DST. However, IL-17 mRNA expression decreased significantly in DST + TSA group in comparison with DST-alone group (Fig. 2a). FACS analysis indicated that the population of CD4+ IL17+ cells in DST + TSA treatment group was significantly lower than that in DST group (Fig. 2c). The representative data of FACS analysis of CD4+ IL17+ cells in spleen are shown in Fig. 2b. Figure 2Open in figure viewerPowerPoint Histone deacetylase inhibitors (HDACis) decreased Il-17 expression. (a) IL-17 mRNA expression decreased significantly in DST + TSA group (P < 0.05). (b) Flow cytometry chart of CD4+ IL17+ T cells in spleen (day 7). The representative data of FACS analysis in spleen were shown. (c) FACS analysis of CD4+ IL17+ cells following DST + TSA treatment IL-17 was significantly lower than that of DST only (P < 0.05). DSA, donor-specific transfusion; TSA, trichostatin A. DST and HDACi changed mRNA expression associated with Treg and Th17 We measured various mRNAs associated with Treg and Th17 from splenocytes of each of the four groups (Fig. 3). Treg secretes IL-10 and TGF-b, and they suppress the immunological reaction. We measured IL-10 and Tgfb1, mRNA of IL-10 and TGF-b, and the expression of those cytokines in recipient splenocytes was significantly higher in DST + TSA treatment relative to TSA only, or control (Fig. 3a and b). Th17 secretes IL-17 family, and they involve in inducing and mediating proinflammatory responses. We measured IL-17a, a member of IL-17 family, and IL-17a mRNA expression in recipient splenocytes was significantly decreased in DST + TSA treatment group in comparison with control and DST-alone groups (Fig. 3c). However, IL-6 and IL-21 mRNA expression was not significantly different between groups (Fig. 3d and e). Moreover, we measured Stat3, a major Th17 transcription factor, to evaluate the activity of Th17 cells. Stat3 was expressed significantly higher following DST treatment relative to control. However, Stat3 expression did not differ between DST + TSA and control. In addition to Treg and Th17 system, IFN-g was measured because it was critical for innate and adaptive immunity and produced from natural killer cells, natural killer T cells, CD4 Th1 cells, and CD8 cytotoxic T cells. Ifng mRNA expression in TSA and DST + TSA was significantly lower than that following DST only. Figure 3Open in figure viewerPowerPoint Donor-specific transfusion (DST) and HDACi changed mRNA expression associated with Treg and Th17. Various mRNAs associated with Treg and Th17 from lymphocytes of the four groups were measured by qPCR. (a) IL-10 mRNA expression in spleen. IL-10 mRNA expression following DST + TSA treatment is significantly higher than following control or TSA alone. (b) Tgfb1 mRNA expression in spleen. Tgfb1 mRNA expressions following DST + TSA treatment or DST only are significantly higher than following control or TSA alone. (c) IL-17 mRNA expression in spleen. IL-17 mRNA expression following DST + TSA treatment is significantly lower than following DST only. (d) IL-6 mRNA expression in spleen. There is no significant difference in IL-6 mRNA expression. (e) IL-21 mRNA expression in spleen. There is no significant difference in IL-21 mRNA expression. (f) Stat3 mRNA expression in spleen. Stat3 mRNA expression following DST + TSA treatment is significantly lower than following DST only. (g) Ifng mRNA expression in spleen. Ifng mRNA expression following DST + TSA treatment is significantly lower than following DST only. TSA, trichostatin A. DST + TSA improved the graft survival in mouse islet transplantation We examined islet graft survival in a mouse model (n = 5). There was no difference in graft survival between mice in the control, DST, and TSA groups. However, with DST + TSA treatment, graft survival was significantly improved. Moreover, we observed extended survival (over 60 days) in the DST + TSA group (Fig. 4). Insulin staining indicated that islets secrete insulin in the transplantation site 60 days after transplantation (Fig. 5a and b). On the other hand, in control group there was no islet secreting insulin, and we recognized the fibrillization and inflammation cells under the renal capsule after rejection (Fig. 5c and d). We observed the similar changes in DST or TSA group. Figure 4Open in figure viewerPowerPoint DST + TSA improved graft survival in a mouse islet transplantation model. A total of 400 islets from donor mice were transplanted into the left renal capsule of recipient mice, and graft survival was observed by checking blood glucose level three times a week. Following DST + TSA treatment, graft survival was significantly improved (P < 0.05). DSA, donor-specific transfusion; TSA, trichostatin A. Figure 5Open in figure viewerPowerPoint Insulin staining of transplantation site in a mouse islet transplantation model. (a) H.E. staining (×100). H.E. staining identified islets under the renal capsule of recipient mice. (b) Insulin staining (×100). Insulin staining identified islets that secrete insulin in the transplantation site 60 days following transplantation. (c) H.E. staining (×100). H.E. staining identified no islets under the renal capsule of recipient mice after rejection. We recognize the fibrillization and inflammation cells under the renal capsule after rejection. (d) Insulin staining (×100). Insulin staining identified no islets that secrete insulin in the transplantation site. Discussion Islet transplantation is a promising treatment for diabetes. However, there are several problems to be solved. These problems include length of graft survival, the reduction of immunosuppressive drugs, and transplantation efficacy. Treg is likely a key regulatory cell type that needs to be managed to solve these problems. Sakaguchi et al. originally identified this cell population as a regulator for autoreactive T cells 16. Treg can strongly regulate other T cells depending on cell-associated molecules such as CTLA-4 and GITR, as well as soluble mediators including IL-10 or TGF-b, and cytotoxic CD8+ T cells. Graft rejections are T-cell-mediated immunoreactions, making Tregs a natural target for researchers to consider in controlling graft rejection. Indeed, it is known that Treg increases in patients with immunological tolerance 17, 18 and that increasing the number of Tregs in recipients prevents both acute and chronic rejection in several animal models 19. Treg can be increased in several experimental models, such as multiple blood transplantations 20, blocking of CD40-CD154 or CD80/CD86-CD28 costimulatory interactions 21-23, anti-CD28 antagonist 24, 25, and ex vivo Treg expansion 26. In this study, we used donor-specific transfusion (DST). DST is a classic and empirical method. However, we still sought to evaluate the utility of this approach. It is reported that anergy 27, 28, clonal deletion 29, 30, regulation of cytokine production 31, 32, microchimerism 33, 34, generation of soluble MHC antigen 35, or a combination of these mechanisms may mediate DST. However, the specific mechanism of DST is still unknown 36, 37. Our data show that DST increased the Treg population and increased Foxp3, IL-10, and Tgfb1 mRNA expression. In this respect, it may be thought that DST has utility by itself. However, other data suggest that DST is not effective for graft survival in an islet transplantation model 38, indicating that DST has limits. We focused on Th17 cells because previous studies showed that Treg enhancement also increases Th17 cells via TGF-b and IL-6 induction. Treg differentiates into Th17 cells. A GAD vaccination study showed that GAD vaccination enhanced not only Treg but also Th1 and Th17 cells, which failed to prevent type 1 diabetes. Moreover, in a mouse syngeneic islet transplantation model, blockade of IL-17 resulted in extended graft survival 39. Therefore, we hypothesized that DST with blockage of anti-inflammatory drugs could improve graft survival. We therefore used HDACi to inhibit inflammatory cytokines (Th1 and Th17). HDACi was also known to increase Treg and decrease Th17 differentiation by sustaining Foxp3 expression and inhibiting IL-6. Moreover, it has been shown that HDACi blocks IL-23 production and inhibits Th17 differentiation 40. Our study showed that TSA increased Treg expression and regulatory cytokines (IL-10 and Tgfb1). Moreover, DST + TSA induced expansion of Tregs and IL-10 and significantly decreased Th17 (IL-17a) and Th1 (Ifng), compared with DST only. In the mouse islet transplantation model, DST + TSA improved graft survival, and we observed extended survival (over 60 days after transplantation). Cytokine analysis indicated that IL-10 and Tgfb1 mRNA were significantly increased by DST + TSA and improving, in principle, Treg function. IL17a and Ifng mRNA expression was decreased by TSA. However, IL-6 and IL-21 expression was not significantly decreased. In conclusion, HDACi increased Treg expression and inhibited Th17 differentiation, accompanied with Treg induction. These results suggest certain therapeutic strategies that may be useful for improving graft survival. Authorship KS: designed and performed research, analyzed data, wrote paper. TI: performed research, analyzed data. MT: performed research, analyzed data. MS: analyzed data. DC: analyzed data. JASR: analyzed data. BN: analyzed data. MFL: analyzed data. MS: analyzed data. SM: designed research, analyzed data. Funding The authors have declared no funding. Acknowledgements The authors thank Ms. Yoshiko Tamura and Zehra Tekin for technical support. This work was supported in part by the Japan IDDM network and the All Saints Health Foundation. References 1Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with Type 1 Diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343: 230. CrossrefCASPubMedWeb of Science®Google Scholar 2Ryan EA, Paty BW, Senior PA, et al. Five-year follow-up after clinical islet transplantation. Diabetes 2005; 54: 2060. CrossrefCASPubMedWeb of Science®Google Scholar 3Morales AE, Thrailkill KM. GAD-alum immunotherapy in Type 1 diabetes mellitus. Immunotherapy 2011; 3: 323. CrossrefCASPubMedWeb of Science®Google Scholar 4Sengar DP, Rashid A, Jindal SL. Effect of blood transfusions on renal allograft survival. Transplant Proc 1979; 11: 179. CASPubMedWeb of Science®Google Scholar 5Velasquez-Lopera MM, Eaton VL, Lerret NM, et al. Induction of transplantation tolerance by allogeneic donor-derived CD4+ CD25+ Foxp3+ regulatory T cells. Transpl Immunol 2008; 19: 127. CrossrefCASPubMedWeb of Science®Google Scholar 6Tao R, de Zoeten EF, Ozkynak E, et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 2007; 13: 1299. CrossrefCASPubMedWeb of Science®Google Scholar 7Wang L, Tao R, Hancock WW. Using histone deacetylase inhibitors to enhance Foxp3+ regulatory T cell function and induce allograft tolerance. Immunol Cell Biol 2009; 87: 195. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 8Tao R, de Zoeten EF, Ozkaynak E, et al. Histone deacetylase inhibitors and transplantation. Curr Opin Immunol 2007; 19: 589. CrossrefCASPubMedWeb of Science®Google Scholar 9Maclaughlin F, La Thangue NB. Histone deacetylase inhibitors open new doors in cancer therapy. Biochem Pharmacol 2004; 67: 1139. CrossrefCASPubMedWeb of Science®Google Scholar 10Lucas JL, Mirshahpanah P, Stapleton EH, et al. Induction of Foxp3+ regulatory T cells with histone deacetylase inhibitors. Cell Immunol 2009; 257: 97. CrossrefCASPubMedWeb of Science®Google Scholar 11Mantel P-Y, Oakud N, Ruckert B, et al. Molecular mechanisms underlying Foxp3 induction in human T cells. J Immunol 2006; 176: 3593. CrossrefCASPubMedWeb of Science®Google Scholar 12Li B, Samanta A, Song X, et al. Foxp3 interactions with histone acetyltransferases and class II histone deacetylases are required for repression. Proc Natl Acad Sci 2007; 104: 4571. CrossrefCASPubMedWeb of Science®Google Scholar 13Moon C, Kim SH, Park KS, et al. Use of epigenetic modification to induce FOXP3 expression in Naïve T cells. Transplant Proc 2009; 41: 1848. CrossrefCASPubMedWeb of Science®Google Scholar 14Lohr J, Knoechel B, Wang JJ, Villarino AV, Abbas AK. Role of IL-17 and regulatory T lymphocytes in a systemic autoimmune disease. J Exp Med 2006; 203: 2785. CrossrefCASPubMedWeb of Science®Google Scholar 15Koenen HJPM, Smeets RL, Vink PM, van Rijssen E, Boots AM, Joosten I. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17 producing cells. Blood 2008; 112: 2340. CrossrefCASPubMedWeb of Science®Google Scholar 16Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155: 1151. CASPubMedWeb of Science®Google Scholar 17Li W, Kuhr CS, Zheng XX, et al. New insights into mechanisms of spontaneous liver transplant tolerance: the role of Foxp3-expressing CD25+CD4+ regulatory T cells. Am J Transplant 2008; 8: 1639. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 18Li Y, Zhao X, Cheng D, et al. The presence of Foxp3 expressing T cells within grafts of tolerant human liver transplant recipients. Transplantation 2008; 86: 1837. CrossrefCASPubMedWeb of Science®Google Scholar 19Joffre O, Santolaria T, Calise D, et al. Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nat Med 2008; 14: 88. CrossrefCASPubMedWeb of Science®Google Scholar 20Bushell A, Karim M, Kingsley CI, Wood KJ. Pretransplant blood transfusion without additional immunotherapy generates CD25+ CD4+ regulatory T cells: a potential explanation for the blood-transfusion effect. Transplantation 2003; 76: 449. CrossrefPubMedWeb of Science®Google Scholar 21Verbinnen B, Billiau AD, Vermeiren J, et al. Contribution of regulatory T cells and effector T cell deletion in tolerance induction by costimulation blockade. J Immunol 2008; 181: 1034. CrossrefCASPubMedWeb of Science®Google Scholar 22Blazar BR, Taylor PA, Linsley PS, Vallera DA. In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. Blood 1994; 83: 3815. CrossrefCASPubMedWeb of Science®Google Scholar 23Lin H, Bolling SF, Linsley PS, et al. Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion. J Exp Med 1993; 178: 1801. CrossrefCASPubMedWeb of Science®Google Scholar 24Azuma H, Isaka Y, Li X, et al. Superagonistic CD28 antibody induces donor-specific tolerance in rat renal allografts. Am J Transplant 2008; 8: 2004. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 25Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol 2002; 2: 116. CrossrefCASPubMedWeb of Science®Google Scholar 26Chai JG, Coe D, Chen D, Simpson E, Dyson J, Scott D. In vitro expansion improves in vivo regulation by CD4+CD25+ regulatory T cells. J Immunol 2008; 180: 858. CrossrefCASPubMedWeb of Science®Google Scholar 27Margenthaler JA, Kataoka M, Flye MW. Donor-specific antigen transfusion-mediated skin-graft tolerance results from the peripheral deletion of donor-reactive CD8+ T cells. Transplantation 2003; 75: 2119. CrossrefCASPubMedWeb of Science®Google Scholar 28Lombardi G, Sidhu S, Batchelor R, Lechler R. Anergic T cells as suppressor cells in vitro. Science 1994; 264: 1587. CrossrefPubMedWeb of Science®Google Scholar 29Manilay J, Pearson D, Sergio J, Swenson K, Sykes M. Intrathymic deletion of alloreactive T cells in mixed bone marrow chimeras prepared with a nonmyeloablative conditioning regime. Transplantation 1998; 66: 96. CrossrefCASPubMedWeb of Science®Google Scholar 30Burlingham WJ, Grailer A, Sondel PM, Sollinger HW. Improved renal allograft survival following donor-specific transfusions. III. Kinetics of mixed lymphocyte culture responses before and after transplantation. Transplantation 1988; 45: 127. CrossrefCASPubMedWeb of Science®Google Scholar 31Kang HG, Zhang D, Degauque N, Mariat C, Alexopoulos S, Zheng XX. Effects of cyclosporine on transplant tolerance: the role of IL-2. Am J Transplant 2007; 7: 1907. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 32Demirkiran A, Bosma BM, Kok A, et al. Allosuppressive donor CD4+ CD25+ regulatory T cells detach from the graft and circulate in recipients after liver transplantation. J Immunol 2007; 178: 6066. CrossrefCASPubMedWeb of Science®Google Scholar 33Miller DM, Thornley TB, Pearson T, et al. TLR agonists prevent the establishment of allogeneic hematopoietic chimerism in mice treated with costimulation blockade. J Immunol 2009; 182: 5547. CrossrefCASPubMedWeb of Science®Google Scholar 34Pree I, Wekerle T. Inducing mixed chimerism and transplantation tolerance through allogeneic bone marrow transplantation with costimulation blockade. Methods Mol Biol 2007; 380: 391. CrossrefCASPubMedGoogle Scholar 35Nicholls S, Piper KP, Mohammed F, et al. Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition. Proc Natl Acad Sci USA 2009; 106: 3889. CrossrefCASPubMedWeb of Science®Google Scholar 36Yang L, Du Temple B, Khan Q, Zhang L. Mechanisms of long-term donor-specific allograft survival induced by pretransplant infusion of lymphocytes. Blood 1998; 91: 324. CrossrefCASPubMedWeb of Science®Google Scholar 37Quezada SA, Fuller B, Jarvinen LZ, et al. Mechanisms of donor-specific transfusion tolerance: preemptive induction of clonal T-cell exhaustion via indirect presentation. Blood 2003; 102: 1920. CrossrefCASPubMedWeb of Science®Google Scholar 38Wojtusciszyn A, Andres A, Morel P, et al. Immunomodulation by blockade of the TRANCE co-stimulatory pathway in murine allogeneic islet transplantation. Transpl Int 2009; 22: 931. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 39Emamaullee JA, Davis J, Merani S, et al. Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice. Diabetes 2009; 58: 1302. CrossrefCASPubMedWeb of Science®Google Scholar 40Bosisio D, Vulcano M, Del Prete A, et al. Blocking TH17-polarizing cytokines by histone deacetylase inhibitors in vitro and in vivo. J Leukoc Biol 2008; 84: 1540. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Citing Literature Volume27, Issue4April 2014Pages 408-415 FiguresReferencesRelatedInformation
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