Interleukin-6 blockade with tocilizumab increases Tregs and reduces T effector cytokines in renal graft inflammation: A randomized controlled trial

Sindhu Chandran, Joey Leung, Crystal Hu, Zoltan G Laszik, Qizhi Tang, Flavio G Vincenti, Sindhu Chandran, Joey Leung, Crystal Hu, Zoltan G Laszik, Qizhi Tang, Flavio G Vincenti

Abstract

Interleukin-6 (IL-6) is a proinflammatory cytokine and key regulator of Treg: T effector cell (Teff) balance. We hypothesized that IL-6 blockade with tocilizumab, a monoclonal antibody to IL-6R, would increase Tregs, dampen Teff function, and control graft inflammation. We conducted a randomized controlled clinical trial (2014-2018) of clinically stable kidney transplant recipients on calcineurin inhibitor, mycophenolate mofetil, and prednisone, with subclinical graft inflammation noted on surveillance biopsies during the first year posttransplant. Subjects received tocilizumab (8 mg/kg IV every 4 weeks; 6 doses; n = 16) or no treatment (controls; n = 14) on top of usual maintenance immunosuppression. Kidney biopsies pre- and post-treatment were analyzed using Banff criteria. Blood was analyzed for serum cytokines, Treg frequencies, and T cell effector molecule expression (IFN-γ, IL-17, granzyme B) post-stimulation ex vivo. Tocilizumab-treated subjects were more likely to show improved Banff ti-score (62.5% vs. 21.4%, p = .03), increased Treg frequency (7.1% ± 5.55% vs. 3.6% ± 1.7%, p = .0168), and a blunted Teff cytokine response compared to controls. Changes in Banff i- and t-scores were not significantly different. The treatment was relatively well tolerated with no patient deaths or graft loss. Blockade of IL-6 is a novel and promising treatment option to regulate the T cell alloimmune response in kidney transplant recipients. NCT02108600.

Keywords: T cell biology; clinical research / practice; cytokines / cytokine receptors; immune regulation; immunobiology; immunosuppression / immune modulation; kidney transplantation / nephrology; protocol biopsy; rejection: subclinical; translational research / science.

© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.

References

REFERENCES

    1. Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant. 2004;4(8):1289-1295.
    1. Heilman RL, Devarapalli Y, Chakkera HA, et al. Impact of subclinical inflammation on the development of interstitial fibrosis and tubular atrophy in kidney transplant recipients. Am J Transplant. 2010;10(3):563-570.
    1. Park WD, Griffin MD, Cornell LD, Cosio FG, Stegall MD. Fibrosis with inflammation at one year predicts transplant functional decline. J Am Soc Nephrol. 2010;21(11):1987-1997.
    1. Thierry A, Thervet E, Vuiblet V, et al. Long-term impact of subclinical inflammation diagnosed by protocol biopsy one year after renal transplantation. Am J Transplant. 2011;11(10):2153-2161.
    1. Lefaucheur C, Gosset C, Rabant M, et al. T cell-mediated rejection is a major determinant of inflammation in scarred areas in kidney allografts. Am J Transplant. 2018;18(2):377-390.
    1. Nankivell BJ, Shingde M, Keung KL, et al. The causes, significance and consequences of inflammatory fibrosis in kidney transplantation: The Banff i-IFTA lesion. Am J Transplant. 2018;18(2):364-376.
    1. Nankivell BJ, Agrawal N, Sharma A, et al. The clinical and pathological significance of borderline T cell-mediated rejection. Am J Transplant. 2019;19(5):1452-1463.
    1. Holsti MA, Raulet DH. IL-6 and IL-1 synergize to stimulate IL-2 production and proliferation of peripheral T cells. J Immunol. 1989;143(8):2514-2519.
    1. Lotz M, Jirik F, Kabouridis P, et al. B cell stimulating factor 2/interleukin 6 is a costimulant for human thymocytes and T lymphocytes. J Exp Med. 1988;167(3):1253-1258.
    1. Fujimoto M, Nakano M, Terabe F, et al. The influence of excessive IL-6 production in vivo on the development and function of Foxp3+ regulatory T cells. J Immunol. 2011;186(1):32-40.
    1. Haruta H, Ohguro N, Fujimoto M, et al. Blockade of interleukin-6 signaling suppresses not only th17 but also interphotoreceptor retinoid binding protein-specific Th1 by promoting regulatory T cells in experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci. 2011;52(6):3264-3271.
    1. Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010;40(7):1830-1835.
    1. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24(2):179-189.
    1. Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science. 2003;299(5609):1033-1036.
    1. Wan S, Xia C, Morel L. IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+ T cell regulatory functions. J Immunol. 2007;178(1):271-279.
    1. Lal G, Yin N, Xu J, et al. Distinct inflammatory signals have physiologically divergent effects on epigenetic regulation of Foxp3 expression and Treg function. Am J Transplant. 2011;11(2):203-214.
    1. Sharma M, Huang L, Choi J-H, et al. An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. Immunity. 2013;38(5):998-1012.
    1. Rochman I, Paul WE, Ben-Sasson SZ. IL-6 increases primed cell expansion and survival. J Immunol. 2005;174(8):4761-4767.
    1. Riella LV, Yang J, Chock S, et al. Jagged2-signaling promotes IL-6-dependent transplant rejection. Eur J Immunol. 2013;43(6):1449-1458.
    1. Zhao X, Boenisch O, Yeung M, et al. Critical role of proinflammatory cytokine IL-6 in allograft rejection and tolerance. Am J Transplant. 2012;12(1):90-101.
    1. Shen H, Goldstein DR. IL-6 and TNF-alpha synergistically inhibit allograft acceptance. J Am Soc Nephrol. 2009;20(5):1032-1040.
    1. Lei J, He F, Wu M, Zheng X, Chen X, Chen Z. Administration of anti-interleukin-6 monoclonal antibody prolongs cardiac allograft survival. Transpl Int. 2010;23(12):1271-1281.
    1. Wang H, Guan Q, Lan Z, et al. Prolonged renal allograft survival by donor interleukin-6 deficiency: association with decreased alloantibodies and increased intragraft T regulatory cells. Am J Physiol Renal Physiol. 2012;302(2):F276-283.
    1. Fogal B, Yi T, Wang C, et al. Neutralizing IL-6 reduces human arterial allograft rejection by allowing emergence of CD161+ CD4+ regulatory T cells. J Immunol. 2011;187(12):6268-6280.
    1. Casiraghi F, Ruggenenti P, Noris M, et al. Sequential monitoring of urine-soluble interleukin 2 receptor and interleukin 6 predicts acute rejection of human renal allografts before clinical or laboratory signs of renal dysfunction. Transplantation. 1997;63(10):1508-1514.
    1. Van Oers MH, Van der Heyden AA, Aarden LA. Interleukin 6 (IL-6) in serum and urine of renal transplant recipients. Clin Exp Immunol. 1988;71(2):314-319.
    1. Kirk AD, Jacobson LM, Heisey DM, Radke NF, Pirsch JD, Sollinger HW. Clinically stable human renal allografts contain histological and RNA-based findings that correlate with deteriorating graft function. Transplantation. 1999;68(10):1578-1582.
    1. Liang Y, Christopher K, Finn PW, Colson YL, Perkins DL. Graft produced interleukin-6 functions as a danger signal and promotes rejection after transplantation. Transplantation. 2007;84(6):771-777.
    1. Raasveld MH, Weening JJ, Kerst JM, Surachno S, ten Berge RJ. Local production of interleukin-6 during acute rejection in human renal allografts. Nephrol Dial Transplant. 1993;8(1):75-78.
    1. Sadeghi M, Daniel V, Wiesel M, Hergesell O, Opelz G. High urine sIL-6R as a predictor of late graft failure in renal transplant recipients. Transplantation. 2003;76(8):1190-1194.
    1. Kocierz M, Siekiera U, Kolonko A, et al. 174G/C interleukin-6 gene polymorphism and the risk of transplanted kidney failure or graft loss during a 5-year follow-up period. Tissue Antigens. 2011;77(4):283-290.
    1. Mihara M, Kasutani K, Okazaki M, et al. Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. Int Immunopharmacol. 2005;5(12):1731-1740.
    1. Genovese MC, Rubbert-Roth A, Smolen JS, et al. Longterm safety and efficacy of tocilizumab in patients with rheumatoid arthritis: a cumulative analysis of up to 4.6 years of exposure. J Rheumatol. 2013;40(6):768-780.
    1. Schiff MH, Kremer JM, Jahreis A, Vernon E, Isaacs JD, van Vollenhoven RF. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther. 2011;13(5):R141.
    1. Pesce B, Soto L, Sabugo F, et al. Effect of interleukin-6 receptor blockade on the balance between regulatory T cells and T helper type 17 cells in rheumatoid arthritis patients. Clin Exp Immunol. 2013;171(3):237-242.
    1. Samson M, Audia S, Janikashvili N, et al. Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum. 2012;64(8):2499-2503.
    1. Vo AA, Choi J, Kim I, et al. A phase I/II trial of the interleukin-6 receptor-specific humanized monoclonal (tocilizumab) + intravenous immunoglobulin in difficult to desensitize patients. Transplantation. 2015;99(11):2356-2363.
    1. Choi J, Aubert O, Vo A, et al. Assessment of tocilizumab (anti-interleukin-6 receptor monoclonal) as a potential treatment for chronic antibody-mediated rejection and transplant glomerulopathy in HLA-sensitized renal allograft recipients. Am J Transplant. 2017;17(9):2381-2389.
    1. Shin BH, Everly MJ, Zhang H, et al. Impact of tocilizumab (anti-IL-6R) treatment on immunoglobulins and anti-HLA antibodies in kidney transplant patients with chronic antibody-mediated rejection. Transplantation. 2020;104(4):856-863.
    1. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461-470.
    1. Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008;8(4):753-760.
    1. Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112(10):3959-3964.
    1. Furst DE, Keystone EC, So AK, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2012. Ann Rheum Dis. 2013;72(Suppl 2):ii2-34.
    1. Keystone EC, Anisfeld A, Ogale S, Devenport JN, Curtis JR. Continued benefit of tocilizumab plus disease-modifying antirheumatic drug therapy in patients with rheumatoid arthritis and inadequate clinical responses by week 8 of treatment. J Rheumatol. 2014;41(2):216-226.

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