#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Autoantibody production significantly decreased with APRIL/BLyS blockade in murine chronic rejection kidney transplant model


Autoři: Natalie M. Bath aff001;  Xiang Ding aff001;  Bret M. Verhoven aff001;  Nancy A. Wilson aff002;  Lauren Coons aff001;  Adarsh Sukhwal aff001;  Weixiong Zhong aff003;  Robert R. Redfield III aff001
Působiště autorů: Department of Surgery, Division of Transplant, University of Wisconsin-Madison, Madison, Wisconsin, United States of America aff001;  Department of Medicine, Division of Nephrology, University of Wisconsin-Madison, Madison, Wisconsin, Unites States of America aff002;  Department of Pathology, University of Wisconsin–Madison, Madison, Wisconsin, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0223889

Souhrn

Chronic antibody mediated rejection (cAMR) remains a significant barrier to achieving long-term graft survival in kidney transplantation, which results from alloantibody production from B lymphocytes and plasma cells. APRIL (A proliferation-inducing ligand) and BLyS (B lymphocyte stimulator) are critical survival factors for B lymphocytes and plasma cells. Here we describe the results of APRIL/BLyS blockade in a murine cAMR kidney transplant model. c57/B6 mice underwent kidney transplantation with Bm12 kidneys (minor MHC mismatch), a well-described model for chronic rejection where animals cannot make donor specific antibody but rather make antinuclear antibody (ANA). Following transplantation, animals received TACI-Ig (to block APRIL and BLyS) or no treatment. Animals were continued on treatment until harvest 4 weeks following transplant. Serum was analyzed for circulating anti-nuclear autoantibodies using HEp-2 indirect immunofluorescence. Spleen and transplanted kidneys were analyzed via H&E. ANA production was significantly decreased in APRIL/BLyS blockade treated animals (p<0.0001). No significant difference in autoantibody production was found between syngeneic transplant control (B6 to B6) and APRIL/BLyS blockade treated animals (p = 0.90). Additionally, disruption of splenic germinal center architecture was noted in the APRIL/BLyS blockade treated animals. Despite the significant decrease in autoantibody production and germinal center disruption, no significant difference in lymphocyte infiltration was noted in the transplanted kidney. APRIL/BLyS blockade resulted in a significant decrease of autoantibody production and disrupted splenic germinal center formation in a chronic kidney transplant model, however in this model no difference in kidney transplant pathology was seen, which may have to do with the absence of any T cell centric immunosuppression. Regardless, these findings suggest that APRIL/BLyS blockade may play a role in decreasing antibody formation long-term in kidney transplantation. Future investigations will use APRIL/BLyS blockade in conjunction with T lymphocyte depleting agents to determine its efficacy in chronic rejection.

Klíčová slova:

B cells – Kidneys – Lymphocytes – Renal transplantation – T cells – Transplant rejection – Plasma cells


Zdroje

1. Senev A, Coemans M, Lerut E, Van Sandt V, Daniels L, Kuypers D, et al. Histological picture of antibody-mediated rejection without donor-specific anti-HLA antibodies: Clinical presentation and implications for outcome. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2019;19(3):763–80.

2. El-Zoghby ZM, Stegall MD, Lager DJ, Kremers WK, Amer H, Gloor JM, et al. Identifying specific causes of kidney allograft loss. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009;9(3):527–35.

3. Orandi BJ, Chow EH, Hsu A, Gupta N, Van Arendonk KJ, Garonzik-Wang JM, et al. Quantifying renal allograft loss following early antibody-mediated rejection. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2015;15(2):489–98.

4. Clatworthy MR. Targeting B cells and antibody in transplantation. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2011;11(7):1359–67.

5. Lund FE, Randall TD. Effector and regulatory B cells: modulators of CD4+ T cell immunity. Nature reviews Immunology. 2010;10(4):236–47. doi: 10.1038/nri2729 20224569

6. Vo AA, Lukovsky M, Toyoda M, Wang J, Reinsmoen NL, Lai CH, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. The New England journal of medicine. 2008;359(3):242–51. doi: 10.1056/NEJMoa0707894 18635429

7. Woodle ES, Shields AR, Ejaz NS, Sadaka B, Girnita A, Walsh RC, et al. Prospective iterative trial of proteasome inhibitor-based desensitization. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2015;15(1):101–18.

8. O'Connell PJ, Kuypers DR, Mannon RB, Abecassis M, Chadban SJ, Gill JS, et al. Clinical Trials for Immunosuppression in Transplantation: The Case for Reform and Change in Direction. Transplantation. 2017;101(7):1527–34. doi: 10.1097/TP.0000000000001648 28207630

9. O'Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. The Journal of experimental medicine. 2004;199(1):91–8. doi: 10.1084/jem.20031330 14707116

10. Benson MJ, Dillon SR, Castigli E, Geha RS, Xu S, Lam KP, et al. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J Immunol. 2008;180(6):3655–9. doi: 10.4049/jimmunol.180.6.3655 18322170

11. Parsons RF, Vivek K, Redfield RR 3rd, Migone TS, Cancro MP, Naji A, et al. B-lymphocyte homeostasis and BLyS-directed immunotherapy in transplantation. Transplantation reviews (Orlando, Fla). 2010;24(4):207–21.

12. Treml JF, Hao Y, Stadanlick JE, Cancro MP. The BLyS family: toward a molecular understanding of B cell homeostasis. Cell biochemistry and biophysics. 2009;53(1):1–16. doi: 10.1007/s12013-008-9036-1 19034695

13. Banham GD, Flint SM, Torpey N, Lyons PA, Shanahan DN, Gibson A, et al. Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial. Lancet (London, England). 2018;391(10140):2619–30.

14. Cho S-F, Anderson KC, Tai Y-T. Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy. Front Immunol. 2018;9:1821-. doi: 10.3389/fimmu.2018.01821 30147690

15. Tai YT, Anderson KC. Targeting B-cell maturation antigen in multiple myeloma. Immunotherapy. 2015;7(11):1187–99. doi: 10.2217/imt.15.77 26370838

16. Wilson NA, Bath NM, Verhoven BM, Ding X, Boldt BA, Sukhwal A, et al. APRIL/BLyS blockade reduces donor specific antibodies in allosensitized mice. Transplantation. 2019.

17. Ali JM, Negus MC, Conlon TM, Harper IG, Qureshi MS, Motallebzadeh R, et al. Diversity of the CD4 T Cell Alloresponse: The Short and the Long of It. Cell reports. 2016;14(5):1232–45. doi: 10.1016/j.celrep.2015.12.099 26804905

18. Callaghan CJ, Win TS, Motallebzadeh R, Conlon TM, Chhabra M, Harper I, et al. Regulation of allograft survival by inhibitory FcgammaRIIb signaling. J Immunol. 2012;189(12):5694–702. doi: 10.4049/jimmunol.1202084 23150718

19. Shimizu K, Libby P, Rocha VZ, Folco EJ, Shubiki R, Grabie N, et al. Loss of myeloid related protein-8/14 exacerbates cardiac allograft rejection. Circulation. 2011;124(25):2920–32. doi: 10.1161/CIRCULATIONAHA.110.009910 22144572

20. Plenter R, Jain S, Ruller CM, Nydam TL, Jani AH. Murine Kidney Transplant Technique. Journal of visualized experiments: JoVE. 2015(105):e52848. doi: 10.3791/52848 26555373

21. Allman D, Pillai S. Peripheral B cell subsets. Current opinion in immunology. 2008;20(2):149–57. doi: 10.1016/j.coi.2008.03.014 18434123

22. Gross JA, Dillon SR, Mudri S, Johnston J, Littau A, Roque R, et al. TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. impaired B cell maturation in mice lacking BLyS. Immunity. 2001;15(2):289–302. doi: 10.1016/s1074-7613(01)00183-2 11520463

23. Haas M, Sis B, Racusen LC, Solez K, Glotz D, Colvin RB, et al. Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2014;14(2):272–83.

24. Kwok C, Pavlosky A, Lian D, Jiang J, Huang X, Yin Z, et al. Necroptosis Is Involved in CD4+ T Cell-Mediated Microvascular Endothelial Cell Death and Chronic Cardiac Allograft Rejection. Transplantation. 2017;101(9):2026–37. doi: 10.1097/TP.0000000000001578 29633982

25. 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. Circulation Heart failure. 2009;2(4):361–9. doi: 10.1161/CIRCHEARTFAILURE.108.827139 19808360

26. Bath NM, Ding X, Wilson NA, Verhoven BM, Boldt BA, Sukhwal A, et al. Desensitization and treatment with APRIL/BLyS blockade in rodent kidney transplant model. PloS one. 2019;14(2):e0211865. doi: 10.1371/journal.pone.0211865 30735519

27. Schiechl G, Brunner SM, Kesselring R, Martin M, Ruemmele P, Mack M, et al. Inhibition of innate co-receptor TREM-1 signaling reduces CD4(+) T cell activation and prolongs cardiac allograft survival. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2013;13(5):1168–80.

28. Ardehali A, Fischbein MP, Yun J, Irie Y, Fishbein MC, Laks H. Indirect alloreactivity and chronic rejection. Transplantation. 2002;73(11):1805–7. doi: 10.1097/00007890-200206150-00018 12085005

29. Nagano H, Mitchell RN, Taylor MK, Hasegawa S, Tilney NL, Libby P. Interferon-gamma deficiency prevents coronary arteriosclerosis but not myocardial rejection in transplanted mouse hearts. The Journal of clinical investigation. 1997;100(3):550–7. doi: 10.1172/JCI119564 9239401

30. DiLillo DJ, Matsushita T, Tedder TF. B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer. Annals of the New York Academy of Sciences. 2010;1183:38–57. doi: 10.1111/j.1749-6632.2009.05137.x 20146707

31. Samy E, Wax S, Huard B, Hess H, Schneider P. Targeting BAFF and APRIL in systemic lupus erythematosus and other antibody-associated diseases. International reviews of immunology. 2017;36(1):3–19. doi: 10.1080/08830185.2016.1276903 28215100

32. Salazar-Camarena DC, Ortiz-Lazareno PC, Cruz A, Oregon-Romero E, Machado-Contreras JR, Munoz-Valle JF, et al. Association of BAFF, APRIL serum levels, BAFF-R, TACI and BCMA expression on peripheral B-cell subsets with clinical manifestations in systemic lupus erythematosus. Lupus. 2016;25(6):582–92. doi: 10.1177/0961203315608254 26424128

33. Koyama T, Tsukamoto H, Miyagi Y, Himeji D, Otsuka J, Miyagawa H, et al. Raised serum APRIL levels in patients with systemic lupus erythematosus. Annals of the rheumatic diseases. 2005;64(7):1065–7. doi: 10.1136/ard.2004.022491 15576416

34. Xin G, Shi W, Xu LX, Su Y, Yan LJ, Li KS. Serum BAFF is elevated in patients with IgA nephropathy and associated with clinical and histopathological features. Journal of nephrology. 2013;26(4):683–90. doi: 10.5301/jn.5000218 23042433

35. Cheema GS, Roschke V, Hilbert DM, Stohl W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis and rheumatism. 2001;44(6):1313–9. doi: 10.1002/1529-0131(200106)44:6<1313::AID-ART223>3.0.CO;2-S 11407690

36. Ramanujam M, Wang X, Huang W, Liu Z, Schiffer L, Tao H, et al. Similarities and differences between selective and nonselective BAFF blockade in murine SLE. The Journal of clinical investigation. 2006;116(3):724–34. doi: 10.1172/JCI26385 16485042

37. Haselmayer P, Vigolo M, Nys J, Schneider P, Hess H. A mouse model of systemic lupus erythematosus responds better to soluble TACI than to soluble BAFFR, correlating with depletion of plasma cells. European journal of immunology. 2017;47(6):1075–85. doi: 10.1002/eji.201746934 28383107


Článek vyšel v časopise

PLOS One


2019 Číslo 10
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Současné pohledy na riziko v parodontologii
nový kurz
Autoři: MUDr. Ladislav Korábek, CSc., MBA

Svět praktické medicíny 3/2024 (znalostní test z časopisu)

Kardiologické projevy hypereozinofilií
Autoři: prof. MUDr. Petr Němec, Ph.D.

Střevní příprava před kolonoskopií
Autoři: MUDr. Klára Kmochová, Ph.D.

Aktuální možnosti diagnostiky a léčby litiáz
Autoři: MUDr. Tomáš Ürge, PhD.

Všechny kurzy
Kurzy Podcasty Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#