Abstract
Acute graft-versus-host disease (aGVHD) is a major complication associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Interleukin (IL)-35 is a novel anti-inflammatory cytokine that suppresses the immune response. This prospective study explored IL-35 plasma levels in 65 patients after HSCT. The results revealed that the peripheral blood of patients with grades III–IV aGVHD (23.46 ng/ml) had reduced IL-35 compared to transplanted patients with grades I–II aGVHD (40.26 ng/ml, p < 0.01) or patients without aGVHD (41.40 ng/ml, p < 0.05). Allografts, including granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cell (PBPC) and G-CSF-primed bone marrow (GBM), from 38 patients were analyzed for IL-35 levels with respect to aGVHD. The patients who received lower levels of IL-35 cells in the GBM (28.0 ng/ml, p = 0.551) or lower levels of IL-35 in PBPC (53.46 ng/ml, p = 0.03) exhibited a higher incidence of aGVHD. Patients with aGVHD have increased platelet aggregation. IL-35 was added to patient blood in vitro, and platelet aggregation was inhibited by IL-35 in a dose-dependent manner. The markers of platelet activation (CD62P/PAC-1) can also be inhibited by IL-35. The results indicate that IL-35 may affect the development of aGVHD by inhibiting platelet activation and aggregation. Our data suggests that IL-35 represents a potentially effective therapeutic agent against aGVHD after allo-HSCT.
Similar content being viewed by others
References
Copelan EA (2006) Hematopoietic stem-cell transplantation. N Engl J Med 354(17):1813–1826. doi:10.1056/NEJMra052638
Ferrara JL, Levine JE, Reddy P, Holler E (2009) Graft-versus-host disease. Lancet 373(9674):1550–1561. doi:10.1016/S0140-6736(09)60237-3
Nakamura K, Amakawa R, Takebayashi M, Son Y, Miyaji M, Tajima K, Nakai K, Ito T, Matsumoto N, Zen K, Kishimoto Y, Fukuhara S (2005) IL-4-producing CD8(+) T cells may be an immunological hallmark of chronic GVHD. Bone Marrow Transplant 36(7):639–647. doi:10.1038/sj.bmt.1705107
Antin JH, Ferrara JL (1992) Cytokine dysregulation and acute graft-versus-host disease. Blood 80(12):2964–2968
Devergne O, Hummel M, Koeppen H, Le Beau MM, Nathanson EC, Kieff E, Birkenbach M (1996) A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes. J Virol 70(2):1143–1153
Niedbala W, Wei XQ, Cai B, Hueber AJ, Leung BP, McInnes IB, Liew FY (2007) IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur J Immunol 37(11):3021–3029. doi:10.1002/eji.200737810
Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, Cross R, Sehy D, Blumberg RS, Vignali DA (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450(7169):566–569. doi:10.1038/nature06306
Whitehead GS, Wilson RH, Nakano K, Burch LH, Nakano H, Cook DN (2012) IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease. J Allerg Clin Immunol 129(1):207–215. doi:10.1016/j.jaci.2011.08.009, e201-205
Graf L, Stern M (2012) Acute phase after haematopoietic stem cell transplantation: bleeding and thrombotic complications. Hamostaseologie 32(1):56–62. doi:10.5482/ha-1176
Wagner DD, Burger PC (2003) Platelets in inflammation and thrombosis. Arterioscler Thromb Vasc Biol 23(12):2131–2137. doi:10.1161/01.ATV.0000095974.95122.EC
Burger PC, Wagner DD (2003) Platelet P-selectin facilitates atherosclerotic lesion development. Blood 101(7):2661–2666. doi:10.1182/blood-2002-07-2209
Yan SL, Russell J, Granger DN (2014) Platelet activation and platelet-leukocyte aggregation elicited in experimental colitis are mediated by interleukin-6. Inflamm Bowel Dis 20(2):353–362. doi:10.1097/01.MIB.0000440614.83703.84
Biedermann BC (2008) Vascular endothelium and graft-versus-host disease. Best Pract Res Clin Haematol 21(2):129–138. doi:10.1016/j.beha.2008.02.003
Piccin A, Murphy WG, Smith OP (2007) Circulating microparticles: pathophysiology and clinical implications. Blood Rev 21(3):157–171. doi:10.1016/j.blre.2006.09.001
Pihusch R, Hohnberg B, Salat C, Pihusch M, Hiller E, Kolb HJ (2002) Platelet flow cytometric findings in patients undergoing conditioning therapy for allogeneic hematopoietic stem cell transplantation. Ann Hematol 81(8):454–461. doi:10.1007/s00277-002-0494-z
Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, Chen YH, Wang JZ, Gao ZY, Zhang YC, Jiang Q, Shi HX, Lu DP (2006) Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 38(4):291–297. doi:10.1038/sj.bmt.1705445
Lu DP, Dong L, Wu T, Huang XJ, Zhang MJ, Han W, Chen H, Liu DH, Gao ZY, Chen YH, Xu LP, Zhang YC, Ren HY, Li D, Liu KY (2006) Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation. Blood 107(8):3065–3073. doi:10.1182/blood-2005-05-2146
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, Lerner KG, Thomas ED (1974) Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 18(4):295–304
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED (1995) 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 15(6):825–828
Zhang S, Yuan J, Yu M, Fan H, Guo ZQ, Yang R, Guo HP, Liao YH, Wang M (2012) IL-17A facilitates platelet function through the ERK2 signaling pathway in patients with acute coronary syndrome. PLoS One 7(7):e40641. doi:10.1371/journal.pone.0040641
Chaturvedi V, Collison LW, Guy CS, Workman CJ, Vignali DA (2011) Cutting edge: human regulatory T cells require IL-35 to mediate suppression and infectious tolerance. J Immunol 186(12):6661–6666. doi:10.4049/jimmunol.1100315
Collison LW, Chaturvedi V, Henderson AL, Giacomin PR, Guy C, Bankoti J, Finkelstein D, Forbes K, Workman CJ, Brown SA, Rehg JE, Jones ML, Ni HT, Artis D, Turk MJ, Vignali DA (2010) IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol 11(12):1093–1101. doi:10.1038/ni.1952
Liu JQ, Liu Z, Zhang X, Shi Y, Talebian F, Carl JW Jr, Yu C, Shi FD, Whitacre CC, Trgovcich J, Bai XF (2012) Increased Th17 and regulatory T cell responses in EBV-induced gene 3-deficient mice lead to marginally enhanced development of autoimmune encephalomyelitis. J Immunol 188(7):3099–3106. doi:10.4049/jimmunol.1100106
Tirotta E, Duncker P, Oak J, Klaus S, Tsukamoto MR, Gov L, Lane TE (2013) Epstein-Barr virus-induced gene 3 negatively regulates neuroinflammation and T cell activation following coronavirus-induced encephalomyelitis. J Neuroimmunol 254(1–2):110–116. doi:10.1016/j.jneuroim.2012.10.005
Tong H, Miyazaki Y, Yamazaki M, Hara H, Waldmann H, Hori S, Yoshida H (2010) Exacerbation of delayed-type hypersensitivity responses in EBV-induced gene-3 (EBI-3)-deficient mice. Immunol Lett 128(2):108–115. doi:10.1016/j.imlet.2010.01.001
Liu Y, Cai Y, Dai L, Chen G, Ma X, Wang Y, Xu T, Jin S, Wu X, Qiu H, Tang X, Li C, Sun A, Wu D, Liu H (2013) The expression of Th17-associated cytokines in human acute graft-versus-host disease. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant 19(10):1421–1429. doi:10.1016/j.bbmt.2013.06.013
Zhai Z, Sun Z, Li Q, Zhang A, Liu H, Xu J, Xu X, Geng L, Harris D, Hu S, Wang Y (2007) Correlation of the CD4 + CD25high T-regulatory cells in recipients and their corresponding donors to acute GVHD. Transplant Int Off J European Soc Organ Transplant 20(5):440–446. doi:10.1111/j.1432-2277.2007.00462.x
Taylor PA, Lees CJ, Blazar BR (2002) The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99(10):3493–3499
Zhao XY, Xu LL, Lu SY, Huang XJ (2011) IL-17-producing T cells contribute to acute graft-versus-host disease in patients undergoing unmanipulated blood and marrow transplantation. Eur J Immunol 41(2):514–526. doi:10.1002/eji.201040793
Guo H, Wang W, Zhao N, He X, Zhu L, Jiang X (2013) Inhibiting cardiac allograft rejection with interleukin-35 therapy combined with decitabine treatment in mice. Transpl Immunol 29(1–4):99–104. doi:10.1016/j.trim.2013.10.001
Gorczynski R, Yu K, Chen Z (2014) Anti-CD200R2, anti-IL-9, anti-IL-35, or anti-TGF-beta abolishes increased graft survival and treg induction induced in cromolyn-treated CD200R1KO.CD200tg mice. Transplantation 97(1):39–46. doi:10.1097/TP.0b013e3182a8936a
Dumler JS, Beschorner WE, Farmer ER, Di Gennaro KA, Saral R, Santos GW (1989) Endothelial-cell injury in cutaneous acute graft-versus-host disease. Am J Pathol 135(6):1097–1103
Biedermann BC, Sahner S, Gregor M, Tsakiris DA, Jeanneret C, Pober JS, Gratwohl A (2002) Endothelial injury mediated by cytotoxic T lymphocytes and loss of microvessels in chronic graft versus host disease. Lancet 359(9323):2078–2083. doi:10.1016/S0140-6736(02)08907-9
Rand ML, Leung R, Packham MA (2003) Platelet function assays. Transfus Apher Sci 28(3):307–317. doi:10.1016/s1473-0502(03)00050-8
Jakubowski JA, Zhou C, Jurcevic S, Winters KJ, Lachno DR, Frelinger AL 3rd, Gupta N, Howard J, Payne CD, Mant TG (2014) A phase 1 study of prasugrel in patients with sickle cell disease: effects on biomarkers of platelet activation and coagulation. Thromb Res 133(2):190–195. doi:10.1016/j.thromres.2013.12.008
Davi G, Patrono C (2007) Platelet activation and atherothrombosis. N Engl J Med 357(24):2482–2494. doi:10.1056/NEJMra071014
Jennings LK (2009) Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost 102(2):248–257. doi:10.1160/TH09-03-0192
Pinomaki A, Volin L, Joutsi-Korhonen L, Virtanen JO, Lemponen M, Ruutu T, Lassila R (2010) Early thrombin generation and impaired fibrinolysis after SCT associate with acute GVHD. Bone Marrow Transplant 45(4):730–737. doi:10.1038/bmt.2009.227
Gerber DE, Segal JB, Levy MY, Kane J, Jones RJ, Streiff MB (2008) The incidence of and risk factors for venous thromboembolism (VTE) and bleeding among 1514 patients undergoing hematopoietic stem cell transplantation: implications for VTE prevention. Blood 112(3):504–510. doi:10.1182/blood-2007-10-117051
Tuncer HH, Rana N, Milani C, Darko A, Al-Homsi SA (2012) Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol WJG 18(16):1851–1860. doi:10.3748/wjg.v18.i16.1851
Tichelli A, Gratwohl A (2008) Vascular endothelium as ‘novel’ target of graft-versus-host disease. Best Pract Res Clin Haematol 21(2):139–148. doi:10.1016/j.beha.2008.02.002
Cheuk DK, Wang P, Lee TL, Chiang AK, Ha SY, Lau YL, Chan GC (2007) Risk factors and mortality predictors of hepatic veno-occlusive disease after pediatric hematopoietic stem cell transplantation. Bone Marrow Transplant 40(10):935–944. doi:10.1038/sj.bmt.1705835
Batts ED, Lazarus HM (2007) Diagnosis and treatment of transplantation-associated thrombotic microangiopathy: real progress or are we still waiting? Bone Marrow Transplant 40(8):709–719. doi:10.1038/sj.bmt.1705758
Stavrou E, Lazarus HM (2010) Thrombotic microangiopathy in haematopoietic cell transplantation: an update. Mediterranean J Hematol Infect Dis 2(3):e2010033. doi:10.4084/MJHID.2010.033
Maione F, Cicala C, Liverani E, Mascolo N, Perretti M, D’Acquisto F (2011) IL-17A increases ADP-induced platelet aggregation. Biochem Biophys Res Commun 408(4):658–662. doi:10.1016/j.bbrc.2011.04.080
Acknowledgments
The authors thank the staff of the Peking University Institute of Hematology for compassionate and competent care of the patients. This work was supported by the National Science Foundation of China (grant no. 81070449), the National Science Foundation of China (grant no. 81270643), the Beijing Natural Science Foundation (grant no. 7132194), and the Beijing Natural Science Foundation (grant no. 7112139).
Ethical standards
All human studies have been approved by the Ethics Committee of Peking University People’s Hospital and have therefore been performed in accordance with the ethical standards laid down in the 1975 Declaration of Helsinki and its later amendments. All persons gave their informed consent prior to their inclusion in the study.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Xiaohui Zhang and Yi Zhou share the first authorship.
Xiaohui Zhang and Xiaojun Huang share the co-corresponding author.
Rights and permissions
About this article
Cite this article
Zhang, X., Zhou, Y., Xu, L. et al. Reduced IL-35 levels are associated with increased platelet aggregation and activation in patients with acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Ann Hematol 94, 837–845 (2015). https://doi.org/10.1007/s00277-014-2278-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-014-2278-7