Interleukin 21 (IL-21) regulates chronic allograft vasculopathy (CAV) in murine heart allograft rejection


Autoři: Mithun Khattar aff001;  Caitlin E. Baum aff001;  Paul Schroder aff002;  Joshua D. Breidenbach aff001;  Steven T. Haller aff003;  Wenhao Chen aff001;  Stanislaw Stepkowski aff001
Působiště autorů: Department of Medical Microbiology and Immunology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States of America aff001;  Department of Surgery, Duke University Medical Center, Durham, NC, United States of America aff002;  Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225624

Souhrn

IL-21 is the most recently discovered common gamma-chain cytokine that promotes persistent T-cell responses in chronic infections, autoimmunity and cancer. However, the therapeutic potential of inhibiting the IL-21-BATF signaling axis, particularly in transplant rejection, remains unclear. We used heart transplant models to examine the effects of IL-21 blockade in prevention of chronic cardiac allograft vasculopathy (CAV) using genetic knock-out and therapeutic approaches. Both wild-type C57BL/6 and IL-21-/- strains acutely rejected Balb/c skin grafts and once immunized with this skin graft, rejected Balb/c heart allografts in an accelerated fashion. However, when transplanted with heart grafts from the class-II major histocompatibility complex mutant, B6bm12 mice; wild-type recipients developed CAV, while IL-21-/- recipients were protected, even at day 100 post-transplant. Similarly, BATF-/- recipients, lacking the transcription factor BATF responsible for IL-21 production, did not develop CAV in B6-bm12 heart allografts. Strikingly, in a transient treatment protocol, the development of CAV in wild-type recipients of B6-bm12 hearts allografts was blocked by the administration of IL-21 receptor fusion protein (R-Fc). Thus, we demonstrate that CAV is regulated at least in part by IL-21 signaling and its blockade by genetic approaches or therapy with IL-21R-Fc prevents CAV in mice.

Klíčová slova:

B cells – Skin grafting – T cells – Transcription factors – Transplant rejection – Transplantation immunology – Cardiac transplantation


Zdroje

1. Mehra MR, Crespo-Leiro MG, Dipchand A, Ensminger SM, Hiemann NE, Kobashigawa JA, et al. International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010. J Heart Lung Transplant. 2010;29(7):717–27. doi: 10.1016/j.healun.2010.05.017 20620917.

2. Mehra MR. Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. Am J Transplant. 2006;6(6):1248–56. doi: 10.1111/j.1600-6143.2006.01314.x 16686747.

3. Jane-Wit D, Manes TD, Yi T, Qin L, Clark P, Kirkiles-Smith NC, et al. Alloantibody and complement promote T cell-mediated cardiac allograft vasculopathy through noncanonical nuclear factor-kappaB signaling in endothelial cells. Circulation. 2013;128(23):2504–16. Epub 2013/09/21. doi: 10.1161/CIRCULATIONAHA.113.002972 24045046; PubMed Central PMCID: PMC3885874.

4. Vassalli G, Gallino A, Weis M, von Scheidt W, Kappenberger L, von Segesser LK, et al. Alloimmunity and nonimmunologic risk factors in cardiac allograft vasculopathy. Eur Heart J. 2003;24(13):1180–8. Epub 2003/07/02. doi: 10.1016/s0195-668x(03)00237-9 12831811.

5. Pethig K, Heublein B, Kutschka I, Haverich A. Systemic inflammatory response in cardiac allograft vasculopathy: high-sensitive C-reactive protein is associated with progressive luminal obstruction. Circulation. 2000;102(19 Suppl 3):III233–6. Epub 2000/11/18. doi: 10.1161/01.cir.102.suppl_3.iii-233 11082393.

6. Taylor DO, Edwards LB, Boucek MM, Trulock EP, Keck BM, Hertz MI. The Registry of the International Society for Heart and Lung Transplantation: twenty-first official adult heart transplant report—2004. J Heart Lung Transplant. 2004;23(7):796–803. doi: 10.1016/j.healun.2004.05.004 15285065.

7. Tian Y, Zajac AJ. IL-21 and T Cell Differentiation: Consider the Context. Trends Immunol. 2016;37(8):557–68. doi: 10.1016/j.it.2016.06.001 27389961; PubMed Central PMCID: PMC4969098.

8. Shi X, Que R, Liu B, Li M, Cai J, Shou D, et al. Role of IL-21 signaling pathway in transplant-related biology. Transplant Rev (Orlando). 2016;30(1):27–30. doi: 10.1016/j.trre.2015.06.003 26219497.

9. Ma CS, Avery DT, Chan A, Batten M, Bustamante J, Boisson-Dupuis S, et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood. 2012;119(17):3997–4008. Epub 2012/03/10. doi: 10.1182/blood-2011-11-392985 22403255; PubMed Central PMCID: PMC3355712.

10. Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem. 2007;282(13):9358–63. Epub 2007/02/06. doi: 10.1074/jbc.C600321200 17277312.

11. Elsaesser H, Sauer K, Brooks DG. IL-21 is required to control chronic viral infection. Science. 2009;324(5934):1569–72. doi: 10.1126/science.1174182 19423777; PubMed Central PMCID: PMC2830017.

12. McGuire HM, Walters S, Vogelzang A, Lee CM, Webster KE, Sprent J, et al. Interleukin-21 is critically required in autoimmune and allogeneic responses to islet tissue in murine models. Diabetes. 2011;60(3):867–75. doi: 10.2337/db10-1157 21357471; PubMed Central PMCID: PMC3046847.

13. Kwun J, Park J, Yi JS, Farris AB, Kirk AD, Knechtle SJ. IL-21 Biased Alemtuzumab Induced Chronic Antibody-Mediated Rejection Is Reversed by LFA-1 Costimulation Blockade. Front Immunol. 2018;9:2323. Epub 2018/10/31. doi: 10.3389/fimmu.2018.02323 30374350; PubMed Central PMCID: PMC6196291.

14. Lindemann M, Korth J, Sun M, Xu S, Struve C, Werner K, et al. The Cytomegalovirus-Specific IL-21 ELISpot Correlates with Allograft Function of Kidney Transplant Recipients. Int J Mol Sci. 2018;19(12). Epub 2018/12/14. doi: 10.3390/ijms19123945 30544783; PubMed Central PMCID: PMC6320857.

15. Garrod KR, Cahalan MD. Murine skin transplantation. J Vis Exp. 2008;(11). doi: 10.3791/634 19066559; PubMed Central PMCID: PMC2582837.

16. Laschinger M, Assfalg V, Matevossian E, Friess H, Hüser N. Potential of Heterotopic Cardiac Transplantation in Mice as a Model for Elucidating Mechanisms of Graft Rejection2012 2012-02–10.

17. Corry RJ, Winn HJ, Russell PS. Primarily vascularized allografts of hearts in mice. The role of H-2D, H-2K, and non-H-2 antigens in rejection. Transplantation. 1973;16(4):343–50. doi: 10.1097/00007890-197310000-00010 4583148.

18. Schroder PM. Targeting Signal 1 of T Cell Activation to Restore Self Tolerance in Type 1 Diabetes 2013.

19. Cherkassky L, Lanning M, Lalli PN, Czerr J, Siegel H, Danziger-Isakov L, et al. Evaluation of alloreactivity in kidney transplant recipients treated with antithymocyte globulin versus IL-2 receptor blocker. Am J Transplant. 2011;11(7):1388–96. doi: 10.1111/j.1600-6143.2011.03540.x 21564525; PubMed Central PMCID: PMC3226763.

20. Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature. 2007;448(7152):480–3. Epub 2007/06/22. doi: 10.1038/nature05969 17581589.

21. McKenzie IF, Morgan GM, Sandrin MS, Michaelides MM, Melvold RW, Kohn HI. B6.C-H-2bm12. A new H-2 mutation in the I region in the mouse. J Exp Med. 1979;150(6):1323–38. doi: 10.1084/jem.150.6.1323 159937; PubMed Central PMCID: PMC2185725.

22. Fischbein MP, Yun J, Laks H, Irie Y, Oslund-Pinderski L, Fishbein MC, et al. Regulated interleukin-10 expression prevents chronic rejection of transplanted hearts. J Thorac Cardiovasc Surg. 2003;126(1):216–23. Epub 2003/07/25. doi: 10.1016/s0022-5223(03)00026-6 12878958.

23. Xin G, Schauder DM, Lainez B, Weinstein JS, Dai Z, Chen Y, et al. A Critical Role of IL-21-Induced BATF in Sustaining CD8-T-Cell-Mediated Chronic Viral Control. Cell Rep. 2015;13(6):1118–24. doi: 10.1016/j.celrep.2015.09.069 26527008; PubMed Central PMCID: PMC4859432.

24. Young DA, Hegen M, Ma HL, Whitters MJ, Albert LM, Lowe L, et al. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum. 2007;56(4):1152–63. doi: 10.1002/art.22452 17393408.

25. Thaunat O, Field AC, Dai J, Louedec L, Patey N, Bloch MF, et al. Lymphoid neogenesis in chronic rejection: evidence for a local humoral alloimmune response. Proc Natl Acad Sci U S A. 2005;102(41):14723–8. doi: 10.1073/pnas.0507223102 16192350; PubMed Central PMCID: PMC1253595.

26. Gu-Trantien C, Migliori E, Buisseret L, de Wind A, Brohee S, Garaud S, et al. CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer. JCI Insight. 2017;2(11). Epub 2017/06/02. doi: 10.1172/jci.insight.91487 28570278; PubMed Central PMCID: PMC5453706.

27. Baan CC, Balk AHMM, Dijke IE, Korevaar SS, Peeters AMA, de Kuiper RP, et al. Interleukin-21: an interleukin-2 dependent player in rejection processes. Transplantation. 2007;83:1485–92. doi: 10.1097/01.tp.0000264998.23349.54 17565322.

28. Fahey LM, Wilson EB, Elsaesser H, Fistonich CD, McGavern DB, Brooks DG. Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells. J Exp Med. 2011;208(5):987–99. Epub 2011/05/04. doi: 10.1084/jem.20101773 21536743; PubMed Central PMCID: PMC3092345.

29. Khattar M, Miyahara Y, Schroder PM, Xie A, Chen W, Stepkowski SM. Interleukin-21 is a critical regulator of CD4 and CD8 T cell survival during priming under Interleukin-2 deprivation conditions. PLoS One. 2014;9(1):e85882. doi: 10.1371/journal.pone.0085882 24416451; PubMed Central PMCID: PMC3887105.

30. Fina D, Sarra M, Caruso R, Del Vecchio Blanco G, Pallone F, MacDonald TT, et al. Interleukin 21 contributes to the mucosal T helper cell type 1 response in coeliac disease. Gut. 2008;57(7):887–92. doi: 10.1136/gut.2007.129882 17965065.

31. Sutherland AP, Joller N, Michaud M, Liu SM, Kuchroo VK, Grusby MJ. IL-21 promotes CD8+ CTL activity via the transcription factor T-bet. J Immunol. 2013;190(8):3977–84. doi: 10.4049/jimmunol.1201730 23479229.

32. Schraml BU, Hildner K, Ise W, Lee WL, Smith WA, Solomon B, et al. The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature. 2009;460(7253):405–9. doi: 10.1038/nature08114 19578362; PubMed Central PMCID: PMC2716014.

33. Ise W, Kohyama M, Schraml BU, Zhang T, Schwer B, Basu U, et al. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nat Immunol. 2011;12(6):536–43. doi: 10.1038/ni.2037 21572431; PubMed Central PMCID: PMC3117275.

34. Itoh S, Nakae S, Axtell RC, Velotta JB, Kimura N, Kajiwara N, et al. IL-17 contributes to the development of chronic rejection in a murine heart transplant model. J Clin Immunol. 2010;30(2):235–40. doi: 10.1007/s10875-009-9366-9 20130970.

35. Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018;13(1):182–92. Epub 2017/04/28. doi: 10.2215/CJN.00700117 28446536; PubMed Central PMCID: PMC5753302.

36. Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M. Diagnosis and management of antibody-mediated rejection: current status and novel approaches. Am J Transplant. 2014;14(2):255–71. Epub 2014/01/10. doi: 10.1111/ajt.12589 24401076; PubMed Central PMCID: PMC4285166.

37. Win TS, Rehakova S, Negus MC, Saeb-Parsy K, Goddard M, Conlon TM, et al. Donor CD4 T cells contribute to cardiac allograft vasculopathy by providing help for autoantibody production. Circ Heart Fail. 2009;2(4):361–9. Epub 2009/10/08. doi: 10.1161/CIRCHEARTFAILURE.108.827139 19808360.

38. Zeng Q, Ng YH, Singh T, Jiang K, Sheriff KA, Ippolito R, et al. B cells mediate chronic allograft rejection independently of antibody production. J Clin Invest. 2014;124(3):1052–6. Epub 2014/02/11. doi: 10.1172/JCI70084 24509079; PubMed Central PMCID: PMC3934170.


Článek vyšel v časopise

PLOS One


2019 Číslo 11