Top

Published in:

Open Access 01-12-2015 | Research article

Effect of induction therapy on the expression of molecular markers associated with rejection and tolerance

Authors: Eva Krepsova, Irena Tycova, Alena Sekerkova, Peter Wohlfahrt, Petra Hruba, Ilja Striz, Birgit Sawitzki, Ondrej Viklicky

Published in: BMC Nephrology | Issue 1/2015

Abstract

Background

Induction therapy can improve kidney transplantation (KTx) outcomes, but little is known about the mechanisms underlying its effects.

Methods

The mRNA levels of T cell-related genes associated with tolerance or rejection (CD247, GZMB, PRF1, FOXP3, MAN1A1, TCAIM, and TLR5) and lymphocyte subpopulations were monitored prospectively in the peripheral blood of 60 kidney transplant recipients before and 7, 14, 21, 28, 60, 90 days, 6 months, and 12 months after KTx. Patients were treated with calcineurin inhibitor-based triple immunosuppression and induction with rabbit anti-thymocyte globulin (rATG, n = 24), basiliximab (n = 17), or without induction (no-induction, n = 19). A generalized linear mixed model with gamma distribution for repeated measures, adjusted for rejection, recipient/donor age and delayed graft function, was used for statistical analysis.

Results

rATG treatment caused an intense reduction in all T cell type population and natural killer (NK) cells within 7 days, then a slow increase and repopulation was observed. This was also noticed in the expression levels of CD247, FOXP3, GZMB, and PRF1. The basiliximab group exhibited higher CD247, GZMB, FOXP3 and TCAIM mRNA levels and regulatory T cell (Treg) counts than the no-induction group. The levels of MAN1A1 and TLR5 mRNA expressions were increased, whereas TCAIM decreased in the rATG group as compared with those in the no-induction group.

Conclusion

The rATG induction therapy was associated with decreased T and NK cell-related transcript levels and with upregulation of two rejection-associated transcripts (MAN1A1 and TLR5) shortly after KTx. Basiliximab treatment was associated with increased absolute number of Treg cells, and increased level of FOXP3 and TCAIM expression.

Jardine AG, Gaston RS, Fellstrom BC, Holdaas H. Prevention of cardiovascular disease in adult recipients of kidney transplants. Lancet. 2011;378:1419–27.CrossRefPubMed

Li B, Hartono C, Ding R, Sharma VK, Ramaswamy R, Qian B, et al. Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. N Engl J Med. 2001;344:947–54.CrossRefPubMed

Simon T, Opelz G, Wiesel M, Ott RC, Susal C. Serial peripheral blood perforin and granzyme B gene expression measurements for prediction of acute rejection in kidney graft recipients. Am J Transplant. 2003;3:1121–7.CrossRefPubMed

Alvarez CM, Paris SC, Arango L, Arbelaez M, Garcia LF. Kidney transplant patients with long-term graft survival have altered expression of molecules associated with T-cell activation. Transplantation. 2004;78:1541–7.CrossRefPubMed

Sagoo P, Perucha E, Sawitzki B, Tomiuk S, Stephens DA, Miqueu P, et al. Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans. J Clin Invest. 2010;120:1848–61.CrossRefPubMedPubMedCentral

Sawitzki B, Bushell A, Steger U, Jones N, Risch K, Siepert A, et al. Identification of gene markers for the prediction of allograft rejection or permanent acceptance. Am J Transplant. 2007;7:1091–102.CrossRefPubMed

Louis S, Braudeau C, Giral M, Dupont A, Moizant F, Robillard N, et al. Contrasting CD25hiCD4 + T cells/FOXP3 patterns in chronic rejection and operational drug-free tolerance. Transplantation. 2006;81:398–407.CrossRefPubMed

Iwase H, Kobayashi T, Kodera Y, Miwa Y, Kuzuya T, Iwasaki K, et al. Clinical significance of regulatory T-cell-related gene expression in peripheral blood after renal transplantation. Transplantation. 2011;91:191–8.CrossRefPubMed

Wood KJ, Goto R. Mechanisms of rejection: current perspectives. Transplantation. 2012;93:1–10.CrossRefPubMed

10.

Baniyash M. TCR zeta-chain downregulation: curtailing an excessive inflammatory immune response. Nat Rev Immunol. 2004;4:675–87.CrossRefPubMed

11.

Bluestone JA. Mechanisms of tolerance. Immunol Rev. 2011;241:5–19.CrossRefPubMed

12.

Herscovics A. Structure and function of Class I alpha 1,2-mannosidases involved in glycoprotein synthesis and endoplasmic reticulum quality control. Biochimie. 2001;83:757–62.CrossRefPubMed

13.

Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9 Suppl 3:S1–155.

14.

Krystufkova E, Sekerkova A, Striz I, Brabcova I, Girmanova E, Viklicky O. Regulatory T cells in kidney transplant recipients: the effect of induction immunosuppression therapy. Nephrol Dial Transplant. 2012;27:2576–82.CrossRefPubMed

15.

Gurkan S, Luan Y, Dhillon N, Allam SR, Montague T, Bromberg JS, et al. Immune reconstitution following rabbit antithymocyte globulin. Am J Transplant. 2010;10:2132–41.CrossRefPubMedPubMedCentral

16.

Vondran FW, Timrott K, Tross J, Kollrich S, Schwarz A, Lehner F, et al. Impact of Basiliximab on regulatory T-cells early after kidney transplantation: down-regulation of CD25 by receptor modulation. Transpl Int. 2010;23:514–23.CrossRefPubMed

17.

Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE, et al. Banff '05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy ('CAN'). Am J Transplant. 2007;7:518–26.CrossRefPubMed

18.

Wang Z, Shi BY, Qian YY, Cai M, Wang Q. Short-term anti-CD25 monoclonal antibody administration down-regulated CD25 expression without eliminating the neogenetic functional regulatory T cells in kidney transplantation. Clin Exp Immunol. 2009;155:496–503.CrossRefPubMedPubMedCentral

19.

Abadja F, Alamartine E, Berthoux F, Mariat C, Genin C, Lambert C. Quantification of circulating regulatory T cells by flow cytometry in kidney transplant patients after basiliximab induction therapy. Transplantation. 2010;89:366–8.CrossRefPubMed

20.

Kho MM, Bouvy AP, Cadogan M, Kraaijeveld R, Baan CC, Weimar W. The effect of low and ultra-low dosages Thymoglobulin on peripheral T, B and NK cells in kidney transplant recipients. Transpl Immunol. 2012;26:186–90.CrossRefPubMed

21.

Sageshima J, Ciancio G, Guerra G, Gaynor JJ, Cova D, Zarak A, et al. Prolonged lymphocyte depletion by single-dose rabbit anti-thymocyte globulin and alemtuzumab in kidney transplantation. Transpl Immunol. 2011;25:104–11.CrossRefPubMed

22.

Vacher-Coponat H, Brunet C, Moal V, Loundou A, Bonnet E, Lyonnet L, et al. Tacrolimus/mycophenolate mofetil improved natural killer lymphocyte reconstitution one year after kidney transplant by reference to cyclosporine/azathioprine. Transplantation. 2006;82:558–66.CrossRefPubMed

23.

Hadaya K, Avila Y, Valloton L, de Rham C, Bandelier C, Ferrari-Lacraz S, et al. Natural killer cell receptor--repertoire and functions after induction therapy by polyclonal rabbit anti-thymocyte globulin in unsensitized kidney transplant recipients. Clin Immunol. 2010;137:250–60.CrossRefPubMed

24.

Sewgobind VD, Kho MM, van der Laan LJ, Hendrikx TK, van Dam T, Tilanus HW, et al. The effect of rabbit anti-thymocyte globulin induction therapy on regulatory T cells in kidney transplant patients. Nephrol Dial Transplant. 2009;24:1635–44.CrossRefPubMed

25.

Simon T, Opelz G, Weimer R, Wiesel M, Feustel A, Ott RC, et al. The effect of ATG on cytokine and cytotoxic T-lymphocyte gene expression in renal allograft recipients during the early post-transplant period. Clin Transplant. 2003;17:217–24.CrossRefPubMed

26.

Kapturczak MH, Meier-Kriesche HU, Kaplan B. Pharmacology of calcineurin antagonists. Transplant Proc. 2004;36:25S–32S.CrossRefPubMed

27.

Janas ML, Groves P, Kienzle N, Kelso A. IL-2 regulates perforin and granzyme gene expression in CD8+ T cells independently of its effects on survival and proliferation. J Immunol. 2005;175:8003–10.CrossRefPubMed

28.

Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA. IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol. 2007;178:280–90.CrossRefPubMed

29.

Murawski MR, Litherland SA, Clare-Salzler MJ, Davoodi-Semiromi A. Upregulation of Foxp3 expression in mouse and human Treg is IL-2/STAT5 dependent: implications for the NOD STAT5B mutation in diabetes pathogenesis. Ann N Y Acad Sci. 2006;1079:198–204.CrossRefPubMed

30.

Cheriyan VT, Thomas C, Balaram P. Augmentation of T-cell immune responses and signal transduction proteins in oral cancer patients: potential for IL-2-mediated immunotherapy. J Cancer Res Clin Oncol. 2011;137:1435–44.CrossRefPubMed

31.

Vogel SZ, Schlickeiser S, Jurchott K, Akyuez L, Schumann J, Appelt C, et al. TCAIM decreases T cell priming capacity of dendritic cells by inhibiting TLR-induced Ca2+ influx and IL-2 production. J Immunol. 2015;194:3136–46.CrossRefPubMed

32.

Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004;5:987–95.CrossRefPubMed

33.

Jenner J, Kerst G, Handgretinger R, Muller I. Increased alpha2,6-sialylation of surface proteins on tolerogenic, immature dendritic cells and regulatory T cells. Exp Hematol. 2006;34:1212–8.CrossRefPubMed

34.

Sawitzki B, Brunstein C, Meisel C, Schumann J, Vogt K, Appelt C, et al. Prevention of graft-versus-host disease by adoptive T regulatory therapy is associated with active repression of peripheral blood Toll-like receptor 5 mRNA expression. Biol Blood Marrow Transplant. 2014;20:173–82.CrossRefPubMed

35.

Uematsu S, Fujimoto K, Jang MH, Yang BG, Jung YJ, Nishiyama M, et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat Immunol. 2008;9:769–76.CrossRefPubMed

36.

Braudeau C, Ashton-Chess J, Giral M, Dugast E, Louis S, Pallier A, et al. Contrasted blood and intragraft toll-like receptor 4 mRNA profiles in operational tolerance versus chronic rejection in kidney transplant recipients. Transplantation. 2008;86:130–6.CrossRefPubMed

37.

Gebuhr I, Keeren K, Vogt K, Höflich C, Appelt C, Schlieer U, et al. Differential expression and function of alpha-mannosidase I in stimulated naive and memory CD4+ T cells. J Immunother. 2011;34:428–37.CrossRefPubMed

38.

Keeren K, Friedrich M, Gebuhr I, Philipp S, Sabat R, Sterry W, et al. Expression of tolerance associated gene-1, a mitochondrial protein inhibiting T cell activation, can be used to predict response to immune modulating therapies. J Immunol. 2009;183:4077–87.CrossRefPubMed

39.

Hutchinson JA, Riquelme P, Sawitzki B, Tomiuk S, Miqueu P, Zuhayra M, et al. Cutting Edge: Immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. J Immunol. 2011;187:2072–8.CrossRefPubMed

40.

Siepert A, Ahrlich S, Vogt K, Appelt C, Stanko K, Kühl A, et al. Permanent CNI treatment for prevention of renal allograft rejection in sensitized hosts can be replaced by regulatory T cells. Am J Transplant. 2012;12:2384–94.CrossRefPubMed

41.

Schumann J, Stanko K, Woertge S, Appelt C, Schumann M, Kühl AA, et al. The Mitochondrial Protein TCAIM Regulates Activation of T Cells and Thereby Promotes Tolerance Induction of Allogeneic Transplants. Am J Transplant. 2014;14:2723–35.CrossRefPubMed

42.

Bluestone JA, Liu W, Yabu JM, Laszik ZG, Putnam A, Belingheri M, et al. The effect of costimulatory and interleukin 2 receptor blockade on regulatory T cells in renal transplantation. Am J Transplant. 2008;8:2086–96.CrossRefPubMedPubMedCentral

43.

de Goer de Herve MG, Gonzales E, Hendel-Chavez H, Décline JL, Mourier O, Abbed K, et al. CD25 appears non essential for human peripheral T(reg) maintenance in vivo. PLoS One. 2010;5, e11784.CrossRef

44.

Bouvy AP, Klepper M, Kho MM, Boer K, Betjes MG, Weimar W, et al. The impact of induction therapy on the homeostasis and function of regulatory T cells in kidney transplant patients. Nephrol Dial Transplant. 2014;29:1587–97.CrossRefPubMed

Title: Effect of induction therapy on the expression of molecular markers associated with rejection and tolerance
Authors: Eva Krepsova
Irena Tycova
Alena Sekerkova
Peter Wohlfahrt
Petra Hruba
Ilja Striz
Birgit Sawitzki
Ondrej Viklicky
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: BMC Nephrology / Issue 1/2015
Electronic ISSN: 1471-2369
DOI: https://doi.org/10.1186/s12882-015-0141-2

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Effect of induction therapy on the expression of molecular markers associated with rejection and tolerance

Abstract

Background

Methods

Results

Conclusion

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2015

Plasma levels of natriuretic peptides and development of chronic kidney disease

Astragaloside IV attenuates proteinuria in streptozotocin-induced diabetic nephropathy via the inhibition of endoplasmic reticulum stress

Validation of two prediction models of undiagnosed chronic kidney disease in mixed-ancestry South Africans

The Kidney Awareness Registry and Education (KARE) study: protocol of a randomized controlled trial to enhance provider and patient engagement with chronic kidney disease

Relationship between parathyroid mass and parathyroid hormone level in hemodialysis patients with secondary hyperparathyroidism

Effect of cool vs. warm dialysate on toxin removal: rationale and study design

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page