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The Lymphotoxin Pathway as a Novel Regulator of Dendritic Cell Function

  • Leslie Summers deLuca
  • Jennifer L. Gommerman
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)

Abstract

Dendritic cells (DC) are critically required for the host response to antigen (Ag) [1, 2]. Upon exposure to antigen, DC take up Ag within the peripheral tissues and subsequently migrate in response to chemokine gradients into the lymphatics [3]. During this initial exposure to Ag, DC become activated by the sensing of microbe-associated molecular patterns (MAMPs) and consequently upregulate co-stimulatory molecules such as B7.1 and B7.2 so that they may optimally prime Ag-specific CD4+ T cells [4–6]. DC leave the tissue and enter the lymphatics where they journey to the inflamed draining lymph node (LN) [7, 8]. Upon entry into the LN via the subcapsular sinus, DC “find” rare Ag-specific CD4+ T cells by taking advantage of the intricate organization of the LN tissue itself [9]. Once DC encounter Ag-specific T cells, the T cells become activated to proliferate. These activated T cells also concurrently provide signals back to the Ag-bearing DC in a process that has been termed DC licensing. Licensed DC can then cross-prime a CD8+ T-cell response so that pathogen may be cleared. The nature of these helper T cell-derived signals and their impact on the Ag-bearing DC remain poorly elucidated.

Keywords

Dendritic Cell Adoptive Transfer High Endothelial Venule Dendritic Cell Function Agonist Antibody 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors wish to acknowledge the support of the Canadian Institutes of Health Research (CIHR/IRSC) for a doctoral award to LSD and an operating grant to JLG (MOP #67157).

References

  1. 1.
    Steinman RM, Gutchinov B, Witmer MD, Nussenzweig CM (1983) Dendritic cells are the principal stimulators of the primary mixed leukocyte reaction in mice. J Exp Med 157: 613–627CrossRefPubMedGoogle Scholar
  2. 2.
    Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18:767–811CrossRefPubMedGoogle Scholar
  3. 3.
    Sallusto F, Schaerli P, Loetscher P, Schaniel C, Lenig D, Mackay CR, Qin S, Lanzavecchia A (1998) Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol 28:2760–2769CrossRefPubMedGoogle Scholar
  4. 4.
    Mellman I, Steinman RM (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106:255–258CrossRefPubMedGoogle Scholar
  5. 5.
    Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S (2002) Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol 20:621–667CrossRefPubMedGoogle Scholar
  6. 6.
    Inaba K, Turley S, Iyoda T, Yamaide F, Shimoyama S, Reis e Sousa C, Germain RN, Mellman I, Steinman RM (2000) The formation of immunogenic major histocompatibility complex class II-peptide ligands in lysosomal compartments of dendritic cells is regulated by inflammatory stimuli. J Exp Med 191:927–936CrossRefPubMedGoogle Scholar
  7. 7.
    Forster R, Schubel A, Breitfeld D, Kremmer E, Renner I -Muller, Wolf E, Lipp M (1999) CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99:23–33CrossRefPubMedGoogle Scholar
  8. 8.
    Ohl L, Mohaupt M, Czeloth N, Hintzen G, Kiafard Z, Zwirner J, Blankenstein T, Henning G, Forster R (2004) CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21:279–288CrossRefPubMedGoogle Scholar
  9. 9.
    von Andrian UH, Mempel TR (2003) Homing and cellular traffic in lymph nodes. Nat Rev Immunol 3:867–878CrossRefGoogle Scholar
  10. 10.
    Hochweller K, Anderton SM (2005) Kinetics of costimulatory molecule expression by T cells and dendritic cells during the induction of tolerance versus immunity in vivo. Eur J Immunol 35:1086–1096CrossRefPubMedGoogle Scholar
  11. 11.
    Summers-DeLuca LE, McCarthy DD, Cosovic B, Ward LA, Lo CC, Scheu S, Pfeffer K, Gommerman JL (2007) Expression of lymphotoxin-alphabeta on antigen-specific T cells is required for DC function. J Exp Med 204:1071–1081CrossRefPubMedGoogle Scholar
  12. 12.
    Bennett SR, Carbone FR, Karamalis F, Flavell RA, Miller JF, Heath WR (1998) Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393:478–480CrossRefPubMedGoogle Scholar
  13. 13.
    Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ (1998) T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393:480–483CrossRefPubMedGoogle Scholar
  14. 14.
    Ridge JP, Di Rosa F, Matzinger P (1998) A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393:474–478CrossRefPubMedGoogle Scholar
  15. 15.
    Wong BR, Josien R, Choi Y (1999) TRANCE is a TNF family member that regulates dendritic cell and osteoclast function. J Leukoc Biol 65:715–724PubMedGoogle Scholar
  16. 16.
    Wong BR, Josien R, Lee SY, Sauter B, Li HL, Steinman RM, Choi Y (1997) TRANCE (Tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor [In Process Citation]. J Exp Med 186:2075–2080CrossRefPubMedGoogle Scholar
  17. 17.
    Ngo VN, Korner H, Gunn MD, Schmidt KN, Riminton DS, Cooper MD, Browning JL, Sedgwick JD, Cyster JG (1999) Lymphotoxin alpha/beta and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen. J Exp Med 189:403–412CrossRefPubMedGoogle Scholar
  18. 18.
    Browning JL, Allaire N, Ngam-Ek A, Notidis E, Hunt J, Perrin S, Fava RA (2005) Lymphotoxin-beta receptor signaling is required for the homeostatic control of HEV differentiation and function. Immunity 23:539–550CrossRefPubMedGoogle Scholar
  19. 19.
    Drayton DL, Ying X, Lee J, Lesslauer W, Ruddle NH (2003) Ectopic LT alpha beta directs lymphoid organ neogenesis with concomitant expression of peripheral node addressin and a HEV-restricted sulfotransferase. J Exp Med 197:1153–1163CrossRefPubMedGoogle Scholar
  20. 20.
    Gommerman JL, Browning JL (2003) Lymphotoxin/light, lymphoid microenvironments and autoimmune disease. Nat Rev Immunol 3:642–655CrossRefPubMedGoogle Scholar
  21. 21.
    Vu F, Dianzani U, Ware CF, Mak T, Gommerman JL (2008) ICOS, CD40, and Lymphotoxin {beta} receptors signal sequentially and interdependently to initiate a germinal center reaction. J Immunol 180:2284–2293PubMedGoogle Scholar
  22. 22.
    Ansel KM, Ngo VN, Hyman PL, Luther SA, Forster R, Sedgwick JD, Browning JL, Lipp M, Cyster JG (2000) A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406:309–314CrossRefPubMedGoogle Scholar
  23. 23.
    Kabashima K, Banks TA, Ansel KM, Lu TT, Ware CF, Cyster JG (2005) Intrinsic lymphotoxin-beta receptor requirement for homeostasis of lymphoid tissue dendritic cells. Immunity 22:439–450CrossRefPubMedGoogle Scholar
  24. 24.
    Guo Z, Wang J, Meng L, Wu Q, Kim O, Hart J, He G, Zhou P, Thistlethwaite JR, Jr, Alegre ML, Fu YX, Newell KA (2001) Cutting edge: membrane lymphotoxin regulates CD8(+) T cell-mediated intestinal allograft rejection. J Immunol 167:4796–4800PubMedGoogle Scholar
  25. 25.
    Tamada K, Tamura H, Flies D, Fu YX, Celis E, Pease LR, Blazar BR, Chen L (2002) Blockade of LIGHT/LTbeta and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease. J Clin Invest 109:549–557PubMedGoogle Scholar
  26. 26.
    Mebius RE (2003) Organogenesis of lymphoid tissues. Nat Rev Immunol 3:292–303CrossRefPubMedGoogle Scholar
  27. 27.
    Rennert PD, James D, Mackay F, Browning JL, Hochman PS (1998) Lymph node genesis is induced by signaling through the lymphotoxin beta receptor. Immunity 9:71–79CrossRefPubMedGoogle Scholar
  28. 28.
    Muller G, Lipp M (2003) Concerted action of the chemokine and lymphotoxin system in secondary lymphoid-organ development. Curr Opin Immunol 15:217–224CrossRefPubMedGoogle Scholar
  29. 29.
    Gonzalez M, Mackay F, Browning JL, Kosco-Vilbois MH, Noelle RJ (1998) The sequential role of lymphotoxin and B cells in the development of splenic follicles. J Exp Med 187: 997–1007CrossRefPubMedGoogle Scholar
  30. 30.
    Gommerman JL, Mackay F, Donskoy E, Meier W, Martin P, Browning JL (2002) Manipulation of lymphoid microenvironments in nonhuman primates by an inhibitor of the lymphotoxin pathway. J Clin Invest 110:1359–1369PubMedGoogle Scholar
  31. 31.
    Mackay F, Browning JL (1998) Turning off follicular dendritic cells. Nature 395:26–27CrossRefPubMedGoogle Scholar
  32. 32.
    Soderberg KA, Linehan MM, Ruddle NH, Iwasaki A (2004) MAdCAM-1 expressing sacral lymph node in the lymphotoxin beta-deficient mouse provides a site for immune generation following vaginal herpes simplex virus-2 infection. J Immunol 173:1908–1913PubMedGoogle Scholar
  33. 33.
    Liao S, Ruddle NH (2006) Synchrony of high endothelial venules and lymphatic vessels revealed by immunization. J Immunol 177:3369–3379PubMedGoogle Scholar
  34. 34.
    Boehm T, Scheu S, Pfeffer K, Bleul CC (2003) Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTbetaR. J Exp Med 198:757–769CrossRefPubMedGoogle Scholar
  35. 35.
    Seach N, Ueno T, Fletcher AL, Lowen T, Mattesich M, Engwerda CR, Scott HS, Ware CF, Chidgey AP, Gray DH, Boyd RL (2008) The lymphotoxin pathway regulates Aire-independent expression of ectopic genes and chemokines in thymic stromal cells. J Immunol 180:5384–5392PubMedGoogle Scholar
  36. 36.
    Zhu M, Chin RK, Tumanov AV, Liu X, Fu YX (2007) Lymphotoxin beta receptor is required for the migration and selection of autoreactive T cells in thymic medulla. J Immunol 179:8069–8075PubMedGoogle Scholar
  37. 37.
    Lorenz RG, Chaplin DD, McDonald KG, McDonough JS, Newberry RD (2003) Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin beta receptor, and TNF receptor I function. J Immunol 170: 5475–5482PubMedGoogle Scholar
  38. 38.
    Newberry RD, McDonough JS, McDonald KG, Lorenz RG (2002) Postgestational lymphotoxin/lymphotoxin beta receptor interactions are essential for the presence of intestinal B lymphocytes. J Immunol 168:4988–4997PubMedGoogle Scholar
  39. 39.
    Kang HS, Chin RK, Wang Y, Yu P, Wang J, Newell KA, Fu YX (2002) Signaling via LTbetaR on the lamina propria stromal cells of the gut is required for IgA production. Nat Immunol 3:576–582CrossRefPubMedGoogle Scholar
  40. 40.
    Dohi T, Rennert PD, Fujihashi K, Kiyono H, Shirai Y, Kawamura YI, Browning JL, McGhee JR (2001) Elimination of colonic patches with lymphotoxin beta receptor-Ig prevents Th2 cell-type colitis. J Immunol 167:2781–2790PubMedGoogle Scholar
  41. 41.
    Wang YG, Kim KD, Wang J, Yu P, Fu YX (2005) Stimulating lymphotoxin beta receptor on the dendritic cells is critical for their homeostasis and expansion. J Immunol 175:6997–7002PubMedGoogle Scholar
  42. 42.
    Abe K, Yarovinsky FO, Murakami T, Shakhov AN, Tumanov AV, Ito D, Drutskaya LN, Pfeffer K, Kuprash DV, Komschlies KL, Nedospasov SA (2003) Distinct contributions of TNF and LT cytokines to the development of dendritic cells in vitro and their recruitment in vivo. Blood 101:1477–1483CrossRefPubMedGoogle Scholar
  43. 43.
    De Trez C, Schneider K, Potter K, Droin N, Fulton J, Norris PS, Ha SW, Fu YX, Murphy T, Murphy KM, Pfeffer K, Benedict CA, Ware CF (2008) The inhibitory HVEM-BTLA pathway counter regulates lymphotoxin receptor signaling to achieve homeostasis of dendritic cells. J Immunol 180:238–248PubMedGoogle Scholar
  44. 44.
    Haybaeck J, Zeller N, Wolf MJ, Weber A, Wagner U, Kurrer MO, Bremer J, Iezzi G, Graf R, Clavien PA, Thimme R, Blum H, Nedospasov SA, Zatloukal K, Ramzan M, Ciesek S, Pietschmann T, Marche PN, Karin M, Kopf M, Browning JL, Aguzzi A, Heikenwalder M (2009) A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 16:295–308CrossRefPubMedGoogle Scholar
  45. 45.
    Lo JC, Wang Y, Tumanov AV, Bamji M, Yao Z, Reardon CA, Getz GS, Fu YX (2007) Lymphotoxin beta receptor-dependent control of lipid homeostasis. Science 316:285–288CrossRefPubMedGoogle Scholar
  46. 46.
    Tumanov AV, Koroleva EP, Christiansen PA, Khan MA, Ruddy MJ, Burnette B, Papa S, Franzoso G, Nedospasov SA, Fu YX, Anders RA (2009) T cell-derived lymphotoxin regulates liver regeneration. Gastroenterology 136:694–704 e694CrossRefPubMedGoogle Scholar
  47. 47.
    Villanueva A, Savic R, Llovet JM (2009) Lymphotoxins: new targets for hepatocellular carcinoma. Cancer Cell 16:272–273CrossRefPubMedGoogle Scholar
  48. 48.
    Elewaut D, Brossay L, Santee SM, Naidenko OV, Burdin N, De Winter H, Matsuda J, Ware CF, Cheroutre H, Kronenberg M (2000) Membrane lymphotoxin is required for the development of different subpopulations of NK T cells. J Immunol 165:671–679PubMedGoogle Scholar
  49. 49.
    Iizuka K, Chaplin DD, Wang Y, Wu Q, Pegg LE, Yokoyama WM, Fu YX (1999) Requirement for membrane lymphotoxin in natural killer cell development. Proc Natl Acad Sci U S A 96:6336–6340CrossRefPubMedGoogle Scholar
  50. 50.
    Ruddle NH (1999) Lymphoid neo-organogenesis: lymphotoxin’s role in inflammation and development. Immunol Res 19:119–125CrossRefPubMedGoogle Scholar
  51. 51.
    Geurtsvan Kessel CH, Willart MA, Bergen IM, van Rijt LS, Muskens F, Elewaut D, Osterhaus AD, Hendriks R, Rimmelzwaan GF, Lambrecht BN (2009) Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J Exp Med 206:2339–2349CrossRefGoogle Scholar
  52. 52.
    Grabner R, Lotzer K, Dopping S, Hildner M, Radke D, Beer M, Spanbroek R, Lippert B, Reardon CA, Getz GS, Fu YX, Hehlgans T, Mebius RE, van der Wall M, Kruspe D, Englert C, Lovas A, Hu D, Randolph GJ, Weih F, Habenicht AJ (2009) Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J Exp Med 206:233–248CrossRefPubMedGoogle Scholar
  53. 53.
    Wu Q, Salomon B, Chen M, Wang Y, Hoffman LM, Bluestone JA, Fu YX (2001) Reversal of spontaneous autoimmune insulitis in nonobese diabetic mice by soluble lymphotoxin receptor. J Exp Med 193:1327–1332CrossRefPubMedGoogle Scholar
  54. 54.
    Ettinger R, Munson SH, Chao CC, Vadeboncoeur M, Toma J, and McDevitt HO (2001) A critical role for lymphotoxin-beta receptor in the development of diabetes in nonobese diabetic mice. J Exp Med 193:1333–1340CrossRefPubMedGoogle Scholar
  55. 55.
    Levisetti MG, Suri A, Frederick K, Unanue ER (2004) Absence of lymph nodes in NOD mice treated with lymphotoxin-beta receptor immunoglobulin protects from diabetes. Diabetes 53:3115–3119CrossRefPubMedGoogle Scholar
  56. 56.
    Lee Y, Chin RK, Christiansen P, Sun Y, Tumanov AV, Wang J, Chervonsky AV, Fu YX (2006) Recruitment and activation of naive T cells in the islets by lymphotoxin beta receptor-dependent tertiary lymphoid structure. Immunity 25:499–509CrossRefPubMedGoogle Scholar
  57. 57.
    Boraska V, Zeggini E, Groves CJ, Rayner NW, Skrabic V, Diakite M, Rockett KA, Kwiatkowski D, McCarthy MI, Zemunik T (2009) Family-based analysis of tumor necrosis factor and lymphotoxin-alpha tag polymorphisms with type 1 diabetes in the population of South Croatia. Hum Immunol 70:195–199CrossRefPubMedGoogle Scholar
  58. 58.
    Stayoussef M, Al-Jenaidi FA, Al-Abbasi A, Al-Ola K, Khayyat H, Mahjoub T, Almawi WY (2008) Modulation of type 1 diabetes susceptibility by tumor necrosis factor alpha -308 G/A and lymphotoxin alpha +249 A/G haplotypes and lack of linkage disequilibrium with predisposing DQB1-DRB1 haplotypes in Bahraini patients. Clin Vaccine Immunol 15:379–381CrossRefPubMedGoogle Scholar
  59. 59.
    Braun A, Takemura S, Vallejo AN, Goronzy JJ, Weyand CM (2004) Lymphotoxin beta-mediated stimulation of synoviocytes in rheumatoid arthritis. Arthritis Rheum 50:2140–2150CrossRefPubMedGoogle Scholar
  60. 60.
    Chin RK, Zhu M, Christiansen PA, Liu W, Ware C, Peltonen L, Zhang X, Guo L, Han S, Zheng B, Fu YX (2006) Lymphotoxin pathway-directed, autoimmune regulator-independent central tolerance to arthritogenic collagen. J Immunol 177:290–297PubMedGoogle Scholar
  61. 61.
    Han S, Zhang X, Marinova E, Ozen Z, Bheekha-Escura R, Guo L, Wansley D, Booth G, Fu YX, Zheng B (2005) Blockade of lymphotoxin pathway exacerbates autoimmune arthritis by enhancing the Th1 response. Arthritis Rheum 52:3202–3209CrossRefPubMedGoogle Scholar
  62. 62.
    Chiang EY, Kolumam GA, Yu X, Francesco M, Ivelja S, Peng I, Gribling P, Shu J, Lee WP, Refino CJ, Balazs M, Paler-Martinez A, Nguyen A, Young J, Barck KH, Carano RA, Ferrando R, Diehl L, Chatterjea D, Grogan JL (2009) Targeted depletion of lymphotoxin-alpha-expressing TH1 and TH17 cells inhibits autoimmune disease. Nat Med 15:766–773CrossRefPubMedGoogle Scholar
  63. 63.
    O’Rourke KP, O’Donoghue G, Adams C, Mulcahy H, Molloy C, Silke C, Molloy M, Shanahan F, O’Gara F (2008) High levels of Lymphotoxin-Beta (LT-Beta) gene expression in rheumatoid arthritis synovium: clinical and cytokine correlations. Rheumatol Int 28: 979–986CrossRefPubMedGoogle Scholar
  64. 64.
    Kang YM, Kim SY, Kang JH, Han SW, Nam EJ, Kyung HS, Park JY, Kim IS (2007) LIGHT up-regulated on B lymphocytes and monocytes in rheumatoid arthritis mediates cellular adhesion and metalloproteinase production by synoviocytes. Arthritis Rheum 56:1106–1117CrossRefPubMedGoogle Scholar
  65. 65.
    Gommerman JL, Giza K, Perper S, Sizing I, Ngam-Ek A, Nickerson-Nutter C, Browning JL (2003) A role for surface lymphotoxin in experimental autoimmune encephalomyelitis independent of LIGHT. J Clin Invest 112:755–767PubMedGoogle Scholar
  66. 66.
    Columba-Cabezas S, Griguoli M, Rosicarelli B, Magliozzi R, Ria F, Serafini B, Aloisi F (2006) Suppression of established experimental autoimmune encephalomyelitis and formation of meningeal lymphoid follicles by lymphotoxin beta receptor-Ig fusion protein. J Neuroimmunol 179:76–86CrossRefPubMedGoogle Scholar
  67. 67.
    Hjelmervik TO, Petersen K, Jonassen I, Jonsson R, Bolstad AI (2005) Gene expression profiling of minor salivary glands clearly distinguishes primary Sjogren’s syndrome patients from healthy control subjects. Arthritis Rheum 52:1534–1544CrossRefPubMedGoogle Scholar
  68. 68.
    Gatumu MK, Skarstein K, Papandile A, Browning JL, Fava RA, Bolstad AI (2009) Blockade of lymphotoxin-beta receptor signaling reduces aspects of Sjogren’s syndrome in salivary glands of non-obese diabetic mice. Arthritis Res Ther 11:R24CrossRefPubMedGoogle Scholar
  69. 69.
    Mackay F, Browning JL, Lawton P, Shah SA, Comiskey M, Bhan AK, Mizoguchi E, Terhorst C, Simpson SJ (1998) Both the lymphotoxin and tumor necrosis factor pathways are involved in experimental murine models of colitis. Gastroenterology 115:1464–1475CrossRefPubMedGoogle Scholar
  70. 70.
    Stopfer P, Obermeier F, Dunger N, Falk W, Farkas S, Janotta M, Moller A, Mannel DN, Hehlgans T (2004) Blocking lymphotoxin-beta receptor activation diminishes inflammation via reduced mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression and leucocyte margination in chronic DSS-induced colitis. Clin Exp Immunol 136:21–29CrossRefPubMedGoogle Scholar
  71. 71.
    An MM, Fan KX, Zhang JD, Li HJ, Song SC, Liu BG, Gao PH, Zhou Q, Jiang YY (2005) Lymphtoxin beta receptor-Ig ameliorates TNBS-induced colitis via blocking LIGHT/HVEM signaling. Pharmacol Res 52:234–244CrossRefPubMedGoogle Scholar
  72. 72.
    Jungbeck M, Stopfer P, Bataille F, Nedospasov SA, Mannel DN, Hehlgans T (2008) Blocking lymphotoxin beta receptor signalling exacerbates acute DSS-induced intestinal inflammation – opposite functions for surface lymphotoxin expressed by T and B lymphocytes. Mol Immunol 45:34–41CrossRefPubMedGoogle Scholar
  73. 73.
    Shao H, Fu Y, Song L, Sun S, Kaplan HJ, Sun D (2003) Lymphotoxin beta receptor-Ig fusion protein treatment blocks actively induced, but not adoptively transferred, uveitis in Lewis rats. Eur J Immunol 33:1736–1743CrossRefPubMedGoogle Scholar
  74. 74.
    Wu Q, Fu YX, Sontheimer RD (2004) Blockade of lymphotoxin signaling inhibits the clinical expression of murine graft-versus-host skin disease. J Immunol 172:1630–1636PubMedGoogle Scholar
  75. 75.
    Xu Y, Flies AS, Flies DB, Zhu G, Anand S, Flies SJ, Xu H, Anders RA, Hancock WW, Chen L, Tamada K (2007) Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease. Blood 109:4097–4104CrossRefPubMedGoogle Scholar
  76. 76.
    Fan K, Wang H, Wei H, Zhou Q, Kou G, Hou S, Qian W, Dai J, Li B, Zhang Y, Zhu T, Guo Y (2007) Blockade of LIGHT/HVEM and B7/CD28 signaling facilitates long-term islet graft survival with development of allospecific tolerance. Transplantation 84:746–754CrossRefPubMedGoogle Scholar
  77. 77.
    Markey KA, Burman AC, Banovic T, Kuns RD, Raffelt NC, Rowe V, Olver SD, Don AL, Morris ES, Pettit AR, Wilson YA, Robb RJ, Randall LM, Korner H, Engwerda CR, Clouston AD, Macdonald KP, Hill GR (2010) Soluble lymphotoxin is an important effector molecule in GVHD and GVL. Blood 115:122–132CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of ImmunologyUniversity of TorontoTorontoCanada

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