Targeted therapy to the IL-2R using diphtheria toxin and caspase-3 fusion proteins modulates Treg and ameliorates inflammatory colitis

European Journal of Immunology

Volumn 39, Issue 10, 2009, Pages 2850-2864

  Yarkoni, Shai ^a   Sagiv, Yuval ^a   Kaminitz, Ayelet ^b   Farkas, Daniel L ^c   Askenasy, Nadir ^b,c  

^a GASR Biotechnology   (Israel)

^b SCHNEIDER CHILDREN S MEDICAL CENTER OF ISRAEL   (Israel)

^c CEDARS SINAI MEDICAL CENTER   (United States)

Author keywords

Apoptosis; Colitogenic T cells; IL 2 fusion proteins; Inflammatory bowel disease; Treg

Indexed keywords

CD4 ANTIGEN; DENILEUKIN DIFTITOX; IMMUNOMODULATING AGENT; INTERLEUKIN 2 CASPASE 3 FUSION PROTEIN; INTERLEUKIN 2 RECEPTOR; INTERLEUKIN 2 RECEPTOR ALPHA; TRANSCRIPTION FACTOR FOXP3; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; APOPTOSIS; ARTICLE; CD25+ T LYMPHOCYTE; COLITIS; CONTROLLED STUDY; DRUG EFFICACY; DRUG MEGADOSE; DRUG TARGETING; IN VITRO STUDY; INTERNALIZATION; LOW DRUG DOSE; LYMPHOCYTOPENIA; MESENTERY LYMPH NODE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTECTION; PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; T CELL DEPLETION;

ANIMALS; APOPTOSIS; BODY WEIGHT; CASPASE 3; CELL PROLIFERATION; COLON; DEXTRAN SULFATE; DIPHTHERIA TOXIN; DRUG DELIVERY SYSTEMS; FORKHEAD TRANSCRIPTION FACTORS; INFLAMMATORY BOWEL DISEASES; INTERLEUKIN-2; LYMPH NODES; MALE; MICE; MICE, INBRED BALB C; RECEPTORS, INTERLEUKIN-2; RECOMBINANT FUSION PROTEINS; SPLEEN; SURVIVAL ANALYSIS; T-LYMPHOCYTE SUBSETS; T-LYMPHOCYTES, REGULATORY; TRINITROBENZENESULFONIC ACID;

EID: 70350547785     PISSN: 00142980     EISSN: 15214141     Source Type: Journal    
DOI: 10.1002/eji.200839190     Document Type: Article

References (86)

1. Kitajima, S., Takoma, S. and Morimoto, M., Changes in colonic mucosal permeability mouse 1. Podolsky, D. K., Inflammatory bowel disease. N. Engl. J. Med. 2002. 347: 417-429.
2. Strober, W., Fuss, I. J. and Blumberg, R. S., The immunology of mucosal models of inflammation. Annu. Rev. Immunol. 2002. 20: 495-549
3. Bamias, G., Nyce, M. R., De La Rue, S. A. and Cominelli, F., New concepts in the pathophysiology of inflammatory bowel disease. Ann. Intern. Med. 2005. 143: 895-904.
4. Neurath, M. F., Finotto, S., Fuss, I., Boirivant, M., Galle, P. R. and Strober, W., Regulation of T-cell apoptosis in inflammatory bowel disease: to die or not to die, that is the mucosal question. Trends Immunol. 2001. 22: 21-26. (Pubitemid 32675276)
5. Peppelenbosch, M. P. and van Deventer, S. J., T cell apoptosis and inflammatory bowel disease. Gut 2004. 53: 1556-1558. (Pubitemid 39434092)
6. Mudter, J. and Neurath, M. F., Apoptosis of T cells and the control of inflammatory bowel disease: therapeutic implications. Gut 2007. 56: 293-303. (Pubitemid 46246220)
7. Boirivant, M., Marini, M., Di Felice, G., Pronio, A. M., Montesani, C., Tersigni, R. and Strober, W., Lamina propria T cells in Crohn's disease and other gastrointestinal inflammation show defective CD2 pathway induced apoptosis. Gastroenterology 1999. 116: 557-565 (Pubitemid 29106763)
8. Ina, K., Itoh, J., Fukushima, K., Kusugami, K., Yamaguchi, T., Kyokane, K., Imada, A. et al., Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance. J. Immunol. 1999. 163: 1081-1090 (Pubitemid 29328123)
9. Atreya, R., Mudter, J., Finotto, S., Müllberg, J., Jostock, T., Wirtz, S., Schütz, M. et al., Blockade of IL-6 transsignaling suppresses T cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn's disease and experimental colitis in vivo. Nat. Med. 2000. 6: 583-588.
10. Sturm, A., Leite, A. Z., Danese, S., Krivacic, K. A., West, G. A., Mohr, S., Jacobberger, J. W. and Fiocchi, C., Divergent cell cycle kinetics underlie the distinct functional capacity of mucosal T cells in Crohn's disease and ulcerative colitis. Gut 2004. 53: 1624-1631. (Pubitemid 39434106)
11. Sturm, A., Mohr, S. and Fiocchi, C., Critical role of caspases in the regulation of apoptosis and proliferation of mucosal T cells. Gastroenterology 2002. 122: 1334-1345. (Pubitemid 34465176)
12. Doering, J., Begue, B., Lentze, M. J., Rieux-Laucat, F., Goulet, O., Schmitz, J., Cerf-Bensussan, N. and Ruemmele, F. M., Induction of T lymphocyte apoptosis by sulphasalazine in patients with Crohn's disease. Gut 2004. 53: 1632-1638. (Pubitemid 39434107)
13. Mullin, G. E., Lazenby, A. J., Harris, M. L., Bayless, T. M. and James, S. P., Increased interleukin-2 messenger RNA in the intestinal mucosal lesions of Crohn's disease but not ulcerative colitis. Gastroenterology 1992. 102: 1620-1627.
14. Sparano, J. A., Brandt, L. J., Dutcher, J. P., DuBois, J. S. and Atkins, M. B., Symptomatic exacerbation of Crohn disease after treatment with high-dose interleukin-2. Ann. Intern. Med. 1993. 118: 617-618.
15. Creed, T. J., Probert, C. S., Norman, M. N., Moorghen, M., Shepherd, N. A., Hearing, S. D. and Dayan, C. M., Basiliximab for the treatment of steroid-resistant ulcerative colitis: further experience in moderate and severe disease. Aliment. Pharmacol. Ther. 2006. 23: 1435-1442.
16. Van Assche, G., Sandborn, W. J., Feagan, B. G., Salzberg, B. A., Silvers, D., Monroe, P. S., Pandak, W. M. et al., Daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), for the treatment of moderately to severely active ulcerative colitis: a randomised, double blind, placebo controlled, dose ranging trial. Gut 2006. 55: 1568-1574. (Pubitemid 44629204)
17. Yarkoni, S., Kaminitz, A., Sagiv, Y., Yaniv, I. and Askenasy, N., Involvement of IL-2 in homeostasis of regulatory T cells: the IL-2 cycle. Bioessays 2008. 30: 875-888.
18. Boyman, O., Kovar, M., Rubinstein, M. P., Surh, C. D. and Sprent, J., Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 2006. 311: 1924-1927.
19. Furtado, G. C., Curotto de Lafaille, M. A., Kutchukhidze, N. and Lafaille, J. J., Interleukin 2 signaling is required for CD4 (+) regulatory T cell function. J. Exp. Med. 2002. 196: 851-857.
20. Malek, T. R. and Bayer, A. L., Tolerance, not immunity, crucially depends on IL-2. Nat. Rev. Immunol. 2004. 4: 665-674.
21. Fujii, M., Sugamura, K., Sano, K., Nakai, M., Sugita, K. and Hinuma, Y., High-affinity receptor-mediated internalization and degradation of interleukin 2 in human T cells. J. Exp. Med. 1986. 163: 550-562.
22. Eklund, J. W. and Kuzel, T. M., Denileukin diftitox: a concise clinical review. Expert Rev. Anticancer Ther. 2005. 5: 33-38.
23. Pacheco-Solva, A., Bastos, M. G., Pankewycz, O., Nichols, J., Murphy, J. R., Strom, T. B. and Rubin-Kelley, V. E., IL-2 toxin treatment blocks diabetogenic autoimmunity in NOD mice. Eur. J. Immunol. 1992. 22: 697-702.
24. Woodworth, T. G., Early clinical studies of IL-2 fusion toxin in patients with severe rheumatoid arthritis and recently onset insulin-dependent diabetes mellitus. Clin. Exp. Rheumatol. 1993. 8: S177-S180.
25. Phillips, S. M., Bhopale, M. K., Constantinescu, C. S., Ciric, B., Hilliard, B., Ventura, E., Lavi, E. and Rostami, A., Effect of DAB(389)IL-2 immunotoxin on the course of experimental autoimmune encephalomyelitis in Lewis rats. J. Neurol. Sci. 2007. 263: 59-69.
26. Bousvaros, A., Stevens, A. C., Strom, T. B., Murphy, J. and Lamont, J. T., Interleukin-2 fusion protein (DAB389IL-2) selectively targets activated human peripheral blood and lamina propria lymphocytes. Dig. Dis. Sci. 1997. 42: 1542-1548.
27. Shteingart, S., Rapoport, M., Grodzovski, I., Sabag, O., Lichtenstein, M., Eavri, R. and Lorberboum-Galski, H., Therapeutic potency of IL2-caspase3 targeted treatment in a murine experimental model of inflammatory bowel disease (IBD). Gut 2009, 58: 790-798.
28. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. and Toda, M., Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor a-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 1995. 155: 1151-1164.
29. Lan, R. Y., Mackay, I. R. and Gershwin, M. E., Regulatory T cells in the prevention of mucosal inflammatory diseases: patrolling the border. J. Autoimmun. 2007. 29: 272-280.
30. Sadlack, B., Merz, H., Schorle, H., Schimpl, A., Feller, A. C. and Horak, I., Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 1993. 75: 203-205. (Pubitemid 23320289)
31. Ehrhardt, R. O., Ludviksson, B. R., Gray, B., Neurath, M. and Strober, W., Induction and prevention of colonic inflammation in IL-2-deficient mice. J. Immunol. 1997. 158: 566-573. (Pubitemid 127492631)
32. Contractor, N. V., Bassirir, H., Reya, T., Park, A. Y., Baumgart, D. C., Wasik, M. A., Emerson, S. G. and Carding, S. R., Lymphoid hyperplasia, autoimmunity, and compromised intestinal intraepithelial lymphocyte development in colitis-free gnotobiotic IL-2-deficient mice. J. Immunol. 1998. 75: 253-261. (Pubitemid 28116753)
33. Poussier, P., Ning, T., Chen, J., Banerjee, D. and Julius, M., Intestinal inflammation observed in IL-2R/IL-2 mutant mice is associated with impaired intestinal T lymphopoiesis. Gastroenterology 2000. 118: 880-891. (Pubitemid 30243751)
34. Setoguchi, R., Hori, S., Takahashi, T., Sakaguchi, S., Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J. Exp. Med. 2005. 201: 723-735.
35. Singh, B., Read, S., Asseman, C., Malmström, V., Mottet, C., Stephens, L. A., Stepankova, R. et al., Control of intestinal inflammation by regulatory T cells. Immunol. Rev. 2001. 182: 190-200.
36. + regulatory T cells cure murine colitis: the role of IL-10, TGF-β, and CTLA4. J. Immunol. 2003. 171: 5012-5017.
37. + regulatory T cells is not essential for suppression of intestinal inflammation. Eur. J. Immunol. 2005. 35: 2886-2895.
38. Paust, S. and Cantor, H., Regulatory T cells and autoimmune disease. Immunol. Rev. 2005. 204: 195-207.
39. + T cells regulate colonic localization of CD4 T cells reactive to a microbial antigen. Inflamm. Bowel Dis. 2005. 11: 541-550.
40. Fantini, M. C., Becker, C., Tubbe, I., Nikolaev, A., Lehr, H. A., Galle, P. and Neurath, M. F., Transforming growth factor beta induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis. Gut 2006. 55: 671-680.
41. +CD44highCD62L- effector memory T cells. Am. J. Physiol. Gastrointest. Liver Physiol. 2006. 290: G1051-G1058.
42. Mottet, C., Uhlig, H. H. and Powrie, F., Cutting edge: cure of colitis by CD4+CD25+regulatory T cells. J. Immunol. 2003. 170: 3939-3943.
43. Asano, M., Toda, M., Sakaguchi, N. and Sakaguchi, S., Autoimmune diseases as a consequence of developmental abnormality of a T cell population. J. Exp. Med. 1996. 184: 387-396.
44. González, M. A., Gonzalez-Rey, E., Rico, L., Büscher, D. and Delgado, M., Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology 2009. 136: 978-989.
45. Fontenot, J. D., Gavin, M. A. and Rudensky, A. Y., Foxp3 programs the development and function of CD4(+)CD25(+) regulatory T cells. Nat. Immunol. 2003. 4: 330-336.
46. Hori, S., Nomura, T. and Sakaguchi, S., Control of regulatory T cell development by the transcription factor Foxp3. Science 2003. 299: 1057-1061. (Pubitemid 36222930)
47. Kitajima, S., Takoma, S. and Morimoto, M., Changes in colonic mucosal permeability mouse colitis induced with dextran sulfate sodium. Exp. Anim. 1999. 48: 137-143.
48. Egger, B., Bajaj-Elliott, M., MacDonald, T. T., Inglin, R., Eysselein, V. E. and Büchler, M. W., Characterization of acute murine dextran sodium sulphate colitis: cytokine profile and dose dependency. Digestion 2000. 62: 240-248. (Pubitemid 30825398)
49. +-cell depleted, athymic and NK-cell depleted SCID mice. Inflamm. Res. 1996. 45: 181-191.
50. Mashimo, H., Wu, D. C., Podolsky, D. K. and Fishman, M. C., Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science 1996. 274: 262-265. (Pubitemid 26353206)
51. Tomita, T., Kanai, T., Fujii, T., Nemoto, Y., Okamoto, R., Tsuchiya, K., Totsuka, T. et al., Continuous generation of colitogenic CD4(+) T cells in persistent colitis. Eur. J. Immunol. 2008. 38: 1264-1274.
52. + T regulatory cells. J. Immunol. 2006. 176: 3301-3305.
53. + T cells are responsible for murine interleukin-2-deficient colitis. Eur. J. Immunol. 1995. 25: 2618-2625.
54. + T cells, are required for the development of experimental autoimmune gastritis. Immunology 1998. 93: 405-408.
55. Okamoto, S., Watanabe, M., Yamazaki, M., Yajima, T., Hayashi, T., Ishii, H., Mukai, M. et al., A synthetic mimetic of CD4 is able to suppress disease in rodent model of immune cells. Eur. J. Immunol. 1999. 29: 355-366
56. Pfister, K., Wittig, B. M., Jüngling, B., Ecker, K. W., Barth, S., Huhn, M., Sasse, S. et al., The in vitro anti-inflammatory effects of recombinant anti-CD25 immunotoxin on lamina propria T cells of patients with inflammatory bowel disease are not sufficient to cure experimental colitis in mice. Int. J. Colorectal Dis. 2002. 17: 77-84.
57. Knutson, K. L., Dang, Y., Lu, H., Lukas, J., Almand, B., Gad, E., Azeke, E. and Disis, ML., IL-2 immunotoxin therapy modulates tumor-associated regulatory T cells and leads to lasting immune-mediated rejection of breast cancers in neu-transgenic mice. J. Immunol. 2006. 177: 84-91. (Pubitemid 43939119)
58. Litzinger, M. T., Fernando, R., Curiel, T. J., Grosenbach, D. W., Schlom, J. and Palena, C., IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. Blood 2007. 110: 3192-3201. (Pubitemid 350106311)
59. King, C., Ilic, A., Koelsch, K. and Sarvetnick, N., Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell 2004. 117: 265-277. (Pubitemid 38496245)
60. Klebanoff, C. A., Khong, H. T. and Antony, P. A., Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 2005. 26: 111-117.
61. Fehervari, Z., Yamaguchi, T. and Sakaguchi, S., The dichotomous role of IL-2: tolerance versus immunity. Trends Immunol. 2006. 27: 109-111. (Pubitemid 43306803)
62. Dang, N. H., Pro, B., Hagemeister, F. B., Samaniego, F., Jones, D., Samuels, B. I., Rodriguez, M. A. et al., Phase II trial of denileukin diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma. Br. J. Haematol. 2007. 136: 439-447.
63. + immunoregulatory T cells in the induction of autoimmune gastritis. Immunol. Cell Biol. 2002. 80: 567-573.
64. + regulatory T cells and IL-10. J. Immunol. 2003. 171: 971-978.
65. Simon, G., Parker, M., Ramiya, V., Wasserfall, C., Huang, Y., Bresson, D., Schwartz, R. F. et al., Murine antithymocyte globulin therapy alters disease progression in NOD mice by a time-dependent induction of immunoregulation. Diabetes 2008. 57: 405-414.
66. Tang, Q., Adams, J. Y., Penaranda, C., Melli, K., Piaggio, E., Sgouroudis, E., Piccirillo, C. A., et al., Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 2008. 28: 687-697.
67. + regulatory T cells in pancreatic lymph nodes in diabetic NOD mice by adjuvant immunotherapy. Transplantation 2009. 87: 198-206.
68. + regulatory T cells. J. Immunol. 2006. 177: 3695-3704.
69. + regulatory T cells. Immunology 2007. 121: 15-28.
70. Fontenot, J. D., Rasmussen, J. P., Williams, L. M., Dooley, J. L., Farr, A. G. and Rudensky, A. Y., Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 2005. 22: 329-341. (Pubitemid 40387475)
71. Weber, S. E., Harbertson, J., Godebu, E., Mros, G. A., Padrick, R. C., Carson, B. D., Ziegler, S. F. and Bradley, L. M., Adaptive islet-specific regulatory CD4 T cells control autoimmune diabetes and mediate the disappearance of pathogenic Th1 cells in vivo. J. Immunol. 2006. 176: 4730-4739.
72. Yolcu, E. S., Ash, S., Kaminitz, A., Sagiv, Y., Askenasy, N. and Yarkoni, S., Apoptosis as a mechanism of T-regulatory cell homeostasis and suppression. Immunol. Cell Biol. 2008. 86: 650-658.
73. Willerford, D. M., Chen, J., Ferry, J. A., Davidson, L., Ma, A. and Alt, F. W., Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 1995. 3: 521-530.
74. Alam, A., Cohen, L. Y., Aouad, S. and Sekaly, R. P., Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. J. Exp. Med. 1999. 190: 1879-1890.
75. Kennedy, N. J., Kataoka, T., Tschopp, J. and Budd, R. C., Caspase activation is required for T cell proliferation. J. Exp. Med. 1999. 190: 1891-1896.
76. + regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 2003. 198: 1875-1886.
77. Bluestone, J. A. and Abbas, A. K., Natural versus adaptive regulatory T cells. Nat. Rev. Immunol. 2003. 3: 253-257.
78. Totsuka, T., Kanai, T., Nemoto, Y., Tomita, T., Tsuchiya, K., Sakamoto, N., Okamoto, R. and Watanabe, M., Immunosenescent colitogenic CD4(+) T cells convert to regulatory cells and suppress colitis. Eur. J. Immunol. 2008. 38: 1275-1286.
79. +CD25 T cells via p53, IL-2, and OX40. Proc. Natl. Acad. Sci. USA 2007. 104: 15478-15483.
80. + T regulatory cells. J. Immunol. 2007. 179: 154-161.
81. Fujii, T., Tomita, T., Kanai, T., Nemoto, Y., Totsuka, T., Sakamoto, N., Nakamura, T. et al., FTY720 suppresses the development of colitis in lymphoid-null mice by modulating the trafficking of colitogenic CD4(+) T cells in bone marrow. Eur. J. Immunol. 2008. 38: 3290-3303.
82. Askenasy, N., Kaminitz, A. and Yarkoni, S., Mechanisms of T regulatory cell function. Autoimmun. Rev. 2008. 7: 370-375.
83. Souza, H. S., Tortori, C. J., Castelo-Branco, M. T., Carvalho, A. T., Margallo, V. S., Delgado, C. F., Dines, I. and Elia, C. C., Apoptosis in the intestinal mucosa of patients with inflammatory bowel disease: evidence of altered expression of FasL and perforin cytotoxic pathways. Int. J. Colorectal Dis. 2005. 20: 277-286.
84. Fayad, R., Brand, M. I., Stone, D., Keshavarzian, A. and Qiao, L., Apoptosis resistance in ulcerative colitis: high expression of decoy receptors by lamina propria T cells. Eur. J. Immunol. 2006. 36: 2215-2222.
85. Itoh, J., de La Motte, C., Strong, S. A., Levine, A. D. and Fiocchi, C., Decreased Bax expression by mucosal T cells favours resistance to apoptosis in Crohn's disease. Gut 2001. 49: 35-41. (Pubitemid 32601877)
86. Festjens, N., van Gurp, M., van Loo, G., Saelens, X. and Vandenabeele, P., Bcl-2 family members as sentinels of cellular integrity and role of mitochondrial intermembrane space proteins in apoptotic cell death. Acta Haematol. 2004. 111: 7-27. (Pubitemid 37499952)