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Inflammation Research
Published in: Inflammation Research 1/2012

01-01-2012 | Original Research Paper

The effects of leflunomide on CD4+CD25+Foxp3+ T regulatory cells in mice receiving allogeneic bone marrow transplantation

Authors: Di Jin, Kaizhong Duan, Lianjun Zhang, Jianxia Peng, Yong Zhao

Published in: Inflammation Research | Issue 1/2012

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Abstract

Objective and design

Leflunomide (LEF) is effective not only in different animal models of autoimmune diseases and the therapy of patients with rheumatoid arthritisbut also in graft rejection. The effect of LEF on CD4+CD25+T regulatory cells (Treg) was determined in a mouse model of allogeneic bone marrow transplantation.

Material or subjects

BALB/c and C57BL/6 mice were used as donors and recipients, respectively.

Treatment

C57BL/6 mice were given 2 Gy total-body irradiation, followed by an intravenous injection of 2 × 107 BALB/c bone marrow cells (BMCs). Mice were treated with LEF daily at a dose of 30 mg/kg/day for 2 weeks.

Results

In naïve mice, LEF significantly decreased the percentage of CD4+CD25+ Treg cells in spleens (P < 0.05), but not in lymph nodes, though LEF enhanced the percentages of CD4+CD25+ Treg cells in CD4 single positive cells in the thymocytes and blood (P < 0.05). Furthermore, LEF significantly decreased the percentage of CD4+CD25+ Treg cells in the spleens of mice that received allogeneic BMCs.

Conclusions

LEF decreases peripheral CD4+CD25+ Treg cells in un-immunizing and immunizing recipients, indicating that LEF might not be an ideal candidate for the treatment of autoimmune diseases or graft rejection with respect to induction of immune tolerance.
Literature
1.
Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6:345–52.PubMedCrossRef
2.
Billiard F, Litvinova E, Saadoun D, Djelti F, Klatzmann D, Cohen JL, Marodon G, Salomon BL. Regulatory and effector T cell activation levels are prime determinants of in vivo immune regulation. J Immunol. 2006;177:2167–74.PubMed
3.
Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S, Nochy D, Debre P, Piette JC, Gorochov G. Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol. 2005;175:8392–400.PubMed
4.
5.
Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes. 2005;54:92–9.PubMedCrossRef
6.
Gartner D, Hoff H, Gimsa U, Burmester GR, Brunner-Weinzierl MC. CD25 regulatory T cells determine secondary but not primary remission in EAE: impact on long-term disease progression. J Neuroimmunol. 2006;172:73–84.PubMedCrossRef
7.
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330–6.PubMedCrossRef
8.
Sakaguchi S. The origin of FOXP3-expressing CD4+ regulatory T cells: thymus or periphery. J Clin Invest. 2003;112:1310–2.PubMed
9.
Zhang L, Yi H, Xia XP, Zhao Y. Transforming growth factor-beta: an important role in CD4+CD25+ regulatory T cells and immune tolerance. Autoimmunity. 2006;39:269–76.PubMedCrossRef
10.
Campbell DJ, Ziegler SF. FOXP3 modifies the phenotypic and functional properties of regulatory T cells. Nat Rev Immunol. 2007;7:305–10.PubMedCrossRef
11.
Ikehara S. Bone marrow transplantation: a new strategy for intractable diseases. Drugs Today (Barc). 2002;38:103–11.CrossRef
12.
Nakagawa T, Nagata N, Hosaka N, Ogawa R, Nakamura K, Ikehara S. Prevention of autoimmune inflammatory polyarthritis in male New Zealand black/KN mice by transplantation of bone marrow cells plus bone (stromal cells). Arthritis Rheum. 1993;36:263–8.PubMed
13.
Rezvani K, Mielke S, Ahmadzadeh M, Kilical Y, Savani BN, Zeilah J, Keyvanfar K, Montero A, Hensel N, Kurlander R, Barrett AJ. High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood. 2006;108:1291–7.PubMedCrossRef
14.
Strauss L, Czystowska M, Szajnik M, Mandapathil M, Whiteside TL. Differential responses of human regulatory T cells (Treg) and effector T cells to rapamycin. PLoS One. 2009;4:e5994.PubMedCrossRef
15.
Schattenkirchner M. The use of leflunomide in the treatment of rheumatoid arthritis: an experimental and clinical review. Immunopharmacology. 2000;47:291–8.PubMedCrossRef
16.
Johansen A, Jensen JE, Horn HC, Nielsen B, Kemp E. Effect of leflunomide and cyclosporine on graft survival and changes in lymphocyte phenotypes in a rat heart allotransplantation model. Transpl Immunol. 1998;6:48–52.PubMedCrossRef
17.
He C, Lu X, Yan Z, Wu M, Liu S, Yu Y, Luo P (2010) Therapeutic effect of leflunomide on the development of experimental lupus nephritis in mice. Rheumatol Int [Epub ahead of print] doi:10.​1007/​s00296-010-1630-z
18.
Snydman DR. Leflunomide: a small step forward in meeting the urgent need for treatment of drug-resistant cytomegalovirus infection. Transplantation. 2010;90:362–3.PubMedCrossRef
19.
Orden AO, Chuluyan JC, Colombini AC, Barbera RF (2011) Leflunomide use in a cytomegalovirus infection of a patient with dermatomyositis. Rheumatol Int [Epub ahead of print] doi:10.​1007/​s00296-010-1786-6
20.
Avery RK, Mossad SB, Poggio E, Lard M, Budev M, Bolwell B, Waldman WJ, Braun W, Mawhorter SD, Fatica R, Krishnamurthi V, Young JB, Shrestha R, Stephany B, Lurain N, Yen-Lieberman B. Utility of leflunomide in the treatment of complex cytomegalovirus syndromes. Transplantation. 2010;90:419–26.PubMedCrossRef
21.
Liacini A, Seamone ME, Muruve DA, Tibbles LA. Anti-BK virus mechanisms of sirolimus and leflunomide alone and in combination: toward a new therapy for BK virus infection. Transplantation. 2010;90:1450–7.PubMedCrossRef
22.
Hail N Jr, Chen P, Bushman LR. Teriflunomide (leflunomide) promotes cytostatic, antioxidant, and apoptotic effects in transformed prostate epithelial cells: evidence supporting a role for teriflunomide in prostate cancer chemoprevention. Neoplasia. 2010;12:464–75.PubMed
23.
Xu X, Williams JW, Bremer EG, Finnegan A, Chong AS. Inhibition of protein tyrosine phosphorylation in T cells by a novel immunosuppressive agent, leflunomide. J Biol Chem. 1995;270:12398–403.PubMedCrossRef
24.
Williamson RA, Yea CM, Robson PA, Curnock AP, Gadher S, Hambleton AB, Woodward K, Bruneau JM, Hambleton P, Moss D, Thomson TA, Spinella-Jaegle S, Morand P, Courtin O, Sautes C, Westwood R, Hercend T, Kuo EA, Ruuth E. Dihydroorotate dehydrogenase is a high affinity binding protein for A77 1726 and mediator of a range of biological effects of the immunomodulatory compound. J Biol Chem. 1995;270:22467–72.PubMedCrossRef
25.
Kutluana U, Oruc N, Nart D, Kaptanoglu B, Yonetci N, Ozutemiz O. Leflunomide: is a new oral agent in treatment of acute pancreatitis? Pancreas. 2010;39:237–42.PubMedCrossRef
26.
Sun Z, Zhao L, Wang H, Sun L, Yi H, Zhao Y. Presence of functional mouse regulatory CD4+CD25+ T cells in xenogeneic neonatal porcine thymus-grafted athymic mice. Am J Transplant. 2006;6:2841–50.PubMedCrossRef
27.
Li XC, Rothstein DM, Sayegh MH. Costimulatory pathways in transplantation: challenges and new developments. Immunol Rev. 2009;229:271–93.PubMedCrossRef
28.
Giorgini A, Noble A. Blockade of chronic graft-versus-host disease by alloantigen-induced CD4+CD25+Foxp3+ regulatory T cells in nonlymphopenic hosts. J Leukoc Biol. 2007;82:1053–61.PubMedCrossRef
29.
Velasquez-Lopera MM, Eaton VL, Lerret NM, Correa LA, Decresce RP, Garcia LF, Jaramillo A. Induction of transplantation tolerance by allogeneic donor-derived CD4(+)CD25(+)Foxp3(+) regulatory T cells. Transpl Immunol. 2008;19:127–35.PubMedCrossRef
30.
Edinger M. Regulatory T cells for the prevention of graft-versus-host disease: professionals defeat amateurs. Eur J Immunol. 2009;39:2966–8.PubMedCrossRef
31.
Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, Del Papa B, Zei T, Ostini RI, Cecchini D, Aloisi T, Perruccio K, Ruggeri L, Balucani C, Pierini A, Sportoletti P, Aristei C, Falini B, Reisner Y, Velardi A, Aversa F, Martelli MF. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117:3921–8.PubMedCrossRef
32.
Bocian K, Borysowski J, Wierzbicki P, Wyzgal J, Klosowska D, Bialoszewska A, Paczek L, Gorski A, Korczak-Kowalska G. Rapamycin, unlike cyclosporine A, enhances suppressive functions of in vitro-induced CD4+CD25+ Tregs. Nephrol Dial Transpl. 2010;25:710–7.CrossRef
33.
Francis RS, Feng G, Tha-In T, Lyons IS, Wood KJ, Bushell A. Induction of transplantation tolerance converts potential effector T cells into graft-protective regulatory T cells. Eur J Immunol. 2011;41:726–38.PubMedCrossRef
34.
Semple K, Yu Y, Wang D, Anasetti C, Yu XZ. Efficient and selective prevention of GVHD by antigen-specific induced Tregs via linked-suppression in mice. Biol Blood Marrow Transpl. 2011;17:309–18.CrossRef
35.
Kinsey GR, Sharma R, Huang L, Li L, Vergis AL, Ye H, Ju ST, Okusa MD. Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury. J Am Soc Nephrol. 2009;20:1744–53.PubMedCrossRef
36.
Zhao Y. The different effects of cyclosporin A and rapamycin on regulatory CD4+CD25+ T cells: potential relationship with transplant tolerance induction. Expert Rev Clin Immunol. 2007;3:245–9.PubMedCrossRef
37.
Friedman J, Weissman I. Two cytoplasmic candidates for immunophilin action are revealed by affinity for a new cyclophilin: one in the presence and one in the absence of CsA. Cell. 1991;66:799–806.PubMedCrossRef
38.
Tajima K, Amakawa R, Ito T, Miyaji M, Takebayashi M, Fukuhara S. Immunomodulatory effects of cyclosporin A on human peripheral blood dendritic cell subsets. Immunology. 2003;108:321–8.PubMedCrossRef
39.
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;108:390–9.PubMedCrossRef
40.
Vincenti F, Jensik SC, Filo RS, Miller J, Pirsch J. A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years. Transplantation. 2002;73:775–82.PubMedCrossRef
41.
Wang H, Zhao L, Sun Z, Sun L, Zhang B, Zhao Y. A potential side effect of cyclosporin A: inhibition of CD4(+)CD25(+) regulatory T cells in mice. Transplantation. 2006;82:1484–92.PubMedCrossRef
42.
Antin JH, Kim HT, Cutler C, Ho VT, Lee SJ, Miklos DB, Hochberg EP, Wu CJ, Alyea EP, Soiffer RJ. Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation. Blood. 2003;102:1601–5.PubMedCrossRef
43.
Busca A, Locatelli F, Moscato D, Falda M. Sirolimus-related toxicity in stem cell transplantation. Biol Blood Marrow Transpl. 2005;11:647–9.CrossRef
44.
Breslin EM, White PC, Shore AM, Clement M, Brennan P. LY294002 and rapamycin co-operate to inhibit T-cell proliferation. Br J Pharmacol. 2005;144:791–800.PubMedCrossRef
45.
Qu Y, Zhang B, Zhao L, Liu G, Ma H, Rao E, Zeng C, Zhao Y. The effect of immunosuppressive drug rapamycin on regulatory CD4+CD25+Foxp3+ T cells in mice. Transpl Immunol. 2007;17:153–61.PubMedCrossRef
46.
Wang TY, Li J, Li CY, Jin Y, Lu XW, Wang XH, Zhou Q. Leflunomide induces immunosuppression in collagen-induced arthritis rats by upregulating CD4+CD25+ regulatory T cells. Can J Physiol Pharmacol. 2010;88:45–53.PubMedCrossRef
47.
Weigmann B, Jarman ER, Sudowe S, Bros M, Knop J, Reske-Kunz AB. Induction of regulatory T cells by leflunomide in a murine model of contact allergen sensitivity. J Invest Dermatol. 2006;126:1524–33.PubMedCrossRef
48.
Mrowka C, Thoenes GH, Langer KH, Bartlett RR. Prevention of the acute graft-versus-host disease (GVHD) in rats by the immunomodulating drug leflunomide. Ann Hematol. 1994;68:195–9.PubMedCrossRef
Metadata
Title
The effects of leflunomide on CD4+CD25+Foxp3+ T regulatory cells in mice receiving allogeneic bone marrow transplantation
Authors
Di Jin
Kaizhong Duan
Lianjun Zhang
Jianxia Peng
Yong Zhao
Publication date
01-01-2012
Publisher
SP Birkhäuser Verlag Basel
Published in
Inflammation Research / Issue 1/2012
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-011-0388-4

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