Low Dose of IL-2 Combined with Rapamycin Restores and Maintains the Long-term Balance of Th17/Treg Cells in Refractory SLE Patients

Overview

Journal BMC Immunol

Publisher Biomed Central

Specialty Allergy & Immunology

Date 2019 Sep 6

PMID 31484501

Citations 35

Authors

Chunmiao Zhao

Yanfang Chu

Zhaoyun Liang

Bingying Zhang

Xuxia Wang

Xiaona Jing

Meihua Hao

Yiqi Wang

Jia An

Xingzhe Zhang

Liguang Sun

Junwei Chen

Affiliations

Soon will be listed here.

Abstract

Background: The development of Systemic lupus erythematosus (SLE) has been associated with the balance of Th17 and Treg cells. IL-2 and rapamycin can influence the populations of both Th17 and Treg cells. However, it is unclear whether low dose of IL-2 and rapamycin can relieve the symptoms of SLE patients and what is the mechanisms. In this study, we aim to analyze the effect of low dose of IL-2 plus rapamycin on the number of Tregs, Th17 cells and the ratio of Th17/Treg cells, as well as to evaluate its therapeutic efficacy in refractory SLE patients.

Result: Fifty refractory SLE patients and 70 healthy controls were enrolled and followed up for 24 weeks. We found that compared with HC, the refractory SLE patients had a lower number of Tregs, a similar number of Th17 cells, but an increased ratio of Th17/Treg. After the treatment, the number of Tregs of the patients at 12th and 24th week was significantly increased. While the number of Th17 cells was unchanged, the ratio of Th17/Treg was significantly decreased at both 6 weeks and 24 weeks. After 6, 12 and 24 weeks of treatment, the SLEDAI score was significantly reduced. The prednison dosage at 6th,12th and 24th week post treatment was significantly decreased.

Conclusion: Our results support that the reduction of Tregs and the imbalance of Th17/Treg cells were correlated with the occurrence and development of refractory SLE. Low dose of IL-2 combined with rapamycin was able to restore the number of Tregs and the balance of Th17/Treg cells. As a result, this approach was able to induce immune tolerance and promote disease remission, allowing for the reduction in prednisone dosage.

Trial Registration: ChiCTR-IPR-16009451 Registration date: 2016/10/16.

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References

Bombardier C, Gladman D, Urowitz M, Caron D, Chang C . Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 1992; 35(6):630-40. DOI: 10.1002/art.1780350606. View

Podolskaya A, Stadermann M, Pilkington C, Marks S, Tullus K . B cell depletion therapy for 19 patients with refractory systemic lupus erythematosus. Arch Dis Child. 2007; 93(5):401-6. DOI: 10.1136/adc.2007.126276. View

Basu S, Golovina T, Mikheeva T, June C, Riley J . Cutting edge: Foxp3-mediated induction of pim 2 allows human T regulatory cells to preferentially expand in rapamycin. J Immunol. 2008; 180(9):5794-8. PMC: 2504517. DOI: 10.4049/jimmunol.180.9.5794. View

Reynolds J, Toescu V, Yee C, Prabu A, Situnayake D, Gordon C . Effects of rituximab on resistant SLE disease including lung involvement. Lupus. 2008; 18(1):67-73. DOI: 10.1177/0961203308094653. View

Yang J, Chu Y, Yang X, Gao D, Zhu L, Yang X . Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum. 2009; 60(5):1472-83. DOI: 10.1002/art.24499. View

Xing Q, Wang B, Su H, Cui J, Li J . Elevated Th17 cells are accompanied by FoxP3+ Treg cells decrease in patients with lupus nephritis. Rheumatol Int. 2011; 32(4):949-58. DOI: 10.1007/s00296-010-1771-0. View

Dolff S, Bijl M, Huitema M, Limburg P, Kallenberg C, Abdulahad W . Disturbed Th1, Th2, Th17 and T(reg) balance in patients with systemic lupus erythematosus. Clin Immunol. 2011; 141(2):197-204. DOI: 10.1016/j.clim.2011.08.005. View

Koreth J, Matsuoka K, Kim H, McDonough S, Bindra B, Alyea 3rd E . Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011; 365(22):2055-66. PMC: 3727432. DOI: 10.1056/NEJMoa1108188. View

Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V . Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med. 2011; 365(22):2067-77. DOI: 10.1056/NEJMoa1105143. View

10.

Kurebayashi Y, Nagai S, Ikejiri A, Ohtani M, Ichiyama K, Baba Y . PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORγ. Cell Rep. 2012; 1(4):360-73. DOI: 10.1016/j.celrep.2012.02.007. View

11.

Cheng G, Yu A, Dee M, Malek T . IL-2R signaling is essential for functional maturation of regulatory T cells during thymic development. J Immunol. 2013; 190(4):1567-75. PMC: 3563871. DOI: 10.4049/jimmunol.1201218. View

12.

Goudy K, Aydin D, Barzaghi F, Gambineri E, Vignoli M, Ciullini Mannurita S . Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immunol. 2013; 146(3):248-61. PMC: 3594590. DOI: 10.1016/j.clim.2013.01.004. View

13.

Matsuoka K, Koreth J, Kim H, Bascug G, McDonough S, Kawano Y . Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med. 2013; 5(179):179ra43. PMC: 3686517. DOI: 10.1126/scitranslmed.3005265. View

14.

Noack M, Miossec P . Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev. 2014; 13(6):668-77. DOI: 10.1016/j.autrev.2013.12.004. View

15.

Hartemann A, Bensimon G, Payan C, Jacqueminet S, Bourron O, Nicolas N . Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014; 1(4):295-305. DOI: 10.1016/S2213-8587(13)70113-X. View

16.

Mak A, Kow N . The pathology of T cells in systemic lupus erythematosus. J Immunol Res. 2014; 2014:419029. PMC: 4017881. DOI: 10.1155/2014/419029. View

17.

Castela E, Le Duff F, Butori C, Ticchioni M, Hofman P, Bahadoran P . Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol. 2014; 150(7):748-51. DOI: 10.1001/jamadermatol.2014.504. View

18.

Macintyre A, Gerriets V, Nichols A, Michalek R, Rudolph M, Deoliveira D . The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 2014; 20(1):61-72. PMC: 4079750. DOI: 10.1016/j.cmet.2014.05.004. View

19.

Kim K, Chung B, Kim B, Cho M, Yang C . The effect of mammalian target of rapamycin inhibition on T helper type 17 and regulatory T cell differentiation in vitro and in vivo in kidney transplant recipients. Immunology. 2014; 144(1):68-78. PMC: 4264911. DOI: 10.1111/imm.12351. View

20.

Szmyrka-Kaczmarek M, Kosmaczewska A, Ciszak L, Szteblich A, Wiland P . Peripheral blood Th17/Treg imbalance in patients with low-active systemic lupus erythematosus. Postepy Hig Med Dosw (Online). 2014; 68:893-8. DOI: 10.5604/17322693.1111127. View