Protective effect of neutralizing anti-IL-18α monoclonal antibody on a mouse model of acute graft-versus-host disease

Li,Xiaocui; Zhang,Cuiping; Chen,Wei; Pan,Bin; Kong,Fanyun; Zheng,Kuiyang; Tang,Renxian; Zeng,Lingyu

doi:10.3892/or.2015.4176

Protective effect of neutralizing anti-IL-18α monoclonal antibody on a mouse model of acute graft-versus-host disease

Authors:
- Xiaocui Li
- Cuiping Zhang
- Wei Chen
- Bin Pan
- Fanyun Kong
- Kuiyang Zheng
- Renxian Tang
- Lingyu Zeng
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Affiliations: Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou, Jiangsu 221004, P.R. China, Blood Diseases Institute, Xuzhou Medical College; Key Laboratory of Bone Marrow Stem Cells; Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu 221002, P.R. China
Published online on: August 5, 2015 https://doi.org/10.3892/or.2015.4176
Pages: 2031-2039

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Abstract

Graft-versus-host disease (GVHD) is a devastating complication of hematopoietic stem cell transplantation (HSCT), and is characterized by systemic inflammation and tissue damage in multiple organs, such as the liver and small intestine. Interleukin-18 (IL-18), an important pro-inflammatory cytokine, is elevated during the course of acute GVHD (aGVHD), and is associated with the severe clinical manifestations of the disease. The biological activity of IL-18 is based on its interaction with the IL-18 receptor (IL-18R) expressed in a variety of cells. The aim of this study was to assess whether blocking the interaction of IL-18 with IL-18R by the anti-IL‑18Rα antibody could attenuate the severity of aGVHD. We used a well-established mouse bone marrow transplantation (BMT) model (B6→BALB/c) to block the IL-18/IL-18R interaction by a neutralizing monoclonal antibody (mAb) against murine IL-18Rα. Administration of anti-IL-18Rα mAb had a significant protective effect on the clinical and pathologic manifestations of aGVHD, resulting in a markedly improved survival rate, modified inflammatory response and decreased tissue damage. Interfering with IL-18/IL-18R interaction affected levels of Th1, Th2 and Th17 subsets in the peripheral blood of the aGVHD animals. Additionally, it led to decreased tissue expression of IL-18 and apoptosis-associated molecules (Fas and FasL), and lower phosphorylation levels of p38MAPK in the liver and small intestine. These changes coincided with the decrease in cell apoptosis in aGVHD target organs. Thus, anti‑IL-18Rα therapy may, therefore, represent a new therapeutic interference approach for treating aGVHD.

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1	Storb R: Allogeneic hematopoietic stem cell transplantation - yesterday, today, and tomorrow. Exp Hematol. 31:1–10. 2003. View Article : Google Scholar : PubMed/NCBI
2	Ferrara JL, Levine JE, Reddy P and Holler E: Graft-versus-host disease. Lancet. 373:1550–1561. 2009. View Article : Google Scholar : PubMed/NCBI
3	Tobin LM, Healy ME, English K and Mahon BP: Human mesenchymal stem cells suppress donor CD4(+) T cell proliferation and reduce pathology in a humanized mouse model of acute graft-versus-host disease. Clin Exp Immunol. 172:333–348. 2013. View Article : Google Scholar : PubMed/NCBI
4	Reddy P: Pathophysiology of acute graft-versus-host disease. Hematol Oncol. 21:149–161. 2003. View Article : Google Scholar
5	Antin JH and Ferrara JL: Cytokine dysregulation and acute graft-versus-host disease. Blood. 80:2964–2968. 1992.PubMed/NCBI
6	Levine JE, Paczesny S and Sarantopoulos S: Clinical applications for biomarkers of acute and chronic graft-versus-host disease. Biol Blood Marrow Transplant. 18(Suppl 1): S116–S124. 2012. View Article : Google Scholar : PubMed/NCBI
7	Pan B, Zhang Y, Sun Y, Cheng H, Wu Y, Song G, Chen W, Zeng L and Xu K: Deviated balance between Th1 and Th17 cells exacerbates acute graft-versus-host disease in mice. Cytokine. 68:69–75. 2014. View Article : Google Scholar : PubMed/NCBI
8	Tawara I, Maeda Y, Sun Y, Lowler KP, Liu C, Toubai T, McKenzie AN and Reddy P: Combined Th2 cytokine deficiency in donor T cells aggravates experimental acute graft-vs-host disease. Exp Hematol. 36:988–996. 2008. View Article : Google Scholar : PubMed/NCBI
9	Reddy P, Arora M, Guimond M and Mackall CL: GVHD: A continuing barrier to the safety of allogeneic transplantation. Biol Blood Marrow Transplant. 15(Suppl 1): 162–168. 2009. View Article : Google Scholar : PubMed/NCBI
10	Schmaltz C, Alpdogan O, Horndasch KJ, Muriglan SJ, Kappel BJ, Teshima T, Ferrara JL, Burakoff SJ and van den Brink MR: Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect. Blood. 97:2886–2895. 2001. View Article : Google Scholar : PubMed/NCBI
11	Maeda Y, Levy RB, Reddy P, Liu C, Clouthier SG, Teshima T and Ferrara JL: Both perforin and Fas ligand are required for the regulation of alloreactive CD8⁺ T cells during acute graft-versus-host disease. Blood. 105:2023–2027. 2005. View Article : Google Scholar
12	Fremond CM, Togbe D, Doz E, Rose S, Vasseur V, Maillet I, Jacobs M, Ryffel B and Quesniaux VF: IL-1 receptor-mediated signal is an essential component of MyD88-dependent innate response to Mycobacterium tuberculosis infection. J Immunol. 179:1178–1189. 2007. View Article : Google Scholar : PubMed/NCBI
13	Chandrasekar B, Vemula K, Surabhi RM, Li-Weber M, Owen-Schaub LB, Jensen LE and Mummidi S: Activation of intrinsic and extrinsic proapoptotic signaling pathways in interleukin-18-mediated human cardiac endothelial cell death. J Biol Chem. 279:20221–20233. 2004. View Article : Google Scholar : PubMed/NCBI
14	Lu Y, Sakamaki S, Kuroda H, Kusakabe T, Konuma Y, Akiyama T, Fujimi A, Takemoto N, Nishiie K, Matsunaga T, et al: Prevention of lethal acute graft-versus-host disease in mice by oral administration of T helper 1 inhibitor, TAK-603. Blood. 97:1123–1130. 2001. View Article : Google Scholar : PubMed/NCBI
15	Cooke KR, Kobzik L, Martin TR, Brewer J, Delmonte J Jr, Crawford JM and Ferrara JL: An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. Blood. 88:3230–3239. 1996.PubMed/NCBI
16	Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ and Littman DR: The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17⁺ T helper cells. Cell. 126:1121–1133. 2006. View Article : Google Scholar : PubMed/NCBI
17	Sun Y, Tawara I, Toubai T and Reddy P: Pathophysiology of acute graft-versus-host disease: Recent advances. Transl Res. 150:197–214. 2007. View Article : Google Scholar : PubMed/NCBI
18	Wilson SP and Cassel SL: Inflammasome-mediated autoinflammatory disorders. Postgrad Med. 122:125–133. 2010. View Article : Google Scholar : PubMed/NCBI
19	Miossec P: IL-17 and Th17 cells in human inflammatory diseases. Microbes Infect. 11:625–630. 2009. View Article : Google Scholar : PubMed/NCBI
20	Nishimoto N and Kishimoto T: Interleukin 6: From bench to bedside. Nat Clin Pract Rheumatol. 2:619–626. 2006. View Article : Google Scholar : PubMed/NCBI
21	Vogelsang GB, Lee L and Bensen-Kennedy DM: Pathogenesis and treatment of graft-versus-host disease after bone marrow transplant. Annu Rev Med. 54:29–52. 2003. View Article : Google Scholar
22	Reddy P, Teshima T, Kukuruga M, Ordemann R, Liu C, Lowler K and Ferrara JL: Interleukin-18 regulates acute graft-versus-host disease by enhancing Fas-mediated donor T cell apoptosis. J Exp Med. 194:1433–1440. 2001. View Article : Google Scholar : PubMed/NCBI
23	Wasem C, Frutschi C, Arnold D, Vallan C, Lin T, Green DR, Mueller C and Brunner T: Accumulation and activation-induced release of preformed Fas (CD95) ligand during the pathogenesis of experimental graft-versus-host disease. J Immunol. 167:2936–2941. 2001. View Article : Google Scholar : PubMed/NCBI
24	Yi T, Zhao D, Lin CL, Zhang C, Chen Y, Todorov I, LeBon T, Kandeel F, Forman S and Zeng D: Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease. Blood. 112:2101–2110. 2008. View Article : Google Scholar : PubMed/NCBI
25	Kalina U, Kauschat D, Koyama N, Nuernberger H, Ballas K, Koschmieder S, Bug G, Hofmann WK, Hoelzer D and Ottmann OG: IL-18 activates STAT3 in the natural killer cell line 92, augments cytotoxic activity, and mediates IFN-gamma production by the stress kinase p38 and by the extracellular regulated kinases p44^erk−1 and p42^erk−21. J Immunol. 165:1307–1313. 2000. View Article : Google Scholar : PubMed/NCBI
26	Calvani N, Tucci M, Richards HB, Tartaglia P and Silvestris F: Th1 cytokines in the pathogenesis of lupus nephritis: The role of IL-18. Autoimmun Rev. 4:542–548. 2005. View Article : Google Scholar : PubMed/NCBI
27	Gracie JA, Forsey RJ, Chan WL, Gilmour A, Leung BP, Greer MR, Kennedy K, Carter R, Wei XQ, Xu D, et al: A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest. 104:1393–1401. 1999. View Article : Google Scholar : PubMed/NCBI
28	Miller WP, Srinivasan S, Panoskaltsis-Mortari A, Singh K, Sen S, Hamby K, Deane T, Stempora L, Beus J, Turner A, et al: GVHD after haploidentical transplantation: A novel, MHC-defined rhesus macaque model identifies CD28⁻ CD8⁺ T cells as a reservoir of breakthrough T-cell proliferation during costimulation blockade and sirolimus-based immunosuppression. Blood. 116:5403–5418. 2010. View Article : Google Scholar : PubMed/NCBI
29	Arnold D, Wasem C, Juillard P, Graber P, Cima I, Frutschi C, Herren S, Jakob S, Alouani S, Mueller C, et al: IL-18-independent cytotoxic T lymphocyte activation and IFN-gamma production during experimental acute graft-versus-host disease. Int Immunol. 14:503–511. 2002. View Article : Google Scholar : PubMed/NCBI
30	Kang MJ, Homer RJ, Gallo A, Lee CG, Crothers KA, Cho SJ, Rochester C, Cain H, Chupp G, Yoon HJ, et al: IL-18 is induced and IL-18 receptor alpha plays a critical role in the pathogenesis of cigarette smoke-induced pulmonary emphysema and inflammation. J Immunol. 178:1948–1959. 2007. View Article : Google Scholar : PubMed/NCBI
31	Halpern MD, Khailova L, Molla-Hosseini D, Arganbright K, Reynolds C, Yajima M, Hoshiba J and Dvorak B: Decreased development of necrotizing enterocolitis in IL-18-deficient mice. Am J Physiol Gastrointest Liver Physiol. 294:G20–G26. 2008. View Article : Google Scholar
32	Schroder K, Hertzog PJ, Ravasi T and Hume DA: Interferon-gamma: An overview of signals, mechanisms and functions. J Leukoc Biol. 75:163–189. 2004. View Article : Google Scholar
33	Olee T, Hashimoto S, Quach J and Lotz M: IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses. J Immunol. 162:1096–1100. 1999.PubMed/NCBI