Original Report: Transplantation
Different Immunosuppressive Combinations on T-Cell Regulation in Renal Transplant RecipientsFourtounas C.a · Dousdampanis P.a · Sakellaraki P.b · Rodi M.b · Georgakopoulos T.b · Vlachojannis J.G.a · Mouzaki A.b
Department of Internal Medicine, Divisions of aNephrology and bHematology, Medical School and University Hospital, Patras, Greece
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Article / Publication Details
Background/Aims: Recent studies indicate that regulatory T-cells (Tregs) promote transplant tolerance. We studied Treg levels in 39 stable renal transplant recipients to determine the sizes of the Treg populations and the effects of treatment regimens thereof. Methods: All patients (19 with good graft function and 20 with chronic allograft nephropathy) received induction therapy (basiliximab) and were on triple immunosuppressive regimens with calcineurin inhibitors (cyclosporine or tacrolimus), mycophenolate mofetil (MMF) or everolimus and steroids. Twenty healthy subjects served as controls. Whole blood samples were stained with anti-CD4, CD25, CD127, and FoxP3 antibodies and analyzed by flow cytometry to determine CD4+CD25highFoxP3± and CD4+ CD25highCD127–/low Treg levels. Results:All patients had significantly reduced CD4+CD25highFoxP3± but no CD4+ CD25highCD127–/low Treg levels compared to controls. Renal allograft function did not correlate with Treg levels. Statistically significant correlations between CD4+CD25highFoxp3+ Tregs and tacrolimus levels and CD4+CD25highFoxp3– Tregs and HLA-DR mismatching were detected. Patients receiving MMF had significantly higher CD4+CD25highFoxp3+ Tregs compared to patients on everolimus who were also receiving lower doses of calcineurin inhibitors. Conclusion:Overall, immunosuppression lowers CD4+CD25highFoxP3± Treg levels significantly in the periphery in renal transplant recipients. In addition, different immunosuppressive regimens have different impacts on CD4+CD25highFoxP3+ Tregs, a fact that may influence long-term allograft survival.
© 2010 S. Karger AG, Basel
- Kang SM, Tang Q, Bluestone JA: CD4+ CD25+ regulatory T cells in transplantation: progress, challenges and prospects. Am J Transplant 2007;7:1457–1463.
De Serres SA, Sayegh MH, Najafian N: Immunosuppressive drugs and Tregs: a critical evaluation! Clin J Am Soc Nephrol 2009;4:1661–1669.
- Boros P, Bromberg JS: Human FOXP3+ regulatory T cells in transplantation. Am J Transplant 2009;9:1719–1724.
- Volk HD: Predicting tolerance by counting natural regulatory T cells (CD4+CD25+ +FOXP3+)? Transpl Int 2007;20:842–844.
- Muthukumar T, Dadhania D, Ding R, Snopkowski C, Naqvi R, Lee JB, Hartono C, Li B, Sharma VK, Seshan SV, Kapur S, Hancock WW, Schwartz JE, Suthanthiran M: Messenger RNA for FOXP3 in the urine of renal allograft recipients. N Engl J Med 2005;353:2342–2351.
- Liu W, Putnam AL, Xu-yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, de St. Groth BF, Clayberger C, Soper DM, Ziegler SF, Bluestone JA: CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006;203:1701–1711.
- Vieira PL, Christensen JR, Minaee S, O’Neill EJ, Barrat FJ, Boonstra A, Barthlott T, Stockinger B, Wraith DC, O’Garra A: IL-10-secreting regulatory T cells do not express FoxP3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol 2004;172:5986–5993.
- Li Y, Koshiba T, Yoshizawa A, Yonekawa Y, Masuda K, Ito A, Ueda M, Mori T, Kawamoto H, Tanaka Y, Sakaguchi S, Minato N, Wood KJ, Tanaka K: Analyses of peripheral blood mononuclear cells in operational tolerance after pediatric living donor liver transplantation. Am J Transplant 2004;4:2118–2125.
- Bunnag S, Allanach K, Jhangri GS, Sis B, Einecke G, Mengel M, Mueller TF, Halloran PF: FOXP3 expression in human kidney transplant biopsies is associated with rejection and time post transplant but not with favorable outcomes. Am J Transplant 2008;8:1423–1433.
- Kreijveld E, Koenen HJ, Klasen IS, Hilbrands LB, Joosten I: Following anti-CD25 treatment a functional CD4+CD25+ regulatory T-cell pool is present in renal transplant recipients. Am J Transplant 2007;7:249–255.
- Segundo DS, Ruiz JC, Izquierdo M, Fernández-Fresnedo G, Gómez-Alamillo C, Merino R, Benito MJ, Cacho E, Rodrigo E, Palomar R, López-Hoyos M, Arias M: Calcineurin inhibitors but not rapamycin reduce percentages of CD4+CD25+FOXP3+ regulatory T cells in renal transplant recipients. Transplantation 2006;82:550–557.
- Noris M, Casiraghi F, Todeschini M, Cravedi P, Cugini D, Monteferrante G, Aiello S, Cassis L, Gotti E, Gaspari F, Cattaneo D, Perico N, Remuzzi G: Regulatory T cells and T cell depletion: role of immunosuppressive drugs. J Am Soc Nephrol 2007;18:1007–1018.
- Baan CC, Velthuis JH, van Gurp EA, Mol WM, Klepper M, Ijzermans JN, Weimar W: Functional CD25(bright+) alloresponsive T cells in fully immunosuppressed renal allograft patients. Clin Transplant 2007;21:63–71.
- Lopez M, Clarkson MR, Albin M, Sayegh MH, Najafian N: A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+FOXP3+ regulatory T cells. J Am Soc Nephrol 2006;17:2844–2853.
- Demirkiran A, Hendrikx TK, Baan CC, van der Laan LJ: Impact of immunosuppressive drugs on CD4+CD25+FOXP3+ regulatory T cells: does in vitro evidence translate to clinical settings? Transplantation 2008;85:783–789.
- Carroll RP, Segundo DS, Hollowood K, Marafioti T, Clark TG, Harden PN, Wood KJ: Immune phenotype predicts risk for post transplantation squamous cell carcinoma. J Am Soc Nephrol 2010;21:713–722.
- Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, Solomon M, Selby W, Alexander SI, Nanan R, Kelleher A, Fazekas de St Groth B: Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med 2006;203:1693–700.
- Louis S, Braudeau C, Giral M, Dupont A, Moizant F, Robillard N, Moreau A, Soulillou JP, Brouard S: Contrasting CD25hiCD4+cells/FOXP3 patterns in chronic rejection and operational drug-free tolerance. Transplantation 2006;81:398–407.
- Akl A, Jones ND, Rogers N, Bakr MA, Mostafa A, El Shehawy el M, Ghoneim MA, Wood KJ: An investigation to access the potential of CD25high CD4+ T cells to regulate responses to donor alloantigens in clinically stable renal transplant recipients. Transpl Int 2008;21:65–73.
- Braudeau C, Racape M, Giral M, Louis S, Moreau A, Berthelot L, Heslan M, Ashton-Chess J, Soulillou JP, Brouard S: Variation in numbers of CD4+CD25highFOXP3+ T cells with normal immunoregulatory properties in long term graft outcome. Transpl Int 2007;20:845–855.
- Sewgobind VD, Kho MM, van der Laan LJ, Hendrikx TK, van Dam T, Tilanus HW, IJzermans JN, Weimar W, Baan CC: The effect of rabbit anti-thymocyte globulin induction therapy on regulatory T cells in kidney transplant patients. Nephrol Dial Transplant 2009;24:1635–1644.
- Zeiser R, Nguyen VH, Beilhack A, Buess M, Schulz S, Baker J, Contag CH, Negrin RS: Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood 2006;108:390–399.
Game DS, Hernadez-Fuentes MP, Lechler RI: Everolimus and basiliximab permit suppression by human CD4+CD25+ cells in vitro. Am J Transplant 2005;5:545–564.
- Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L: Regulatory T cells induced by 1α,25-dihydroxyvitamin D3 and mycoplenolate mofetil treatment mediate transplantation tolerance. J Immunol 2001;167:1945–1953.
- Demirkiran A, Sewgobind VD, van der Weijde J, Kok A, Baan CC, Kwekkeboom J, Tilanus HW, Metselaar HJ, van der Laan LJ: Conversion from calcineurin inhibitor to mycophenolate mofetil-based immunosuppression changes the frequency and phenotype of CD4+FOXP3+ regulatory T cells. Transplantation 2009;87:1062–1068.
- Le NT, Chao N: Regulating regulatory T cells. Bone Marrow Transplant 2007;39:1–9.
- Jiang S, Lechler RI, He XS, Huang JF: Regulatory T cells and transplantation tolerance. Human Immunol 2006;67:765–776.
- Salama AD, Najafian N, Clarkson MR, Harmon WE, Sayegh MH: Regulatory CD25+ T cells in human kidney transplant recipients. J Am Soc Nephrol 2003;14:1643–1651.
- Sánchez-Fueyo A, Domenig CM, Mariat C, Alexopoulos S, Zheng XX, Strom TB: Influence of direct and indirect allorecognition pathways on CD4+CD25+ regulatory T-cell function in transplantation. Transpl Int 2007;20:534–541.
Article / Publication Details
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