[en] Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. The role of Th17 cells in its pathophysiology remains a matter of debate. In this study, we assessed whether enrichment of human peripheral blood mononuclear cells (PBMCs) with in vitro Th17-polarized CD4(+) T cells would exacerbate xenogeneic GVHD (xGVHD) into NOD-scid IL-2Rgamma null (NSG) mice. Naive human CD4(+) T cells were stimulated under Th17-skewing conditions for 8 to 10 days and then coinjected in NSG mice with fresh PBMCs from the same donor. We observed that Th17-polarized cells engrafted and migrated toward xGVHD target organs. They also acquired a double-expressing IL-17A(+)IFNgamma(+) profile in vivo. Importantly, cotransfer of Th17-polarized cells (1x10(6)) with PBMCs (1x10(6)) exacerbated xGVHD compared with transplantation of PBMCs alone (2x10(6)). Furthermore, PBMC cotransfer with Th17-polarized cells was more potent for xGVHD induction than cotransfer with naive CD4(+) T cells stimulated in nonpolarizing conditions (Th0 cells, 1x10(6)+1x10(6) PBMCs) or with Th1-polarized cells (1x10(6)+1x10(6) PBMCs). In summary, our results suggest that human Th17-polarized cells can cooperate with PBMCs and be pathogenic in the NSG xGVHD model.
SEIDEL, Laurence ; Centre Hospitalier Universitaire de Liège - CHU > Département de gestion des systèmes d'informations (GSI) > Secteur d'appui à la recherche clinique et biostatistique
Servais, S., Beguin, Y., Delens, L., et al. Novel approaches for preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Expert Opin Investig Drugs 25 (2016), 957–972.
Zeiser, R., Socié G., Blazar, B.R., Pathogenesis of acute graft-versus-host disease: from intestinal microbiota alterations to donor T cell activation. Br J Haematol 175 (2016), 191–207.
Zeiser, R., Blazar, B.R., Acute graft-versus-host disease: biologic process, prevention, and therapy. N Engl J Med 377 (2017), 2167–2179.
Aversa, F., Tabilio, A., Velardi, A., et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 339 (1998), 1186–1193.
Muranski, P., Restifo, N.P., Essentials of Th17 cell commitment and plasticity. Blood 121 (2013), 2402–2414.
Lu, S.X., Alpdogan, O., Lin, J., et al. STAT-3 and ERK 1/2 phosphorylation are critical for T-cell alloactivation and graft-versus-host disease. Blood 112 (2008), 5254–5258.
Carlson, M.J., West, M.L., Coghill, J.M., Panoskaltsis-Mortari, A., Blazar, B.R., Serody, J.S., In vitro-differentiated Th17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations. Blood 113 (2009), 1365–1374.
Iclozan, C., Yu, Y., Liu, C., et al. T helper17 cells are sufficient but not necessary to induce acute graft-versus-host disease. Biol Blood Marrow Transplant 16 (2010), 170–178.
Kappel, L.W., Goldberg, G.L., King, C.G., et al. IL-17 contributes to CD4-mediated graft-versus-host disease. Blood 113 (2009), 945–952.
Malard, F., Gaugler, B., Lamarthee, B., Mohty, M., Translational opportunities for targeting the Th17 axis in acute graft-vs.-host disease. Mucosal Immunol 9 (2016), 299–308.
Gartlan, K.H., Varelias, A., Koyama, M., et al. Th17 plasticity and transition toward a pathogenic cytokine signature are regulated by cyclosporine after allogeneic SCT. Blood Adv 1 (2017), 341–351.
Liu, Y., Cai, Y., Dai, L., et al. The expression of Th17-associated cytokines in human acute graft-versus-host disease. Biol Blood Marrow Transplant 19 (2013), 1421–1429.
Bossard, C., Malard, F., Arbez, J., et al. Plasmacytoid dendritic cells and Th17 immune response contribution in gastrointestinal acute graft-versus-host disease. Leukemia 26 (2012), 1471–1474.
Betts, B.C., Sagatys, E.M., Veerapathran, A., et al. CD4+ T cell STAT3 phosphorylation precedes acute GVHD, and subsequent Th17 tissue invasion correlates with GVHD severity and therapeutic response. J Leukoc Biol 97 (2015), 807–819.
Elmaagacli, A.H., Koldehoff, M., Landt, O., Beelen, D.W., Relation of an interleukin-23 receptor gene polymorphism to graft-versus-host disease after hematopoietic-cell transplantation. Bone Marrow Transplant 41 (2008), 821–826.
Broady, R., Yu, J., Chow, V., et al. Cutaneous GVHD is associated with the expansion of tissue-localized Th1 and not Th17 cells. Blood 116 (2010), 5748–5751.
Ratajczak, P., Janin, A., Peffault de Latour, R., et al. Th17/Treg ratio in human graft-versus-host disease. Blood 116 (2010), 1165–1171.
Nguyen, Y., Al-Lehibi, A., Gorbe, E., et al. Insufficient evidence for association of NOD2/CARD15 or other inflammatory bowel disease-associated markers on GVHD incidence or other adverse outcomes in T-replete, unrelated donor transplantation. Blood 115 (2010), 3625–3631.
Ernst, P.B., Carvunis, A.R., Of mice, men and immunity: a case for evolutionary systems biology. Nat Immunol 19 (2018), 421–425.
Targan, S.R., Feagan, B., Vermeire, S., et al. A randomized, double-blind, placebo-controlled phase 2 study of brodalumab in patients with moderate-to-severe Crohn's disease. Am J Gastroenterol 111 (2016), 1599–1607.
Hueber, W., Sands, B.E., Lewitzky, S., et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61 (2012), 1693–1700.
Hohenberger, M., Cardwell, L.A., Oussedik, E., Feldman, S.R., Interleukin-17 inhibition: role in psoriasis and inflammatory bowel disease. J Dermatolog Treat 29 (2018), 13–18.
Ito, R., Katano, I., Kawai, K., et al. A novel xenogeneic graft-versus-host disease model for investigating the pathological role of human CD4+ or CD8+ T cells using immunodeficient NOG mice. Am J Transplant 17 (2017), 1216–1228.
Ito, R., Katano, I., Kawai, K., et al. Highly sensitive model for xenogenic GVHD using severe immunodeficient NOG mice. Transplantation 87 (2009), 1654–1658.
Hannon, M., Lechanteur, C., Lucas, S., et al. Infusion of clinical-grade enriched regulatory T cells delays experimental xenogeneic graft-versus-host disease. Transfusion 54 (2014), 353–363.
Ehx, G., Fransolet, G., de Leval, L., et al. Azacytidine prevents experimental xenogeneic graft-versus-host disease without abrogating graft-versus-leukemia effects. Oncoimmunology, 6, 2017, e1314425.
Burlion, A., Brunel, S., Petit, N.Y., Olive, D., Marodon, G., Targeting the human T-cell inducible COStimulator molecule with a monoclonal antibody prevents graft-vs-host disease and preserves graft vs leukemia in a xenograft murine model. Front Immunol, 8, 2017, 756.
Cuende, J., Liénart, S., Dedobbeleer, O., et al. Monoclonal antibodies against GARP/TGF-ß1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo. Sci Transl Med, 7, 2015, 284ra56.
Kawasaki, Y., Sato, K., Hayakawa, H., et al. Comprehensive analysis of the activation and proliferation kinetics and effector functions of human lymphocytes, and antigen presentation capacity of antigen-presenting cells in xenogeneic graft-versus-host disease. Biol Blood Marrow Transplant 24 (2018), 1563–1574.
King, M.A., Covassin, L., Brehm, M.A., et al. Human peripheral blood leucocyte non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft-versus-host-like disease and the role of host major histocompatibility complex. Clin Exp Immunol 157 (2009), 104–118.
van Rijn, R.S., Simonetti, E.R., Hagenbeek, A., et al. A new xenograft model for graft-versus-host disease by intravenous transfer of human peripheral blood mononuclear cells in RAG2−/−gammac−/−double-mutant mice. Blood 102 (2003), 2522–2531.
Betts, B.C., Veerapathran, A., Pidala, J., et al. Targeting Aurora kinase A and JAK2 prevents GVHD while maintaining Treg and antitumor CTL function. Sci Transl Med, 9, 2017 eaai8269.
Covassin, L., Laning, J., Abdi, R., et al. Human peripheral blood CD4 T cell-engrafted non-obese diabetic-scid IL2rγ(null) H2-Ab1 (tm1Gru) Tg (human leucocyte antigen D-related 4) mice: a mouse model of human allogeneic graft-versus-host disease. Clin Exp Immunol 166 (2011), 269–280.
Ehx, G., Somja, J., Warnatz, H.J., et al. Xenogeneic graft-versus-host disease in humanized NSG and NSG-HLA-A2/HHD mice. Front Immunol, 9, 2018, 1943.
Søndergaard, H., Kvist, P.H., Haase, C., Human T cells depend on functional calcineurin, tumour necrosis factor-α and CD80/CD86 for expansion and activation in mice. Clin Exp Immunol 172 (2013), 300–310.
Hippen, K.L., Bucher, C., Schirm, D.K., et al. Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes. Blood 119 (2012), 619–628.
Bruck, F., Belle, L., Lechanteur, C., et al. Impact of bone marrow-derived mesenchymal stromal cells on experimental xenogeneic graft-versus-host disease. Cytotherapy 15 (2013), 267–279.
Gregoire-Gauthier, J., Durrieu, L., Duval, A., et al. Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/γc- mouse model. Bone Marrow Transplant 47 (2012), 439–450.
Coulie, P.G., Stevens, M., Van Snick, J., High- and low-affinity receptors for murine interleukin 6: distinct distribution on B and T cells. Eur J Immunol 19 (1989), 2107–2114.
Hammacher, A., Ward, L.D., Weinstock, J., Treutlein, H., Yasukawa, K., Simpson, R.J., Structure-function analysis of human IL-6: identification of two distinct regions that are important for receptor binding. Protein Sci 3 (1994), 2280–2293.
Hatano, R., Ohnuma, K., Yamamoto, J., Dang, N.H., Yamada, T., Morimoto, C., Prevention of acute graft-versus-host disease by humanized anti-CD26 monoclonal antibody. Br J Haematol 162 (2013), 263–277.
Kleinewietfeld, M., Manzel, A., Titze, J., et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496 (2013), 518–522.
Ghoreschi, K., Laurence, A., Yang, X.P., et al. Generation of pathogenic T(H)17 cells in the absence of TGF-ß signalling. Nature 467 (2010), 967–971.
Lee, Y., Awasthi, A., Yosef, N., et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 13 (2012), 991–999.
McGeachy, M.J., Bak-Jensen, K.S., Chen, Y., et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8 (2007), 1390–1397.
Acosta-Rodriguez, E.V., Rivino, L., Geginat, J., et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 8 (2007), 639–646.
Lee, Y.K., Turner, H., Maynard, C.L., et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30 (2009), 92–107.
Mukasa, R., Balasubramani, A., Lee, Y.K., et al. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity 32 (2010), 616–627.
Wang, Y., Godec, J., Ben-Aissa, K., et al. The transcription factors T-bet and Runx are required for the ontogeny of pathogenic interferon-γ-producing T helper 17 cells. Immunity 40 (2014), 355–366.
El-Behi, M., Ciric, B., Dai, H., et al. The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol 12 (2011), 568–575.
King, M., Pearson, T., Shultz, L.D., et al. A new Hu-PBL model for the study of human islet alloreactivity based on NOD-scid mice bearing a targeted mutation in the IL-2 receptor gamma chain gene. Clin Immunol 126 (2008), 303–314.
Ankathatti Munegowda, M., Deng, Y., Mulligan, S.J., Xiang, J., Th17 and Th17-stimulated CD8+ T cells play a distinct role in Th17-induced preventive and therapeutic antitumor immunity. Cancer Immunol Immunother 60 (2011), 1473–1484.
Hemmi, M., Tachibana, M., Fujimoto, N., et al. T helper 17 promotes induction of antigen-specific gut-mucosal cytotoxic T lymphocytes following adenovirus vector vaccination. Front Immunol, 8, 2017, 1456.
Acharya, D., Wang, P., Paul, A.M., et al. Interleukin-17A promotes CD8+ T cell cytotoxicity to facilitate West Nile virus clearance. J Virol, 91, 2016 e01529-16.
Martin, B., Hirota, K., Cua, D.J., Stockinger, B., Veldhoen, M., Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity 31 (2009), 321–330.
Hill, G.R., Olver, S.D., Kuns, R.D., et al. Stem cell mobilization with G-CSF induces type 17 differentiation and promotes scleroderma. Blood 116 (2010), 819–828.
Qian, Y., Liu, C., Hartupee, J., et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol 8 (2007), 247–256.
Korn, T., Bettelli, E., Oukka, M., Kuchroo, V.K., IL-17 and Th17 cells. Annu Rev Immunol 27 (2009), 485–517.
Liu, Y., Mei, J., Gonzales, L., et al. IL-17A and TNF-α exert synergistic effects on expression of CXCL5 by alveolar type II cells in vivo and in vitro. J Immunol 186 (2011), 3197–3205.
Bulek, K., Liu, C., Swaidani, S., et al. The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammation. Nat Immunol 12 (2011), 844–852.
Veldhoen, M., Interleukin 17 is a chief orchestrator of immunity. Nat Immunol 18 (2017), 612–621.
Ueha, S., Yokochi, S., Ishiwata, Y., et al. Combination of anti-CD4 antibody treatment and donor lymphocyte infusion ameliorates graft-versus-host disease while preserving graft-versus-tumor effects in murine allogeneic hematopoietic stem cell transplantation. Cancer Sci 108 (2017), 1967–1973.
Ni, X., Song, Q., Cassady, K., et al. PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cells. J Clin Invest 127 (2017), 1960–1977.
Bailey, S.R., Nelson, M.H., Himes, R.A., Li, Z., Mehrotra, S., Paulos, C.M., Th17 cells in cancer: the ultimate identity crisis. Front Immunol, 5, 2014, 276.
Downs-Canner, S., Berkey, S., Delgoffe, G.M., et al. Suppressive IL-17A+Foxp3+ and ex-Th17 IL-17A−Foxp3+ Treg cells are a source of tumour-associated Treg cells. Nat Commun, 8, 2017, 14649.
Gagliani, N., Amezcua Vesely, M.C., Iseppon, A., et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523 (2015), 221–225.
Hirota, K., Turner, J.E., Villa, M., et al. Plasticity of Th17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses. Nat Immunol 14 (2013), 372–379.
Voo, K.S., Wang, Y.H., Santori, F.R., et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci U S A 106 (2009), 4793–4798.
Cantoni, N., Hirsch, H.H., Khanna, N., et al. Evidence for a bidirectional relationship between cytomegalovirus replication and acute graft-versus-host disease. Biol Blood Marrow Transplant 16 (2010), 1309–1314.
