Host bone marrow-derived IL-12 enhances donor T cell engraftment in a mouse model of bone marrow transplantation

Journal of Hematology & Oncology

Edmund K Waller¹  Chunzi Huang¹  Cynthia R Giver¹  Wayne AC Harris¹  Jian-Ming Li¹  Ying Wang²  Katarzyna A Darlak¹ 

[1] Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365B Clifton Rd. NE, Room B5119, Atlanta, GA, USA;Leukemia Center, Institute of Hematology and blood Diseases Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China

关键词: T-cells;    Transplantation;    Engraftment;    Interleukin-12;   

Others  :  801892
DOI  :  10.1186/1756-8722-7-16

 received in 2013-11-07, accepted in 2014-02-12,  发布年份 2014

【 摘 要 】

Background

Donor cell engraftment is critical for the success of allogeneic bone marrow transplants. Graft failure is a result of donor cells either failing to engraft initially or being eliminated at later time points. Donor cell engraftment is facilitated by donor T cells, which eliminate residual host hemato-lymphoid effector cells such as NK cells and T cells.

Methods

We aimed to explore the role of host hematopoietic cell derived IL-12 on donor cell engraftment in a murine model of BMT. We established radiation chimeras by transplanting C57BL6/J (B6) mice with BM from either congenic B6 mice or IL-12p40 KO mice. These WT → WT or IL-12 KO → WT chimeras then underwent a secondary transplant with allogeneic (FVB) BM. Survival, engraftment, donor T cell expansion, cytokine production by donor T cells, as well as expression of stimulatory markers on donor T cells was analyzed.

Results

Mice whose residual host hematopoietic cells were capable of producing IL-12 had modestly higher survival, higher donor T cell engraftment, and significantly higher donor erythroid engraftment. We have also found that an increased number of donor T cells in IL-12 KO → WT chimeras have a regulatory phenotype, expressing FoxP3, producing lower levels of TNF-α, higher levels of IL-10, and expressing higher levels of ICOS as well as PD-1 on CD4+ T cells.

Conclusions

To our knowledge, this is the first report of a beneficial role of IL-12 production by host cells in the context of bone marrow engraftment in a murine model of BMT. These findings support the clinical use of exogenous IL-12 for use in settings where graft failure is of concern.

【 授权许可】

   
2014 Darlak et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Rocha V, Cornish J, Sievers EL, Filipovich A, Locatelli F, Peters C, Remberger M, Michel G, Arcese W, Dallorso S, Tiedemann K, Busca A, Chan KW, Kato S, Ortega J, Vowels M, Zander A, Souillet G, Oakill A, Woolfrey A, Pay AL, Green A, Garnier F, Ionescu I, Wernet P, Sirchia G, Rubinstein P, Chevret S, Gluckman E: Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia. Blood 2001, 97:2962-2971.
• [2]Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, Cutler CS, Westervelt P, Woolfrey A, Couban S, Ehninger G, Johnston L, Maziarz RT, Pulsipher MA, Porter DL, Mineishi S, McCarty JM, Khan SP, Anderlini P, Bensinger WI, Leitman SF, Rowley SD, Bredeson C, Carter SL, Horowitz MM, Confer DL: Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med 2012, 367:1487-1496.
• [3]Le Blanc K, Remberger M, Uzunel M, Mattsson J, Barkholt L, Ringden O: A comparison of nonmyeloablative and reduced-intensity conditioning for allogeneic stem-cell transplantation. Transplantation 2004, 78:1014-1020.
• [4]Storb R, Epstein RB, Bryant J, Ragde H, Thomas ED: Marrow grafts by combined marrow and leukocyte infusions in unrelated dogs selected by histocompatibility typing. Transplantation 1968, 6:587-593.
• [5]Deeg HJ, Storb R, Weiden PL, Shulman HM, Graham TC, Torok-Storb BJ, Thomas ED: Abrogation of resistance to and enhancement of DLA-nonidentical unrelated marrow grafts in lethally irradiated dogs by thoracic duct lymphocytes. Blood 1979, 53:552-557.
• [6]Shlomchik WD, Couzens MS, Tang CB, McNiff J, Robert ME, Liu J, Shlomchik MJ, Emerson SG: Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 1999, 285:412-415.
• [7]Darlak KA, Wang Y, Li JM, Harris WA, Owens LM, Waller EK: Enrichment of IL-12-producing plasmacytoid dendritic cells in donor bone marrow grafts enhances graft-versus-leukemia activity in allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013, 19(9):1331-9.
• [8]Yang YG, Sergio JJ, Pearson DA, Szot GL, Shimizu A, Sykes M: Interleukin-12 preserves the graft-versus-leukemia effect of allogeneic CD8 T cells while inhibiting CD4-dependent graft-versus-host disease in mice. Blood 1997, 90:4651-4660.
• [9]Neta R, Stiefel SM, Finkelman F, Herrmann S, Ali N: IL-12 protects bone marrow from and sensitizes intestinal tract to ionizing radiation. J Immunol 1994, 153:4230-4237.
• [10]Chen T, Burke KA, Zhan Y, Wang X, Shibata D, Zhao Y: IL-12 facilitates both the recovery of endogenous hematopoiesis and the engraftment of stem cells after ionizing radiation. Exp Hematol 2007, 35:203-213.
• [11]Aragane Y, Riemann H, Bhardwaj RS, Schwarz A, Sawada Y, Yamada H, Luger TA, Kubin M, Trinchieri G, Schwarz T: IL-12 is expressed and released by human keratinocytes and epidermoid carcinoma cell lines. J Immunol 1994, 153:5366-5372.
• [12]Bost KL, Ramp WK, Nicholson NC, Bento JL, Marriott I, Hudson MC: Staphylococcus aureus infection of mouse or human osteoblasts induces high levels of interleukin-6 and interleukin-12 production. J Infect Dis 1999, 180:1912-1920.
• [13]Cooke KR, Kobzik L, Martin TR, Brewer J, Delmonte J Jr, Crawford JM, Ferrara JL: An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. Blood 1996, 88:3230-3239.
• [14]Wang X, Li H, Matte-Martone C, Cui W, Li N, Tan HS, Roopenian D, Shlomchik WD: Mechanisms of antigen presentation to T cells in murine graft-versus-host disease: cross-presentation and the appearance of cross-presentation. Blood 2011, 118:6426-6437.
• [15]Haspot F, Fehr T, Gibbons C, Zhao G, Hogan T, Honjo T, Freeman GJ, Sykes M: Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway. Blood 2008, 112:2149-2155.
• [16]Sykes M, Szot GL, Nguyen PL, Pearson DA: Interleukin-12 inhibits murine graft-versus-host disease. Blood 1995, 86:2429-2438.
• [17]Yang YG, Dey B, Sergio JJ, Sykes M: Interleukin-12 prevents severe acute graft-versus-host disease (GVHD) and GVHD-associated immune dysfunction in a fully major histocompatibility complex haplotype-mismatched murine bone marrow transplantation model. Transplantation 1997, 64:1343-1352.
• [18]Yang YG, Dey BR, Sergio JJ, Pearson DA, Sykes M: Donor-derived interferon gamma is required for inhibition of acute graft-versus-host disease by interleukin 12. J Clin Invest 1998, 102:2126-2135.
• [19]Mullen AC, High FA, Hutchins AS, Lee HW, Villarino AV, Livingston DM, Kung AL, Cereb N, Yao TP, Yang SY, Reiner SL: Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 2001, 292:1907-1910.
• [20]Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY, Murphy TL, Murphy KM: T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nat Immunol 2002, 3:549-557.
• [21]Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, Kroczek RA: ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 1999, 397:263-266.
• [22]Gonzalo JA, Delaney T, Corcoran J, Goodearl A, Gutierrez-Ramos JC, Coyle AJ: Cutting edge: the related molecules CD28 and inducible costimulator deliver both unique and complementary signals required for optimal T cell activation. J Immunol 2001, 166:1-5.
• [23]Swallow MM, Wallin JJ, Sha WC: B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNFalpha. Immunity 1999, 11:423-432.
• [24]Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T: Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996, 8:765-772.
• [25]Vibhakar R, Juan G, Traganos F, Darzynkiewicz Z, Finger LR: Activation-induced expression of human programmed death-1 gene in T-lymphocytes. Exp Cell Res 1997, 232:25-28.
• [26]Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K, Azuma M, Yagita H: Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 2002, 169:5538-5545.
• [27]Dong H, Zhu G, Tamada K, Chen L: B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999, 5:1365-1369.
• [28]Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T: Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000, 192:1027-1034.
• [29]Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ: PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001, 2:261-268.
• [30]Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, Shalabi A, Shin T, Pardoll DM, Tsuchiya H: B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 2001, 193:839-846.
• [31]Keir ME, Francisco LM, Sharpe AH: PD-1 and its ligands in T-cell immunity. Curr Opin Immunol 2007, 19:309-314.
• [32]Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, Azuma M, Krummel MF, Bluestone JA: Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol 2009, 10:1185-1192.
• [33]Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA: Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000, 13:715-725.
• [34]Bettelli E, Korn T, Kuchroo VK: Th17: the third member of the effector T cell trilogy. Curr Opin Immunol 2007, 19:652-657.
• [35]Hanash AM, Dudakov JA, Hua G, O'Connor MH, Young LF, Singer NV, West ML, Jenq RR, Holland AM, Kappel LW, Ghosh A, Tsai JJ, Rao UK, Yim NL, Smith OM, Velardi E, Hawryluk EB, Murphy GF, Liu C, Fouser LA, Kolesnick R, Blazar BR, van den Brink MR: Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity 2012, 37:339-350.
• [36]Yi T, Zhao D, Lin CL, Zhang C, Chen Y, Todorov I, LeBon T, Kandeel F, Forman S, Zeng D: Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease. Blood 2008, 112:2101-2110.
• [37]Yi T, Chen Y, Wang L, Du G, Huang D, Zhao D, Johnston H, Young J, Todorov I, Umetsu DT, Chen L, Iwakura Y, Kandeel F, Forman S, Zeng D: Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease. Blood 2009, 114:3101-3112.
• [38]Nishimura R, Baker J, Beilhack A, Zeiser R, Olson JA, Sega EI, Karimi M, Negrin RS: In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity. Blood 2008, 112:2563-2574.
• [39]Waller EK, Ship AM, Mittelstaedt S, Murray TW, Carter R, Kakhniashvili I, Lonial S, Holden JT, Boyer MW: Irradiated donor leukocytes promote engraftment of allogeneic bone marrow in major histocompatibility complex mismatched recipients without causing graft-versus-host disease. Blood 1999, 94:3222-3233.