Cytokines as adjuvants for vaccine and cellular therapies for cancer

American Journal of Immunology

Volumn 5, Issue 3, 2009, Pages 65-83

  Capitini, Christian M ^a,c   Fry, Terry J ^a,b   Mackall, Crystal L ^a  

^a NATIONAL CANCER INSTITUTE   (United States)

^b CHILDREN'S NATIONAL MEDICAL CENTER   (United States)

^c NONE   (United States)

Author keywords

Interleukin 15; Interleukin 2; Interleukin 21; Interleukin 7; Tumor vaccines

Indexed keywords

CANCER VACCINE; INTERLEUKIN 15; INTERLEUKIN 15 RECEPTOR; INTERLEUKIN 2; INTERLEUKIN 21; INTERLEUKIN 7;

ACUTE GRANULOCYTIC LEUKEMIA; ANTINEOPLASTIC ACTIVITY; ARTICLE; AUTOIMMUNE DISEASE; AUTOIMMUNE THYROIDITIS; CANCER ADJUVANT THERAPY; CAPILLARY LEAK SYNDROME; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL ACTIVATION; CELL DIFFERENTIATION; CELL EXPANSION; CELL PROLIFERATION; CLINICAL TRIAL; COLON CANCER; CYTOTOXICITY; DEPRESSION; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG MEGADOSE; DRUG SAFETY; EWING SARCOMA; GENE OVEREXPRESSION; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; INSULIN DEPENDENT DIABETES MELLITUS; KIDNEY CARCINOMA; LOW DRUG DOSE; MALIGNANT NEOPLASTIC DISEASE; MELANOMA; MULTIPLE CYCLE TREATMENT; NATURAL KILLER CELL; NEUROBLASTOMA; NONHUMAN; OSTEOLYSIS; OVERALL SURVIVAL; REGULATORY T LYMPHOCYTE; SIDE EFFECT; SIGNAL TRANSDUCTION; T LYMPHOCYTE; TH17 CELL; UPREGULATION; VITILIGO;

EID: 70349560862     PISSN: 1553619X     EISSN: None     Source Type: Journal    
DOI: 10.3844/ajisp.2009.65.83     Document Type: Article

References (159)

1. Fehniger, T.A., M.A. Cooper and M.A. Caligiuri, 2002 Interleukin-2 and interleukin-15: Immunotherapy for cancer. Cytokine Growth Factor Rev., 13:169-183 http://www.ncbi.nlm.nih.gov/pubmed/11900992
2. Waldmann, T.A., 2006. The biology of interleukin-2 and interleukin-15: Implications for cancer therapy and vaccine design. Nature Rev. Immunol., 6: 595-601. http://www.nature.com/nri/journal/v6/n8/abs/ nri1901.html
3. Zhang, H., K.S. Chua and M. Guimond et al., 2005. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nat. Med., 11: 1238-1243. http://www.ncbi.nlm.nih.gov/pubmed/16227988
4. Chapman, P.B., 2008. Combining a peptide vaccine with high-dose interleukin-2. J. Clin. Oncol., 26: 2250-2251. http://www.ncbi.nlm.nih.gov/pubmed/18467715
5. Coppin, C., 2008. Immunotherapy for renal cell cancer in the era of targeted therapy. Expert Rev. Anticancer Ther., 8: 907-919. http://www.ncbi.nlm.nih.gov/pubmed/18533800
6. Rosenberg, S.A., J.C. Yang and D.J. Schwartzentruber et al., 1998. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nature Med., 4: 321-327 http://www.ncbi.nlm.nih.gov/pubmed/9500606
7. Rosenberg, S.A., J.C. Yang and D.J. Schwartzentruber et al., 1999. Impact of cytokine administration on the generation of antitumor reactivity in patients with metastatic melanoma receiving a peptide vaccine. J. Immunol., 163: 1690-1695. http://www.pubmedcentral.nih.gov/ articlerender.fcgi?artid=2249693
8. Roberts, J.D., D. Niedzwiecki and W.E. Carson et al., 2006. Phase 2 study of the g209-2M melanoma peptide vaccine and low-dose interleukin-2 in advanced melanoma. J. Immunotherapy, 29: 95-101. http://www.ncbi.nlm.nih.gov/pubmed/16365605
9. Sosman, J.A., C. Carrillo, W.J. Urba et al., 2008. Three phase II cytokine working group trials of gp100 (210M) peptide plus high-dose interleukin-2 in patients with HLA-A2-positive advanced melanoma. J. Clin. Oncol., 26: 2292-2298. http://www.ncbi.nlm.nih.gov/pubmed/18467720
10. Slingluff, C.L., G.R. Petroni and G.V. Yamshchikov et al., 2004. Immunologic and clinical outcomes of vaccination with a multiepitope melanoma peptide vaccine plus low-dose interleukin-2 administered either concurrently or on a delayed schedule. J. Clin. Oncol., 22: 4474-4485. DOI: 10.1200/JCO.2004.10.212
11. Hersey, P., G. Halliday, M. Farrelly, C. DeSilva, M. Lett and S. Menzies, 2008. Phase I/II study of treatment with matured dendritic cells with or without low dose IL-2 in patients with disseminated melanoma. Cancer Immunol. Immunotherapy, 57: 1039-1051. http://www.ncbi.nlm.nih.gov/pubmed/18157724
12. Panelli, M.C., J. Wunderlich and J. Jeffries, et al., 2000. Phase 1 study in patients with metastatic melanoma of immunization with dendritic cell presenting epitopes derived from the melanoma-associated antigens MART-1 and gp100. J. Immunotherapy, 23: 487-498. http://cat.inist.fr/?aModele=afficheN&cpsidt=1430817
13. Redman, B.G., A.E. Chang and J. Whitfield et al., 2008. Phase IB trial assessing autologous, tumor-pulsed dendritic cells as a vaccine administered with or without IL-2 in patients with metastatic melanoma. J. Immunotherapy, 31: 591-598. http://www.ncbi.nlm.nih.gov/pubmed/ 18528294
14. Nagayama, H., K. Sato and M. Morishita et al., 2003. Results of a phase I clinical study using autologous tumor lysate-pulsed monocyte-derived mature dendritic cell vaccinations for stage IV malignant melanoma patients combined with low dose interleukin-2. Melanoma Res., 13: 521-530. http://direct.bl.uk/bld/ PlaceOrder.do?UIN=137327593&ETOC=RN&from=searchengine
15. Haenssle, H., S.W. Krause and S. Emmert et al., 2004. Hydrid cell vaccination in metastatic melanoma: Clinical and immunologic results of a phase I/II study. J. Immunother., 27: 147-155. http://cat.inist.fr/ ?aModele=afficheN&cpsidt=15570299
16. Escobar, A., M. Lopez and A. Serrano et al., 2005. Dendritic cell immunizations alone or combined with low doses of interleukin-2 induce specific immune responses in melanoma patients. Clin. Exp. Immunol., 142: 555-568. DOI: 10.1111/j.1365-2249.2005.02948.x
17. Wei, Y., R.P. Sticca and L.M. Holmes et al., 2006. Dendritoma vaccination combined with low dose interleukin-2 in metastatic melanoma patients induced immunological and clinical responses. Int. J. Oncol., 28: 585-593. http://www.spandidos-publications.com/ijo/28/3/585
18. Powell, D.J., M.E. Dudley, K.A. Hogan, J.R. Wunderlich and S.A. Rosenberg, 2006. Adoptive transfer of vaccine-induced peripheral blood mononuclear cells to patients with metastatic melanoma following lymphodepletion. J. Immunol., 177: 6527-6539. http://www.jimmunol.org/ cgi/content/abstract/177/9/6527
19. Lotem, M., E. Shiloni and I. Pappo et al., 2004. Interleukin-2 improves tumor response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma. Br. J. Cancer, 90: 773-780. http://www.ncbi.nlm.nih.gov/pubmed/14970852
20. Rosenberg, S., Y. Zhai and J. Yang et al., 1998. Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens. J. Natl. Cancer Inst., 90: 1894-1900. http://www.ncbi.nlm.nih.gov/pubmed/9862627
21. Rosenberg, S.A., J.C. Yang and D.J. Schwartzentruber et al., 2003. Recombinant fowlpox viruses encoding the anchor-modified gp100 melanoma antigen can generate antitumor immune responses in patients with metastatic melanoma. Clin. Cancer Res., 9: 2973-2980. http://www.ncbi.nlm.nih.gov/pubmed/12912944
22. Dudek, A.Z., M.F. Mescher and I. Okazaki et al., 2008. Autologous large multivalent immunogen vaccine in patients with metastatic melanoma and renal cell carcinoma. Am. J. Clin. Oncol. Cancer Clin. Trial., 1: 173-181. http://cat.inist.fr/?aModele=afficheN&cpsidt=20306783
23. Nicholson, S., K. Guile and J. John et al., 2003. A randomized phase II trial of SRL172 (Mycobacterium vaccae) +/- low-dose interleukin-2 in the treatment of metastatic malignant melanoma. Melanoma Res., 13: 389-393. http://www.ncbi.nlm.nih.gov/pubmed/12883365
24. Smith, F.O., S.G. Downey and J.A. Klapper et al., 2008. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin. Cancer Res., 14: 5610-5618. http://www.ncbi.nlm.nih.gov/ pubmed/18765555
25. Rousseau, R.F., A.E. Haight, C.H. Jax et al., 2003. Local and systemic effects of an allogeneic tumor cell vaccine combining transgenic human lymphotactin with interleukin-2 in patients with advanced or refractory neuroblastoma. Blood, 101: 1718-1726 http://www.ncbi.nlm.nih.gov/pubmed/12406881
26. Russell, H.V., D. Strother and Z. Mei et al., 2007. Phase I trial of vaccination with autologous neuroblastoma tumor cells genetically modified to secrete IL-2 and lymphotactin. J. Immunother., 30: 227-233. http://www.ncbi.nlm.nih.gov/pubmed/17471169
27. Russell, H.V., D. Strother and Z. Mei et al., 2008. A phase 1/2 study of autologous neuroblastoma tumor cells genetically modified to secrete IL-2 in patients with high-risk neuroblastoma. J. Immunother., 31: 812-819. http://www.ncbi.nlm.nih.gov/pubmed/18833006
28. Yu, A., A. Gilman and M. Ozkaynak et al., 2009. A phase III randomized trial of the chimeric anti-GD2 antibody ch14.18 with GM-CSF and IL2 as immunotherapy following dose intensive chemotherapy for high-risk neuroblastoma: Children's Oncology Group (COG) study ANBL0032. J. Clin. Oncol., 27: abstr 10067z. http://www.curesearch.org/ our_research/index_sub.aspx?id=7444
29. Dagher, R., L. Long and E. Read et al., 2002. Pilot trial of tumor-specific peptide vaccination and continuous infusion interleukin-2 in patients with recurrent Ewing sarcoma and alveolar rhabdomyosarcoma: An inter-institute NIH study. Med. Pediatr. Oncol., 38: 158-164. http://www.ncbi.nlm.nih.gov/pubmed/11836714
30. Mackall, C.L., E.H. Rhee and E.J. Read et al., 2008. A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas. Clin. Cancer Res., 14: 4850-4858. http://cat.inist.fr/ ?aModele=afficheN&cpsidt=20842243
31. Rousseau, R.F., E. Biagi and A. Dutour et al., 2006. Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation. Blood, 107: 1332-1341. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1895421
32. Mitchell, M.S., 2003. Immunotherapy as part of combinations for the treatment of cancer. Int. Immunopharmacol., 3: 1051-1059. http://www.ncbi.nlm.nih.gov/pubmed/12860162
33. Chianese-Bullock, K.A., E.M. Woodson and H. Tao et al., 2005. Autoimmune toxicities associated with the administration of antitumor vaccines and low-dose interleukin-2. J. Immunother., 28: 412-419. http://www.ncbi.nlm.nih.gov/pubmed/16000961
34. Strauchen, J.A. and B.A. Breakstone, 1987. IL-2 receptor expression in human lymphoid lesions. Immunohistochemical study of 166 cases. Am. J. Pathol., 126: 506-512. http://www.pubmedcentral.nih.gov/ articlerender.fcgi?artid=1899648
35. Sheibani, K., C.D. Winberg, S. van de Velde, D.W. Blayney and H. Rappaport, 1987. Distribution of lymphocytes with interleukin-2 receptors (TAC antigens) in reactive lymphoproliferative processes, Hodgkin's disease and non-Hodgkin's lymphomas. An immunohistol study of 300 cases. Am. J. Pathol., 127: 27-37. http://www.pubmedcentral.nih.gov/ articlerender.fcgi?artid=1899594
36. Peuchmaur, M., D. Emilie and M.C. Crevon et al., 1990. IL-2 mRNA expression in Tac-positive malignant l ymphomas. Am. J. Pathol., 136: 383-390. http://www.pubmedcentral.nih.gov/ articlerender.fcgi?artid=1877409
37. Olejniczak, K. and A. Kasprzak, 2008. Biological properties of interleukin 2 and its role in pathogenesis of selected diseases-a review. Med. Sci. Monitor, 14: RA179-189. http://cat.inist.fr/ ?aModele=afficheN&cpsidt=20839827
38. Horiuchi, S., Y. Koyanagi and Y. Tanaka et al., 1997. Altered interleukin-2 receptor alpha-chain is expressed in human T-cell leukaemia virus type-I-infected T-cell lines and human peripheral blood mononuclear cells of adult T-cell leukaemia patients through an alternative splicing mechanism. Immunologym, 91: 28-34. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1364031
39. Tsilivakos, V., A. Tsapis, S. Kakolyris, P. Iliakis, M. Perraki and V. Georgoulias, 1994. Characterization of interleukin 2 receptors on B-cell chronic lymphocytic leukemia cells. Leukemia, 8: 1571-1578. http://www.ncbi.nlm.nih.gov/pubmed/8090033
40. Lin, W.C., S. Yasumura and Y. Suminami et al., 1995. Constitutive production of IL-2 by human carcinoma cells, expression of IL-2 receptor and tumor cell growth. J. Immunol., 155: 4805-4816. http://www.jimmunol.org/cgi/content/abstract/155/10/4805
41. Kuhn, D.J. and Q.P. Dou, 2005. Direct inhibition of interleukin-2 receptor alpha-mediated signaling pathway induces G1 arrest and apoptosis in human head-and-neck cancer cells. J. Cell. Biochem., 95: 379-390. http://www.biomedexperts.com/Abstract.bme/15779002/ Direct_inhibition_of_interleukin-2_receptor_alpha- mediated_signaling_pathway_induces_G1_arrest_and_apoptosis_in_human_he
42. Marzec, M., K. Halasa and M. Kasprzycka et al., 2008. Differential effects of interleukin-2 and interleukin-15 versus interleukin-21 on CD4+ cutaneous T-Cell lymphoma cells. Cancer Res., 68: 1083-1091. http://cancerres.aacrjournals.org/cgi/content/abstract/68/4/1083
43. Blattman, J.N., J.M. Grayson, E.J. Wherry, S.M. Kaech, K.A. Smith and R. Ahmed, 2003. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nat. Med., 9: 540-547. http://www.ncbi.nlm.nih.gov/pubmed/12692546
44. Fry, T.J. and C.L. Mackall, 2002. Interleukin-7: From bench to clinic. Blood, 99: 3892-3904. http://www.ncbi.nlm.nih.gov/pubmed/12010786
45. Guimond, M., R.G. Veenstra and D.J. Grindler et al., 2009. Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat. Immunol., 10: 149-157. http://www.ncbi.nlm.nih.gov/pubmed/19136960
46. Palmer, M.J., V.S. Mahajan, L.C. Trajman, D.J. Irvine, D.A. Lauffenburger and J. Chen, 2008. Interleukin-7 receptor signaling network: An integrated systems perspective. Cell. Mol. Immunol., 5: 79-89. http://www.ncbi.nlm.nih.gov/pubmed/18445337
47. Capitini, C., A. Chisti, C. Mackall, 2009. Modulating T-cell homeostasis with IL-7: Preclinical and clinical studies. J. Int. Med. 266: 141-153. DOI: 10.1111/j.1365-2796.2009.02085.x
48. Rosenberg, S.A., C. Sportès and M. Ahmadzadeh et al., 2006. IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells. J. Immunother., 29: 313-319. http://www.pubmedcentral.nih.gov/ articlerender.fcgi?artid=1473976
49. Sportes, C., F.T. Hakim and S.A. Memon et al., 2008. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J. Exp. Med., 205: 1701-1714. http://www.ncbi.nlm.nih.gov/pubmed/18573906
50. Möller, P., Y. Sun and T. Dorbic et al., 1998. Vaccination with IL-7 gene-modified autologous melanoma cells can enhance the anti-melanoma lytic activity in peripheral blood of patients with a good clinical performance status: A clinical phase I study. Br. J. Cancer, 77: 1907-1916. http://www.ncbi.nlm.nih.gov/pubmed/9667667
51. Pellegrini, M., T. Calzascia and A.R. Elford et al., 2009. Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nat. Med., 15: 528-536. http://www.ncbi.nlm.nih.gov/pubmed/19396174
52. Colombetti, S., F. Levy and L. Chapatte, 2009. IL-7 adjuvant treatment enhances long-term tumor antigen-specific CD8+ T cell responses following immunization with recombinant lentivectors. Blood, 113: 6629-6637. DOI: 10.1182/blood-2008-05-155309
53. Habibi, M., M. Kmieciak, L. Graham, J.K. Morales, H.D. Bear and M.H. Manjili, 2009. Radiofrequency thermal ablation of breast tumors combined with intralesional administration of IL-7 and IL-15 augments anti-tumor immune responses and inhibits tumor development and metastasis. Breast Cancer Res. Treat., 114: 423-431. http://www.pubmedcentral.nih.gov/ articlerender.fcgi?artid=2649692
54. Wu, B., R.N. Shen, W.X. Wang, H.E. Broxmeyer and L. Lu, 1993. Antitumor effect of interleukin 7 in combination with local hyperthermia in mice bearing B16a melanoma cells. Stem. Cell., 11: 412-421. http://stemcells.alphamedpress.org/cgi/content/abstract/11/5/412
55. Murphy, W.J., T.C. Back and K.C. Conlon et al., 1993. Antitumor effects of interleukin-7 and adoptive immunotherapy on human colon carcinoma xenografts. J. Clin. Investigat., 92: 1918-1924. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=288358
56. Otto, M., R.C. Barfield and W.J. Martin et al., 2005. Combination Immunotherapy with clinical-scale enriched human {gamma}{delta} T cells, hu14.18 Antibody and the Immunocytokine Fc-IL7 in disseminated neuroblastoma. Clin. Cancer Res., 11: 8486-8491. http://clincancerres.aacrjournals.org/cgi/reprint/11/23/8486
57. Mackall, C.L., T.J. Fry, C.Bare, P. Morgan, A. Galbraith and R.E. Gress, 2001. IL-7 increases both thymic-dependent and thymic-independent T-cell regeneration after bone marrow transplantation. Blood, 97: 1491-1497. http://www.ncbi.nlm.nih.gov/pubmed/11222398
58. Cosenza, L., G. Gorgun, A. Urbano and F. Foss, 2002. Interleukin-7 receptor expression and activation in nonhaematopoietic neoplastic cell lines. Cell. Signall., 14: 317-325. DOI: 10.1016/S0898-6568(01)00245-5
59. Ming, J., Q. Zhang, X. Qiu and E. Wang, 2009. Interleukin 7/interleukin 7 receptor induce c-Fos/c-Jun-dependent vascular endothelial growth factor-D up-regulation: A mechanism of lymphangiogenesis in lung cancer. Eur. J. Cancer, 45: 866-873. DOI: 10.1016/J.EJCA.2008.12.006
60. Brown, V.I., J. Fang and K. Alcorn et al., 2003. Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc. Natl. Acad. Sci. USA., pp: 15113-15118. http://www.ncbi.nlm.nih.gov/pubmed/14657335
61. González-García, S., M. García-Peydró and E. Martín-Gayo et al., 2009. CSL-MAML-dependent Notch1 signaling controls T lineage-specific IL-7R{alpha} gene expression in early human thymopoiesis and leukemia. J. Exp. Med., 206: 779-791. http://www.ncbi.nlm.nih.gov/pubmed/19349467
62. Cattaruzza, L., A. Gloghini and K. Olivo et al., 2009. Functional coexpression of Interleukin (IL)-7 and its receptor (IL-7R) on Hodgkin and Reed-Sternberg cells: Involvement of IL-7 in tumor cell growth and microenvironmental interactions of Hodgkin's lymphoma. Int. J. Cancer, 125: 1092-1101. http://www.ncbi.nlm.nih.gov/pubmed/19391137
63. Korte, A., A. Möricke and B. Beyermann et al., 1999. Extensive alternative splicing of interleukin-7 in malignant hematopoietic cells: Implication of distinct isoforms in modulating IL-7 activity. J. Interferon Cytokine Res., 19: 495-503. http://www.ncbi.nlm.nih.gov/pubmed/10386862
64. Vudattu, N.K., I. Magalhaes, H. Hoehn, D. Pan and M.J. Maeurer, 2008. Expression analysis and functional activity of interleukin-7 splice variants. Genes Immun., 10: 132-140. http://www.ncbi.nlm.nih.gov/pubmed/ 19092841
65. Dean, R.M., T. Fry and C. Mackall et al., 2008. Association of serum interleukin-7 levels with the development of acute graft-versus-host disease. J. Clin. Oncol., 26: 5735-5741. http://www.ncbi.nlm.nih.gov/pubmed/19001329
66. Sinha, M.L., T.J. Fry, D.H. Fowler, G. Miller and C.L. Mackall, 2002. Interleukin 7 worsens graft-versus-host disease. Blood, 100: 2642-2649. http://www.ncbi.nlm.nih.gov/pubmed/12239180
67. Snyder, K.M., C.L. Mackall and T.J. Fry, 2006. IL-7 in allogeneic transplant: Clinical promise and potential pitfalls. Leukemia Lymphoma, 47: 1222-1228. http://www.ncbi.nlm.nih.gov/pubmed/16923550
68. Roato, I., G. Brunetti and E. Gorassini et al., 2006. IL-7 up-regulates TNF-[alpha]-dependent osteoclastogenesis in patients affected by solid tumor. PLoS One, 1: e124. http://www.ncbi.nlm.nih.gov/ pubmed/17205128
69. Budagian, V., E. Bulanova, R. Paus and S.B. Paus, 2006. IL-15/IL-15 receptor biology: A guided tour through an expanding universe. Cytokine Growth Factor Rev., 17: 259-280. http://cat.inist.fr/ ?aModele=afficheN&cpsidt=17986039
70. Oh, S., L.P. Perera, D.S. Burke, T.A. Waldmann and J.A. Berzofsky, 2004. IL-15/IL-15Ralpha-mediated avidity maturation of memory CD8+ T cells. Proc. Natl. Acad. Sci. USA., 101: 15154-15159. http://www.biomedexperts.com/Abstract.bme/1547 7598/IL-15_IL-15Ralpha- mediated_avidity_maturation_of_memory_CD8_T_cells
71. Huntington, N.D., N. Legrand and N.L. Alves et al., 2008. IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J. Exp. Med., 206: 25-34. http://jem.rupress.org/cgi/content/abstract/206/1/25
72. Stonier, S.W., L.J. Ma, E.F.Castillo and K.S. Schluns, 2008. Dendritic cells drive memory CD8 T-cell homeostasis via IL-15 transpresentation. Blood, 112: 4546-4554. http://www.ncbi.nlm.nih.gov/pubmed/18812469
73. Daudt, L., R. Maccario and F. Locatelli et al., 2008. Interleukin-15 favors the expansion of central memory CD8+ T cells in ex vivo generated, antileukemia human cytotoxic T lymphocyte lines. J. Immunother., 31: 385-393. http://www.biomedexperts.com/ Abstract.bme/18391757/Interleukin-15_favors_the_expansion_of_central_ memory_CD8_T_cells_in_ex_vivo_generated_antileukemia_human_cytotoxic_T
74. Kokaji, A.I., D.L. Hockley and K.P. Kane, 2008. IL-15 transpresentation augments CD8+ T cell activation and is required for optimal recall responses by central memory CD8+ T cells. J. Immunol., 180: 4391-4401. http://www.ncbi.nlm.nih.gov/pubmed/18354159
75. Huntington, N.D., H. Puthalakath and P. Gunn et al., 2007. Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. Nat. Immunol., 8: 856-863. http://www.ncbi.nlm.nih.gov/pubmed/17618288
76. Ozdemir, O. and S. Savasan, 2005. Combinational IL-2/IL-15 induction does not further enhance IL-15-induced lymphokine-activated killer cell cytotoxicity against human leukemia/lymphoma cells. Clin. Immunol., 115: 240-249. DOI: 10.1016/j.clim.2005.01.008
77. Vallabhapurapu, S., S.P. Budnicka and M. Riemann et al., 2008. Rel/NF-kappaB family member RelA regulates NK1.1- to NK1.1+ transition as well as IL-15-induced expansion of NKT cells. Eur. J. Immunol., 38: 3508-3519. http://www.ncbi.nlm.nih.gov/pubmed/19003818
78. Ullrich, E., M. Bonmort and G. Mignot et al., 2008. Trans-presentation of IL-15 dictates IFN-producing killer dendritic cells effector functions. J. Immunol., 180: 7887-7897. http://www.ncbi.nlm.nih.gov/pubmed/18523252
79. Mignot, G., E. Ullrich and M. Bonmort et al., 2008. The critical role of IL-15 in the antitumor effects mediated by the combination therapy imatinib and IL-2. J. Immunol., 180: 6477-6483. http://www.ncbi.nlm.nih.gov/pubmed/18453565
80. Nakazato, K., H.Yamada, T. Yajima, Y. Kagimoto, H. Kuwano and Y. Yoshikai, 2007. Enforced expression of Bcl-2 partially restores cell numbers but not functions of TCR{gamma}{delta} intestinal intraepithelial T lymphocytes in IL-15-deficient mice. J. Immunol., 178: 757-764. http://www.ncbi.nlm.nih.gov/pubmed/17202336
81. Zhao, H., H. Nguyen and J. Kang, 2005. Interleukin 15 controls the generation of the restricted T cell receptor repertoire of [gamma][delta] intestinal intraepithelial lymphocytes. Nat. Immunol., 6: 1263-1271. http://www.ncbi.nlm.nih.gov/pubmed/16273100
82. Gill, N., G. Paltser and A.A. Ashkar, 2009. Interleukin-15 expression affects homeostasis and function of B cells through NK cell-derived interferon-[gamma]. Cell. Immunol., 258: 59-64. DOI: 10.1016/ j.cellimm.2009.03.010
83. Abdel-Salam, B.K.A.H. and H. Ebaid, 2008. Upregulation of major histocompatibility complex class II, CD83, CD64 and CD14 on polymorphonuclear neutrophils stimulated with interleukin-15. J. Microbiol. Immunol. Infect., 41: 462-468. http://www.ncbi.nlm.nih.gov/ pubmed/19255689
84. Brilot, F., T. Strowig, S.M. Roberts, F. Arrey and C. Münz, 2007. NK cell survival mediated through the regulatory synapse with human DCs requires IL-15Ralpha. J. Clin. Invest., 117: 3316-3329. http://cat.inist.fr/?aModele=afficheN&cpsidt=19213387
85. Lucas, M., W. Schachterlle, K. Oberle, P. Aichele and A. Diefenbach, 2007. Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity, 26: 503-517. http://www.ncbi.nlm.nih.gov/ pubmed/17398124
86. Fujisaki, H., H. Kakuda and N. Shimasaki et al., 2009. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res., 69: 4010-4017. http://www.ncbi.nlm.nih.gov/pubmed/19383914
87. Fujisaki, H., H. Kakuda, C. Imai, C. Mullighan and D. Campana, 2009. Replicative potential of human natural killer cells. Br. J. Haematol., 145: 606-613. DOI: 10.1111/j.1365-2141.2009.07667.x
88. Numbenjapon, T., L.M. Serrano, W.C. Chang, S.J. Forman, M.C. Jensen and L.J.N. Cooper, 2007. Antigen-independent and antigen-dependent methods to numerically expand CD19-specific CD8+ T cells. Experim. Hematol., 35: 1083-1090. http://cat.inist.fr/?aModele=afficheN&cpsidt=18891004
89. Tang, F., L.T. Zhao, Y. Jiang, D.N. Ba, L.X. Cui and W. He, 2008. Activity of recombinant human interleukin-15 against tumor recurrence and metastasis in mice. Cell. Mol. Immunol., 5: 189-196. http://www.curehunter.com/public/pubmed18582400.do
90. Zhang, M., Z. Yao, S. Dubois, W. Ju, Muller JrR and T.A. Waldmann, 2009. Interleukin-15 combined with an anti-CD40 antibody provides enhanced therapeutic efficacy for murine models of colon cancer. Proc. Natl. Acad. Sci., 106: 7513-7518. http://www.ncbi.nlm.nih.gov/pubmed/19383782
91. Vera, M., N. Razquin, J. Prieto, I. Melero, P. Fortes and G. Gonzalez-Aseguinolaza, 2005. Intratumoral injection of dendritic cells transduced by an sv40-based vector expressing interleukin-15 induces curative immunity mediated by CD8+ T lymphocytes and NK cells. Mol. Ther., 12: 950-959. http://www.ncbi.nlm.nih.gov/pubmed/15921960
92. Sasahira, T., T. Sasaki and H. Kuniyasu, 2005. Interleukin-15 and transforming growth factor alpha are associated with depletion of tumor-associated macrophages in colon cancer. J. Exp. Clin. Cancer Res., 24: 69-74. http://www.ncbi.nlm.nih.gov/pubmed/15943034
93. Ugen, K.E., M.A. Kutzler and B. Marrero et al., 2006. Regression of subcutaneous B16 melanoma tumors after intratumoral delivery of an IL-15-expressing plasmid followed by in vivo electroporation. Cancer Gene. Ther., 13: 969-974. http://www.ncbi.nlm.nih.gov/pubmed/ 16763607
94. Epardaud, M., K.G. Elpek and M.P. Rubinstein et al., 2008. Interleukin-15/Interleukin-15R{alpha} complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells. Cancer Res., 68: 2972-2983. http://www.ncbi.nlm.nih.gov/pubmed/18413767
95. Le, H., L. Graham, C. Miller, M. Kmieciak, M. Manjili and H. Bear, Incubation of antigen-sensitized T lymphocytes activated with bryostatin 1 + ionomycin in IL-7 + IL-15 increases yield of cells capable of inducing regression of melanoma metastases compared to culture in IL-2. Cancer Immunol. Immunotherapy. http://www.ncbi.nlm.nih.gov/pubmed/ 19198835
96. Basak, G.W., L. Zapala, P.J. Wysocki, A. Mackiewicz, M. Jakóbisiak and W. Lasek, 2008. Interleukin 15 augments antitumor activity of cytokine gene-modified melanoma cell vaccines in a murine model. Oncol. Rep., 19: 1173-1179. http://cat.inist.fr/?aModele=afficheN&cpsidt= 20320525
97. Verhoeven, D.H.J., A.S.K. de Hooge and E.C.K. Mooiman et al., 2008. NK cells recognize and lyse Ewing sarcoma cells through NKG2D and DNAM-1 receptor dependent pathways. Mol. Immunol., 45: 3917-3925. http://www.ncbi.nlm.nih.gov/pubmed/18657862
98. Castriconi, R., A. Daga and A. Dondero et al., 2009. NK cells recognize and kill human glioblastoma cells with stem cell-like properties. J. Immunol., 182: 3530-3539. http://www.ncbi.nlm.nih.gov/ pubmed/19265131
99. King, J.W., S.Thomas and F. Corsi et al., 2009. IL15 Can reverse the unresponsiveness of wilms' tumor antigen-specific CTL in patients with prostate cancer. Clin. Cancer Res., 15: 1145-1154. http://www.ncbi.nlm.nih.gov/pubmed/19228720
100. Teague, R.M., B.D. Sather and J.A. Sacks et al., 2006. Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat. Med., 12: 335-341. http://www.ncbi.nlm.nih.gov/pubmed/16474399
101. Melchionda, F., T.J. Fry, M.J. Milliron, M.A. McKirdy, Y. Tagaya and C.L. Mackall, 2005. Adjuvant IL-7 or IL-15 overcomes immunodominance and improves survival of the CD8+ memory cell pool. J. Clin. Invest., 115: 1177-1187. http://www.ncbi.nlm.nih.gov/pubmed/15841203
102. Boyiadzis, M., S. Memon, J. Carson et al., 2008. Up-regulation of NK Cell activating receptors following allogeneic hematopoietic stem cell transplantation under a lymphodepleting reduced intensity regimen is associated with elevated IL-15 Levels. Biol. Blood Marrow Transplant., 14: 290-300. http://www.ncbi.nlm.nih.gov/pubmed/18275895
103. Chen, G., D. Wu and Y. Wang et al., 2008. Expanded donor natural killer cell and IL-2, IL-15 treatment efficacy in allogeneic hematopoietic stem cell transplantation. Eur. J. Haematol., 81: 226-235. http://www.ncbi.nlm.nih.gov/pubmed/18573173
104. Alpdogan, O., J.M. Eng and S.J. Muriglan et al., 2005. Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation. Blood, 105: 865-873. http://www.ncbi.nlm.nih.gov/ pubmed/15280205
105. Zambello, R., M. Facco and L. Trentin et al., 1997. Interleukin-15 Triggers the proliferation and cytotoxicity of granular lymphocytes in patients with lymphoproliferative disease of granular lymphocytes. Blood, 89: 201-211. http://www.biomedexperts.com/Abstract.bme/8978293/ Interleukin-15_triggers_the_proliferation_and_cytotoxicity_of_ granular_lymphocytes_in_patients_with_lymphoproliferative
106. Zhang, R., M.V. Shah and J. Yang et al., 2008. Network model of survival signaling in large granular lymphocyte leukemia. Proc. Natl. Acad. Sci. USA., 105: 16308-16313. http://www.ncbi.nlm.nih.gov/pubmed/ 18852469
107. de Totero, D., R. Meazza and M. Capaia et al., 2008. The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways. Blood, 111: 517-524. http://www.ncbi.nlm.nih.gov/pubmed/17938255
108. Badoual, C., G. Bouchaud and N.E.H. Agueznay et al., 2008. The soluble {alpha} chain of interleukin-15 receptor: A proinflammatory molecule associated with tumor progression in head and neck cancer. Cancer Res., 68: 3907-3914. http://cancerres.aacrjournals.org/cgi/ content/abstract/68/10/3907
109. Tejman-Yarden, N., M. Zlotnik, E. Lewis, O. Etzion, C. Chaimovitz and A. Douvdevani, 2005. Renal cells express a functional interleukin-15 receptor. Nephrol. Dial. Transplant., 20: 516-523. http://www.ncbi.nlm.nih.gov/pubmed/15671076
110. Khawam, K., J. Giron-Michel and Y. Gu et al., 2009. Human renal cancer cells express a novel membrane-bound interleukin-15 that induces, in response to the soluble interleukin-15 Receptor {alpha} chain, epithelial-to-mesenchymal transition. Cancer Res., 69: 1561-1569. http://cancerres.aacrjournals.org/cgi/content/abstract/69/4/1561
111. Cario, G., S. Izraeli and A. Teichert et al., 2007. High interleukin-15 expression characterizes childhood acute lymphoblastic leukemia with involvement of the CNS. J. Clin. Oncol., 25: 4813-4820. http://www.ncbi.nlm.nih.gov/pubmed/17947730
112. Wu, S., R. Geflner, A. von Stackelberg, R. Kirchner, G. Henze and K. Seeger, 2005. Cytokine/cytokine receptor gene expression in childhood acute lymphoblastic leukemia. Cancer, 103: 1054-1063. http://www.ncbi.nlm.nih.gov/pubmed/15651075
113. Fehniger, T.A., K. Suzuki and A. Ponnappan et al., 2001. Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T Cells. J. Exp. Med., 193: 219-232. http://www.ncbi.nlm.nih.gov/pubmed/11208862
114. Lee, C., S. Lin, P. Cheng and M. Kuo, 2009. The regulatory function of umbilical cord blood CD4+CD25+ T cells stimulated with anti-CD3/ anti-CD28 and exogenous interleukin (IL)-2 or IL-15. Pediatr. Allergy Immunol. http://www.tripdatabase.com/ SearchLander.html?s=1&gk=The+regulatory+function+ of+umbilical+cord+blood+&itemId=862399
115. Vang, K.B., J. Yang, S.A. Mahmud, M.A. Burchill, A.L. Vegoe and M.A. Farrar, 2008. IL-2, -7 and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory t cell development. J. Immunol., 181: 3285-3290. http://www.jimmunol.org/cgi/content/abstract/ 181/5/3285
116. Imamichi, H., I. Sereti and H.C. Lane, 2008. IL-15 acts as a potent inducer of CD4 (+)CD25(hi) cells expressing FOXP3. Eur. J. Immunol., 38: 1621-1630. http://www.ncbi.nlm.nih.gov/pubmed/18493981
117. Blaser, B.W., N.R. Schwind and S. Karol et al., 2006. Trans-presentation of donor-derived interleukin 15 is necessary for the rapid onset of acute graft-versus-host disease but not for graft-versus-tumor activity. Blood, 108: 2463-2469. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1895554
118. Blaser, B.W., S. Roychowdhury and D.J. Kim et al., 2005. Donor-derived IL-15 is critical for acute allogeneic graft-versus-host disease. Blood, 105: 894-901. http://cat.inist.fr/ ?aModele=afficheN&cpsidt=16550063
119. Roychowdhury, S., B.W. Blaser, A.G. Freud et al., 2005. IL-15 but not IL-2 rapidly induces lethal xenogeneic graft-versus-host disease. Blood, 106: 2433-2435. http://www.ncbi.nlm.nih.gov/pubmed/15976176
120. Habib, T., S. Senadheera, K. Weinberg and K. Kaushansky, 2002. The common gamma chain (gamma c) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3. Biochemistry, 41: 8725-8731. http://www.ncbi.nlm.nih.gov/pubmed/12093291
121. Asao, H., C. Okuyama and S. Kumaki et al., 2001. Cutting edge: The common gamma-chain is an indispensable subunit of the IL-21 receptor complex. J. Immunol., 167: 1-5. http://www.ncbi.nlm.nih.gov/pubmed/ 11418623
122. Wurster, A.L., V.L. Rodgers and A.R. Satoskar et al., 2002. Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon gamma-producing Th1 cells. J. Exp. Med., 196: 969-977. http://www.jem.org/cgi/content/abstract/196/7/969
123. Mehta, D.S., A.L. Wurster, A.S. Weinmann and M.J. Grusby, 2005. NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proc. Natl. Acad. Sci. USA., 102: 2016-2021. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=548571
124. Skak, K., K. Frederiksen and D. Lundsgaard, 2008. Interleukin-21 activates human natural killer cells and modulates their surface receptor expression. Immunology, 123: 575-583. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2433320
125. Takaki, R., Y. Hayakawa, A. Nelson et al., 2005. IL-21 Enhances tumor rejection through a NKG2D-dependent mechanism. J. Immunol., 175: 2167-2173. http://www.ncbi.nlm.nih.gov/pubmed/16081783
126. Wang, G., M. Tschoi and R. Spolski et al., 2003. In vivo antitumor activity of interleukin 21 mediated by natural killer cells. Cancer Res., 63: 9016-9022. http://cat.inist.fr/ ?aModele=afficheN&cpsidt=15382654
127. Kasaian, M.T., M.J. Whitters and L.L. Carter et al., 2002. IL-21 limits NK cell responses and promotes antigen-specific T cell activation: A mediator of the transition from innate to adaptive immunity. Immunity, 6: 559-569. http://www.ncbi.nlm.nih.gov/pubmed/ 11970879
128. Parrish-Novak, J., S.R. Dillon and A. Nelson et al., 2000. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature, 408: 57-63. http://www.nature.com/nature/journal/v408/n6808/abs/408057a0.html
129. Zeng, R., Spolski, R. and S.E. Finkelstein et al., 2005. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J. Exp. Med., 201: 139-148. http://www.ncbi.nlm.nih.gov/pubmed/15630141
130. Van Leeuwen, E.M., L.E. Gamadia, P.A. Baars, E.B. Remmerswaal, I.J. Ten Berge and R.A. Van Lier, 2002. Proliferation requirements of cytomegalovirus-specific, effector-type human CD8+ T cells. J. Immunol., 169: 5838-5843. http://www.ncbi.nlm.nih.gov/pubmed/12421965
131. Mehta, D.S., A.L. Wurster, M.J. Whitters, D.A. Young, M. Collins and M.J. Grusby, 2003. IL-21 induces the apoptosis of resting and activated primary B cells. J. Immunol., 170: 4111-4118. http://www.ncbi.nlm.nih.gov/pubmed/12682241
132. Spolski, R., H.P. Kim, W. Zhu, D.E. Levy and W.J. Leonard, 2009. IL-21 mediates suppressive effects via its induction of IL-10. J. Immunol., 182: 2859-2867. http://www.ncbi.nlm.nih.gov/pubmed/19234181
133. Thompson, J.A., B.D. Curti and B.G. Redman et al., 2008. Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J. Clin. Oncol., 26: 2034-2039. http://jco.ascopubs.org/cgi/content/abstract/26/12/2034
134. Davis, I.D., B.K. Skrumsager and J. Cebon et al., 2007. An Open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma. Clin. Cancer Res., 13: 3630-3636. http://clincancerres.aacrjournals.org/cgi/content/abstract/13/12/3630
135. Davis, I.D., B. Brady and R.F. Kefford et al., 2009. Clinical and biological efficacy of recombinant human interleukin-21 in patients with stage IV malignant melanoma without prior treatment: A phase IIa trial. Clin. Cancer Res., 15: 2123-2129. http://www.ncbi.nlm.nih.gov/pubmed/ 19276257
136. Dodds, M., K. Frederiksen and K. Skak et al., 2009. Immune activation in advanced cancer patients treated with recombinant IL-21: Multianalyte profiling of serum proteins. Cancer Immunol. Immunotherapy, 58: 843-854. http://www.ncbi.nlm.nih.gov/pubmed/18925392
137. Frederiksen, K., D. Lundsgaard and J. Freeman et al., 2008. IL-21 induces in vivo immune activation of NK cells and CD8+ T cells in patients with metastatic melanoma and renal cell carcinoma. Cancer Immunol. Immunother., 57: 1439-1449. http://www.pubmedcentral.nih.gov/ articlerender.fcgi?artid=2491425
138. de Totero, D., R. Meazza and S. Zupo et al., 2006. Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells. Blood, 107: 3708-3715. http://www.ncbi.nlm.nih.gov/pubmed/16391014
139. Gowda, A., J. Roda and S.R.A. Hussain et al., 2008. IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody-dependent cellular cytotoxicity in primary chronic lymphocytic leukemia cells in vitro. Blood, 111: 4723-4730. http://www.ncbi.nlm.nih.gov/pubmed/18182577
140. Akamatsu, N., Y. Yamada and H. Hasegawa et al., 2007. High IL-21 receptor expression and apoptosis induction by IL-21 in follicular lymphoma. Cancer Lett., 256: 196-206. http://cat.inist.fr/ ?aModele=afficheN&cpsidt=19137592
141. Fang, L., K. Wang and X. Liu et al. 2008. A study on anti-tumor immunity induced by gene-modified melanoma B16 cells. Oncol. Rep., 19: 1589-1595. http://www.ncbi.nlm.nih.gov/pubmed/18497970
142. Hinrichs, C.S., R. Spolski and C.M. Paulos et al., 2008. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood, 111: 5326-5333. http://bloodjournal.hematologylibrary.org/cgi/content/short/111/11/5326
143. Dou, J., L. Chu and F. Zhao et al., 2007. Study of immunotherapy of murine myeloma by an IL-21-based tumor vaccine in BALB/C mice. Cancer Biol. Therapy,6: 1871-1879. http://www.ncbi.nlm.nih.gov/pubmed/18059168
144. Kumano, M., I. Hara and J. Furukawa et al., 2007. Interleukin-21 activates cytotoxic T lymphocytes and natural killer cells to generate antitumor response in mouse renal cell carcinoma. J. Urol., 178:1 504-1509. DOI: 10.1016/j.juro.2007.05.115
145. Furukawa, J., I. Hara, H. Nagai, A. Yao, S. Oniki and M. Fujisawa, 2006. Interleukin-21 gene transfection into mouse bladder cancer cells results in tumor rejection through the cytotoxic T lymphocyte response. J. Urol., 176: 1198-1203. http://cat.inist.fr/ ?aModele=afficheN&cpsidt=18035748
146. Daga, A., A. Orengo and R. Maria et al., 2007. Glioma immunotherapy by IL-21 gene-modified cells or by recombinant IL-21 involves antibody responses. Int. J. Cancer, 121: 1756-1763. http://www.ncbi.nlm.nih.gov/pubmed/17582604
147. Kim-Schulze, S., H.S. Kim, Q. Fan, D.W. Kim and H.L. Kaufman, 2009. Local IL-21 promotes the therapeutic activity of effector t cells by decreasing regulatory T cells within the tumor microenvironment. Mol. Ther., 17: 380-388. http://www.ncbi.nlm.nih.gov/pubmed/19034262
148. Thedrez, A., C. Harly, A. Morice, S. Salot, M. Bonneville and E. Scotet, 2009. IL-21-Mediated Potentiation of antitumor cytolytic and proinflammatory responses of human V{gamma}9V{delta}2 T cells for adoptive immunotherapy. J. Immunol., 182: 3423-3431. http://cat.inist.fr/ ?aModele=afficheN&cpsidt=21224523
149. Iuchi, T., S. Teitz-Tennenbaum and J. Huang et al., 2008. Interleukin-21 Augments the efficacy of T-cell therapy by eliciting concurrent cellular and humoral responses. Cancer Res., 68: 4431-4441. http://cancerres.aacrjournals.org/cgi/content/abstract/68/11/4431
150. Eriksen, K.W., H. Sndergaard and A. Woetmann et al., 2009. The combination of IL-21 and IFN-[alpha] boosts STAT3 activation, cytotoxicity and experimental tumor therapy. Mol. Immunol., 46: 812-820. http://www.ncbi.nlm.nih.gov/pubmed/18947877
151. Liu, S., G. Lizee and Y. Lou et al., 2007. IL-21 synergizes with IL-7 to augment expansion and anti-tumor function of cytotoxic T cells. Int. Immunol., 19: 1213-1221. http://intimm.oxfordjournals.org/cgi/ content/abstract/19/10/1213
152. Smyth, M.J., M.W.L. Teng and J. Sharkey et al., 2008. Interleukin 21 enhances antibody-mediated tumor rejection. Cancer Res., 68: 3019-3025. http://cancerres.aacrjournals.org/cgi/content/abstract/68/8/ 3019
153. Roda, J.M., R. Parihar, A. Lehman, A. Mani, S. Tridandapani and W.E. Carson, 2006. III. Interleukin-21 enhances NK cell activation in response to antibody-coated targets. J. Immunol., 177: 120-129. http://www.ncbi.nlm.nih.gov/pubmed/16785506
154. Croce, M., R. Meazza and A. Orengo et al., 2008. Immunotherapy of neuroblastoma by an Interleukin-21-secreting cell vaccine involves survivin as antigen. Cancer Immunol. Immunother., 57: 1625-1634. http://www.ncbi.nlm.nih.gov/pubmed/18324400
155. Søndergaard, H., K. Frederiksen and P. Thygesen et al., 2007. Interleukin 21 therapy increases the density of tumor infiltrating CD8+ T cells and inhibits the growth of syngeneic tumors. Cancer Immunol. Immunother., 56: 1417-1428. DOI: 10.1007/s00262-007-0285-4
156. Lamprecht, B., S. Kreher and I. Anagnostopoulos et al., 2008. Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3{alpha}. Blood, 112: 3339-3347. http://edoc.mdc-berlin.de/9646/
157. Scheeren F.A., S.A. Diehl and L.A. Smit et al. IL-21 is expressed in Hodgkin lymphoma and activates STAT5: Evidence that activated STAT5 is required for Hodgkin lymphomagenesis. Blood. 111: 4706-4715. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2343600
158. Menoret, E., S. Maiga and G. Descamps et al., 2008. IL-21 Stimulates human myeloma cell growth through an autocrine IGF-1 Loop. J. Immunol., 181: 6837-6842. http://www.ncbi.nlm.nih.gov/pubmed/18981102
159. Ettinger, R., S. Kluchen and P.E. Lipsky, 2008. Interleukin 21 as a target of intervention in autoimmune disease. Ann. Rheum. Dis., 67: 83-86. http://www.ncbi.nlm.nih.gov/pubmed/19022821