Effects of Immunosuppressive Drugs on CD4+CD25+ Regulatory T Cells: A Systematic Review of Clinical and Basic Research△_Chinese Journal of Evidence-Based Medicine

Authors：

ZHANG Chuntao ¹ , SHAN Juan ¹ , FENG Li ¹ , LU Jun ¹ , XIAO Zheng ¹ , LUO Lei ¹ , LI Chengwen ¹ , GUO Yingjia ¹ ,  LI Youping ^1,2

1. Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China; 2. Chinese Evidence-Based Medicine Center, Chengdu 610041, China;

Corresponding author：

LI Youping, Email: yzmylab@hotmail.com

Keywords：

CD4+CD25+ Regulatory T cells; Immunosuppressive drugs; Systematic review; Clinical and basic studies

DOI：

10.7507/1672-2531.20100485

Video：

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Objective 　To assess the effects of different immunosuppressive drugs on proliferation and function of regulatory T cells (Tregs).
Methods 　We searched MEDLINE (1966 to November 2009), EMbase (from inception to September 2009), and The Cochrane Library (Issue 4, 2009) for clinical and basic research about the effects of various immunosuppressive drugs on Tregs. Data were extracted and methodological quality was assessed by two independent reviewers. Outcome measures for clinical research included blood Tregs levels, acute rejection episodes, and graft function. Outcome measures for basic research included percentage of Tregs proliferation, function, Tregs phenotype, and evidence for possible mechanisms. We analyzed data qualitatively.
Results 　Forty-two studies, including 19 clinical trials and 23 basic studies, were included. The immunosuppressive drugs studied were calcineurin inhibitors (CNIs), Rapa, anti-metabolism drugs, IL-2 receptor-blocking antibodies, T-cell depleting antibodies, and co-stimulation blockade antibodies. Most of the studies were on Rapa and CNIs. Eight basic studies on Rapa and CNIs showed that Rapa could promote the proliferation and function of Tregs, while CNIs could not. Five clinical trials involving a total of 158 patients showed that patients taking Rapa had higher blood concentration of Tregs than those taking CNIs, but no differences were found in graft function (6-42-month follow-up).
Conclusion 　There is substantial evidence that Rapa favors Tregs survival and function. However, the larger number of the blood Tregs in the patients treated with Rapa does not show any correlation with better graft function. Large-sample and high-quality clinical studies with longer follow-up are needed to thoroughly assess the efficacy of immunosuppressive drugs on Tregs and to reveal whether a relationship exists between Tregs and graft function.

Citation： ZHANG Chuntao,SHAN Juan,FENG Li,LU Jun,XIAO Zheng,LUO Lei,LI Chengwen,GUO Yingjia,LI Youping. Effects of Immunosuppressive Drugs on CD4+CD25+ Regulatory T Cells: A Systematic Review of Clinical and Basic Research△. Chinese Journal of Evidence-Based Medicine, 2010, 10(6): 740-748. doi: 10.7507/1672-2531.20100485 Copy

1.	Lechler RI, Sykes M, Thomson AW, et al. Organ transplantation-how much of the promise has been realized? Nat Med, 2005, 11(6): 605-613.
2.	Lukes DJ, Herlenius G, Rizell M, et al. Late mortality in. 679 consecutive liver transplant recipients: the Gothenburg liver transplant experience. Transplant Proc, 2006, 38(8): 2671-2672.
3.	Puig N, de la Rubia J, Remigia MJ, et al. Morbidity and transplant-related mortality of CBV and BEAM preparative regimens for patients with lymphoid malignancies undergoing autologous stem-cell transplantation. Leuk Lymphoma, 2006, 47(8): 1488-1494.
4.	Sykes M. Immune tolerance: mechanisms and application in clinical transplantation. J Intern Med, 2007, 262(3): 288-310.
5.	Xia G, Shah M, Luo X. Prevention of allograft rejection by amplification of Foxp3+CD4+CD25+ regulatory T cells. Transl Res, 2009, 153(2): 60-70.
6.	Joffre 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(1): 88-92.
7.	Meloni F, Vitulo P, Bianco AM, et al. Regulatory CD4+CD25+ T cells in the peripheral blood of lung transplant recipients: Correlation with transplant outcome. Transplantation, 2004, 77(5): 762-766.
8.	Louis S, Braudeau C, Giral M, et al. Contrasting CD25hiCD4+T cells/FOXP3 patterns in chronic rejection and operational drug-free tolerance. Transplantation, 2006, 81(3): 398-407.
9.	Daniel V, Naujokat C, Sadeghi M, et al. Observational support for an immunoregulatory role of CD3+CD4+CD25+IFN-gamma+ blood lymphocytes in kidney transplant recipients with good long-term graft outcome. Transpl Int, 2008, 21(7): 646-660.
10.	Akl A, Jones ND, Rogers N, et al. An investigation to assess the potential of CD25highCD4+ T cells to regulate responses to donor alloantigens in clinically stable renal transplant recipients. Transpl Int, 2008, 21(1): 65-73.
11.	Jia LY, Yuan BB, Wang J, et al. Methods of Systematic Review of Health Policy Researches. Chin J Evid-Based Med, 2009, 9(10): 1037-1043.
12.	Gregori S, Casorati M, Amuchastegui S, et al. Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol, 2001, 167(4): 1945-1953.
13.	Chiffoleau E, Bériou G, Dutartre P, et al. Role for thymic and splenic regulatory CD4+ T cells induced by donor dendritic cells in allograft tolerance by LF15-0195 treatment. J Immunol, 2002, 168(10): 5058-5069.
14.	Baan CC, van der Mast BJ, Klepper M, et al. Differential effect of calcineurin inhibitors, anti-CD25 antibodies and rapamycin on the induction of FOXP3 in human T cells. Transplantation, 2005, 80(1): 110-117.
15.	Demirkiran A, Kok A, Kwekkeboom J, et al. Decrease of CD4+CD25+ T cells in peripheral blood after liver transplantation: association with immunosuppression. Transplant Proc, 2005, 37(2): 1194-1196.
16.	Tang W, Yang Y, Zhang F, et al. Prevention of graft-versus-host disease by a novel immunosuppressant, (5R)-5-hydroxytriptolide (LLDT-8), through expansion of regulatory T cells. Int Immunopharmacol, 2005, 5(13-14): 1904-1913.
17.	Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood, 2005, 105(12): 4743-4748.
18.	Wang H, Zhao L, Sun Z, et al. A potential side effect of cyclosporin A: inhibition of CD4(+)CD25(+) regulatory T cells in mice. Transplantation, 2006, 82(11): 1484-1492.
19.	Li W, Carper K, Liang Y, et al. Anti-CD25 mAb administration prevents spontaneous liver transplant tolerance. Transplant Proc, 2006,38(10): 3207-3208.
20.	San Segundo D, Ruiz JC, Fernández-Fresnedo G, et al. Calcineurin inhibitors affect circulating regulatory T cells in stable renal transplant recipients. Transplant Proc, 2006, 38(8): 2391-2393.
21.	Coenen JJ, Koenen HJ, van Rijssen E, et al. Rapamycin, and not cyclosporin A, preserves the highly suppressive CD27+ subset of human CD4+CD25+ regulatory T cells. Blood, 2006, 107(3): 1018-1023.
22.	Chavez H, Beaudreuil S, Abbed K, et al. Absence of CD4CD25 regulatory T cell expansion in renal transplanted patients treated in vivo with Belatacept mediated CD28-CD80/86 blockade. Transpl Immunol, 2007, 17(4): 243-248.
23.	Ardalan MR, Maljaei H, Shoja MM, et al. Calcitriol started in the donor, expands the population of CD4+CD25+ T cells in renal transplant recipients. Transplant Proc, 2007, 39(4): 951-953.
24.	Lim DG, Joe IY, Park YH, et al. Effect of immunosuppressants on the expansion and function of naturally occurring regulatory T cells. Transpl Immunol, 2007, 18(2): 94-100.
25.	Kreijveld E, Koenen HJ, Klasen IS, et al. Following anti-CD25 treatment, a functional CD4+CD25+ regulatory T-cell pool is present in renal transplant recipients. Am J Transplant, 2007, 7(1): 249-255.
26.	Kopf H, de la Rosa GM, Howard OM, et al. Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int Immunopharmacol, 2007, 7(13): 1819-1824.
27.	Coenen JJ, Koenen HJ, van Rijssen E, et al. Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+ CD25+ FoxP3+ T cells. Bone Marrow Transplant, 2007, 39(9): 537-545.
28.	San Segundo D, Fábrega E, López-Hoyos M, et al. Reduced numbers of blood natural regulatory T cells in stable liver transplant recipients with high levels of calcineurin inhibitors. Transplant Proc, 2007, 39(7): 2290-2292.
29.	Noris M, Casiraghi F, Todeschini M, et al. Regulatory T cells and T cell depletion: role of immunosuppressive drugs. J Am Soc Nephrol, 2007, 18(3): 1007-1018.
30.	Ruggenenti P, Perico N, Gotti E, et al. Sirolimus versus cyclosporine therapy increases circulating regulatory T cells, but does not protect renal transplant patients given alemtuzumab induction from chronic allograft injury. Transplantation, 2007, 84(8): 956-964.
31.	Qu Y, Zhang B, Zhao L, et al. The effect of immunosuppressive drug rapamycin on regulatory CD4+CD25+Foxp3+T cells in mice. Transpl Immunol, 2007, 17(3): 153-161.
32.	Korczak-Kowalska G, Wierzbicki P, Bocian K, et al. The influence of immuosuppressive therapy on the development of CD4+CD25+ T cells after renal transplantation. Transplant Proc, 2007, 39(9): 2721-2723.
33.	Kreijveld E, Koenen HJ, Hilbrands LB, et al. The immunosuppressive drug FK778 induces regulatory activity in stimulated human CD4+ CD25- T cells. Blood, 2007, 109(1): 244-252.
34.	Morales J, Bono MR, Fierro A, et al. Alemtuzumab induction in kidney transplantation: clinical results and impact on T-regulatory cells. Transplant Proc, 2008, 40(9): 3223-3228.
35.	Pascual J, Bloom D, Torrealba J, et al. Calcineurin inhibitor withdrawal after renal transplantation with alemtuzumab: clinical outcomes and effect on T-regulatory cells. Am J Transplant, 2008, 8(7): 1529-1536.
36.	Bloom DD, Chang Z, Fechner JH, et al. CD4+ CD25+ FOXP3+ regulatory T cells increase de novo in kidney transplant patients after immunodepletion with Campath-1H. Am J Transplant, 2008, 8(4): 793-802.
37.	Long SA, Buckner JH. Combination of rapamycin and IL-2 increases de novo induction of human CD4(+)CD25(+)FOXP3(+) T cells. J Autoimmun, 2008, 30(4): 293-302.
38.	Liu Y, Chen Y, Liu FQ, et al. Combined treatment with triptolide and rapamycin prolongs graft survival in a mouse model of cardiac transplantation. Transpl Int, 2008, 21(5): 483-494.
39.	Yi H, Zhen Y, Zeng C, et al. Depleting anti-CD4 monoclonal antibody (GK1.5) treatment: influence on regulatory CD4+CD25+Foxp3+ T cells in mice. Transplantation, 2008, 85(8): 1167-1174.
40.	Meng L, Wu Z, Wang Y, et al. Differential impact of CD154 costimulation blockade on alloreactive effector and regulatory T cells in murine renal transplant recipients. Transplantation, 2008, 85(9): 1332-1338.
41.	Liu Z, Fang Y, Wang X, et al. Upregulation of molecules associated with T-regulatory function by thymoglobulin pretreatment of human CD4+ cells. Transplantation, 2008, 86(10): 1419-1426.
42.	Bluestone JA, Liu W, Yabu JM, et al. The effect of costimulatory and interleukin 2 receptor blockade on regulatory T cells in renal transplantation. Am J Transplant, 2008, 8(10): 2086-2096.
43.	Zeiser R, Leveson-Gower DB, Zambricki EA, et al. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood, 2008, 111(1): 453-462.
44.	Wang Z, Xiao L, Shi BY, et al. Short-term anti-CD25 monoclonal antibody treatment and neogenetic CD4(+)CD25(high) regulatory T cells in kidney transplantation. Transpl Immunol, 2008, 19(1): 69-73.
45.	Hendrikx TK, Velthuis JH, Klepper M, et al. Monotherapy rapamycin allows an increase of CD4 CD25 FoxP3 T cells in renal recipients. Transpl Int, 2009, 22(9): 884-891.
46.	Calvo-Turrubiartes M, Romano-Moreno S, García-Hernández M, et al. Quantitative analysis of regulatory T cells in kidney graft recipients: a relationship with calcineurin inhibitor level. Transpl Immunol, 2009, 21(1): 43-49.
47.	Demirkiran A, Sewgobind VD, van der Weijde J, et al. Conversion from calcineurin inhibitor to mycophenolate mofetil-based immunosuppression changes the frequency and phenotype of CD4+FOXP3+ regulatory T cells. Transplantation, 2009, 87(7): 1062-1068.
48.	Levitsky J, Miller J, Wang E, et al. Immunoregulatory profiles in liver transplant recipients on different immunosuppressive agents. Hum Immunol, 2009, 70(3): 146-150.
49.	Singh AK, Horvath KA, Mohiuddin MM. Rapamycin promotes the enrichment of CD4(+)CD25(hi)FoxP3(+) T regulatory cells from na?ve CD4(+) T cells of baboon that suppress antiporcine xenogenic response in vitro. Transplant Proc, 2009, 41(1): 418-421.
50.	Javeed A, Zhang B, Qu Y, et al. The significantly enhanced frequency of functional CD4+CD25+Foxp3+ T regulatory cells in therapeutic dose aspirin-treated mice. Transpl Immunol, 2009, 20(4): 253-260.

1. Lechler RI, Sykes M, Thomson AW, et al. Organ transplantation-how much of the promise has been realized? Nat Med, 2005, 11(6): 605-613.
2. Lukes DJ, Herlenius G, Rizell M, et al. Late mortality in. 679 consecutive liver transplant recipients: the Gothenburg liver transplant experience. Transplant Proc, 2006, 38(8): 2671-2672.
3. Puig N, de la Rubia J, Remigia MJ, et al. Morbidity and transplant-related mortality of CBV and BEAM preparative regimens for patients with lymphoid malignancies undergoing autologous stem-cell transplantation. Leuk Lymphoma, 2006, 47(8): 1488-1494.
4. Sykes M. Immune tolerance: mechanisms and application in clinical transplantation. J Intern Med, 2007, 262(3): 288-310.
5. Xia G, Shah M, Luo X. Prevention of allograft rejection by amplification of Foxp3+CD4+CD25+ regulatory T cells. Transl Res, 2009, 153(2): 60-70.
6. Joffre 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(1): 88-92.
7. Meloni F, Vitulo P, Bianco AM, et al. Regulatory CD4+CD25+ T cells in the peripheral blood of lung transplant recipients: Correlation with transplant outcome. Transplantation, 2004, 77(5): 762-766.
8. Louis S, Braudeau C, Giral M, et al. Contrasting CD25hiCD4+T cells/FOXP3 patterns in chronic rejection and operational drug-free tolerance. Transplantation, 2006, 81(3): 398-407.
9. Daniel V, Naujokat C, Sadeghi M, et al. Observational support for an immunoregulatory role of CD3+CD4+CD25+IFN-gamma+ blood lymphocytes in kidney transplant recipients with good long-term graft outcome. Transpl Int, 2008, 21(7): 646-660.
10. Akl A, Jones ND, Rogers N, et al. An investigation to assess the potential of CD25highCD4+ T cells to regulate responses to donor alloantigens in clinically stable renal transplant recipients. Transpl Int, 2008, 21(1): 65-73.
11. Jia LY, Yuan BB, Wang J, et al. Methods of Systematic Review of Health Policy Researches. Chin J Evid-Based Med, 2009, 9(10): 1037-1043.
12. Gregori S, Casorati M, Amuchastegui S, et al. Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol, 2001, 167(4): 1945-1953.
13. Chiffoleau E, Bériou G, Dutartre P, et al. Role for thymic and splenic regulatory CD4+ T cells induced by donor dendritic cells in allograft tolerance by LF15-0195 treatment. J Immunol, 2002, 168(10): 5058-5069.
14. Baan CC, van der Mast BJ, Klepper M, et al. Differential effect of calcineurin inhibitors, anti-CD25 antibodies and rapamycin on the induction of FOXP3 in human T cells. Transplantation, 2005, 80(1): 110-117.
15. Demirkiran A, Kok A, Kwekkeboom J, et al. Decrease of CD4+CD25+ T cells in peripheral blood after liver transplantation: association with immunosuppression. Transplant Proc, 2005, 37(2): 1194-1196.
16. Tang W, Yang Y, Zhang F, et al. Prevention of graft-versus-host disease by a novel immunosuppressant, (5R)-5-hydroxytriptolide (LLDT-8), through expansion of regulatory T cells. Int Immunopharmacol, 2005, 5(13-14): 1904-1913.
17. Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood, 2005, 105(12): 4743-4748.
18. Wang H, Zhao L, Sun Z, et al. A potential side effect of cyclosporin A: inhibition of CD4(+)CD25(+) regulatory T cells in mice. Transplantation, 2006, 82(11): 1484-1492.
19. Li W, Carper K, Liang Y, et al. Anti-CD25 mAb administration prevents spontaneous liver transplant tolerance. Transplant Proc, 2006,38(10): 3207-3208.
20. San Segundo D, Ruiz JC, Fernández-Fresnedo G, et al. Calcineurin inhibitors affect circulating regulatory T cells in stable renal transplant recipients. Transplant Proc, 2006, 38(8): 2391-2393.
21. Coenen JJ, Koenen HJ, van Rijssen E, et al. Rapamycin, and not cyclosporin A, preserves the highly suppressive CD27+ subset of human CD4+CD25+ regulatory T cells. Blood, 2006, 107(3): 1018-1023.
22. Chavez H, Beaudreuil S, Abbed K, et al. Absence of CD4CD25 regulatory T cell expansion in renal transplanted patients treated in vivo with Belatacept mediated CD28-CD80/86 blockade. Transpl Immunol, 2007, 17(4): 243-248.
23. Ardalan MR, Maljaei H, Shoja MM, et al. Calcitriol started in the donor, expands the population of CD4+CD25+ T cells in renal transplant recipients. Transplant Proc, 2007, 39(4): 951-953.
24. Lim DG, Joe IY, Park YH, et al. Effect of immunosuppressants on the expansion and function of naturally occurring regulatory T cells. Transpl Immunol, 2007, 18(2): 94-100.
25. Kreijveld E, Koenen HJ, Klasen IS, et al. Following anti-CD25 treatment, a functional CD4+CD25+ regulatory T-cell pool is present in renal transplant recipients. Am J Transplant, 2007, 7(1): 249-255.
26. Kopf H, de la Rosa GM, Howard OM, et al. Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int Immunopharmacol, 2007, 7(13): 1819-1824.
27. Coenen JJ, Koenen HJ, van Rijssen E, et al. Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+ CD25+ FoxP3+ T cells. Bone Marrow Transplant, 2007, 39(9): 537-545.
28. San Segundo D, Fábrega E, López-Hoyos M, et al. Reduced numbers of blood natural regulatory T cells in stable liver transplant recipients with high levels of calcineurin inhibitors. Transplant Proc, 2007, 39(7): 2290-2292.
29. Noris M, Casiraghi F, Todeschini M, et al. Regulatory T cells and T cell depletion: role of immunosuppressive drugs. J Am Soc Nephrol, 2007, 18(3): 1007-1018.
30. Ruggenenti P, Perico N, Gotti E, et al. Sirolimus versus cyclosporine therapy increases circulating regulatory T cells, but does not protect renal transplant patients given alemtuzumab induction from chronic allograft injury. Transplantation, 2007, 84(8): 956-964.
31. Qu Y, Zhang B, Zhao L, et al. The effect of immunosuppressive drug rapamycin on regulatory CD4+CD25+Foxp3+T cells in mice. Transpl Immunol, 2007, 17(3): 153-161.
32. Korczak-Kowalska G, Wierzbicki P, Bocian K, et al. The influence of immuosuppressive therapy on the development of CD4+CD25+ T cells after renal transplantation. Transplant Proc, 2007, 39(9): 2721-2723.
33. Kreijveld E, Koenen HJ, Hilbrands LB, et al. The immunosuppressive drug FK778 induces regulatory activity in stimulated human CD4+ CD25- T cells. Blood, 2007, 109(1): 244-252.
34. Morales J, Bono MR, Fierro A, et al. Alemtuzumab induction in kidney transplantation: clinical results and impact on T-regulatory cells. Transplant Proc, 2008, 40(9): 3223-3228.
35. Pascual J, Bloom D, Torrealba J, et al. Calcineurin inhibitor withdrawal after renal transplantation with alemtuzumab: clinical outcomes and effect on T-regulatory cells. Am J Transplant, 2008, 8(7): 1529-1536.
36. Bloom DD, Chang Z, Fechner JH, et al. CD4+ CD25+ FOXP3+ regulatory T cells increase de novo in kidney transplant patients after immunodepletion with Campath-1H. Am J Transplant, 2008, 8(4): 793-802.
37. Long SA, Buckner JH. Combination of rapamycin and IL-2 increases de novo induction of human CD4(+)CD25(+)FOXP3(+) T cells. J Autoimmun, 2008, 30(4): 293-302.
38. Liu Y, Chen Y, Liu FQ, et al. Combined treatment with triptolide and rapamycin prolongs graft survival in a mouse model of cardiac transplantation. Transpl Int, 2008, 21(5): 483-494.
39. Yi H, Zhen Y, Zeng C, et al. Depleting anti-CD4 monoclonal antibody (GK1.5) treatment: influence on regulatory CD4+CD25+Foxp3+ T cells in mice. Transplantation, 2008, 85(8): 1167-1174.
40. Meng L, Wu Z, Wang Y, et al. Differential impact of CD154 costimulation blockade on alloreactive effector and regulatory T cells in murine renal transplant recipients. Transplantation, 2008, 85(9): 1332-1338.
41. Liu Z, Fang Y, Wang X, et al. Upregulation of molecules associated with T-regulatory function by thymoglobulin pretreatment of human CD4+ cells. Transplantation, 2008, 86(10): 1419-1426.
42. Bluestone JA, Liu W, Yabu JM, et al. The effect of costimulatory and interleukin 2 receptor blockade on regulatory T cells in renal transplantation. Am J Transplant, 2008, 8(10): 2086-2096.
43. Zeiser R, Leveson-Gower DB, Zambricki EA, et al. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood, 2008, 111(1): 453-462.
44. Wang Z, Xiao L, Shi BY, et al. Short-term anti-CD25 monoclonal antibody treatment and neogenetic CD4(+)CD25(high) regulatory T cells in kidney transplantation. Transpl Immunol, 2008, 19(1): 69-73.
45. Hendrikx TK, Velthuis JH, Klepper M, et al. Monotherapy rapamycin allows an increase of CD4 CD25 FoxP3 T cells in renal recipients. Transpl Int, 2009, 22(9): 884-891.
46. Calvo-Turrubiartes M, Romano-Moreno S, García-Hernández M, et al. Quantitative analysis of regulatory T cells in kidney graft recipients: a relationship with calcineurin inhibitor level. Transpl Immunol, 2009, 21(1): 43-49.
47. Demirkiran A, Sewgobind VD, van der Weijde J, et al. Conversion from calcineurin inhibitor to mycophenolate mofetil-based immunosuppression changes the frequency and phenotype of CD4+FOXP3+ regulatory T cells. Transplantation, 2009, 87(7): 1062-1068.
48. Levitsky J, Miller J, Wang E, et al. Immunoregulatory profiles in liver transplant recipients on different immunosuppressive agents. Hum Immunol, 2009, 70(3): 146-150.
49. Singh AK, Horvath KA, Mohiuddin MM. Rapamycin promotes the enrichment of CD4(+)CD25(hi)FoxP3(+) T regulatory cells from na?ve CD4(+) T cells of baboon that suppress antiporcine xenogenic response in vitro. Transplant Proc, 2009, 41(1): 418-421.
50. Javeed A, Zhang B, Qu Y, et al. The significantly enhanced frequency of functional CD4+CD25+Foxp3+ T regulatory cells in therapeutic dose aspirin-treated mice. Transpl Immunol, 2009, 20(4): 253-260.

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Effects of Immunosuppressive Drugs on CD4+CD25+ Regulatory T Cells: A Systematic Review of Clinical and Basic Research△

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