A novel therapeutic strategy targeting multiple members of the γc-family cytokines; principles, relevance and potentially broad clinical applications.

Main Article Content

Yutaka Tagaya Nazli Azimi

Abstract

Abstract

Cytokines play diverse roles in normal and abnormal immunity. Dysregulated production of cytokines underlies a variety of disorders in humans by causing improper immune responses. Intervention to such abnormal cytokine action has been utilized in the clinical field as "anti-cytokine therapy" and proven effective as treatments. However the current anti-cytokine approaches lack effective and safe options for treating human diseases involving more than two cytokines as the pathogenic reason. This is an issue as the list of multi-cytokine diseases is expanding. To address this, a novel technology was developed by generating a novel class of multi-cytokine inhibitors (MCI). In short, cytokine-mimetic peptides were rationally designed each of which contains a motif shared only by the cytokines of the target and tested using specific biological assay. Peptides showing desired antagonistic activity were screened further for target specificity. The lead MCI, BNZ 132-1, specifically inhibits IL-2, -9 and -15 while it does not affect other γc-cytokines (IL-4, -7. and -21) or non-γc cytokines. This design ensures safety of the peptide upon clinical use by limiting off-target effects to the minimum, unlike small-molecule Jak kinase inhibitors which suppress a diverse array of cytokines and cause multiple adverse effects. Currently, we are conducting clinical trials involving BNZ 132-1 and saw expected transient decrease of select subsets of lymphocytes with minimum toxicity. BNZ 132-1 may provide a novel opportunity for treating many diseases such as myelopathy caused by human T-cell leukemia virus-1 (HTLV-1), non-viral human T-cell malignancies, autoimmunity (Alopecia areata, rheumatoid arthritis), graft-versus-host disease (GvH) upon transplant and cytokine release syndromes post microbial infections.

Article Details

How to Cite
TAGAYA, Yutaka; AZIMI, Nazli. A novel therapeutic strategy targeting multiple members of the γc-family cytokines; principles, relevance and potentially broad clinical applications.. Medical Research Archives, [S.l.], v. 5, n. Issue 9, sep. 2017. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/1491>. Date accessed: 28 mar. 2024.
Section
Research Articles

References

References

1. Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proceedings of the National Academy of Sciences of the United States of America. 1990;87(18):6934-8. PubMed PMID: 2169613; PMCID: 54656.
2. Boulay JL, O'Shea JJ, Paul WE. Molecular phylogeny within type I cytokines and their cognate receptors. Immunity. 2003;19(2):159-63. PubMed PMID: 12932349.
3. Schorle H, Holtschke T, Hunig T, Schimpl A, Horak I. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature. 1991;352(6336):621-4. doi: 10.1038/352621a0. PubMed PMID: 1830926.
4. Antony PA, Paulos CM, Ahmadzadeh M, Akpinarli A, Palmer DC, Sato N, Kaiser A, Hinrichs CS, Klebanoff CA, Tagaya Y, Restifo NP. IL-2-dependent mechanisms of tolerance and immunity in vivo. Journal of immunology. 2006;176(9):5255-66. PubMed PMID: 16621991; PMCID: 1473163.
5. Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL, Embers M, Matsuki N, Charrier K, Sedger L, Willis CR, Brasel K, Morrissey PJ, Stocking K, Schuh JC, Joyce S, Peschon JJ. Reversible defects in natural killer and memory CD8 T cell lineages in IL15-deficient mice. The Journal of experimental medicine. 2000;191(5):771-80. PubMed PMID: 10704459; PMCID: 2195858.
6. Marks-Konczalik J, Dubois S, Losi JM, Sabzevari H, Yamada N, Feigenbaum L, Waldmann TA, Tagaya Y. IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(21):11445-50. doi: 10.1073/pnas.200363097. PubMed PMID: 11016962; PMCID: 17219.
7. Fehniger TA, Suzuki K, Ponnappan A, VanDeusen JB, Cooper MA, Florea SM, Freud AG, Robinson ML, Durbin J, Caligiuri MA. Fatal leukemia in IL15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. The Journal of experimental medicine. 2001;193(2):219-31. PubMed PMID: 11208862; PMCID: 2193336.
8. Fehniger TA, Suzuki K, Ponnappan A, VanDeusen JB, Cooper MA, Florea SM, Freud AG, Robinson ML, Durbin J, Caligiuri MA. Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. The Journal of experimental medicine. 2001;193(2):219-31. PubMed PMID: 11208862; PMCID: PMC2193336.
9. von Freeden-Jeffry U, Vieira P, Lucian LA, McNeil T, Burdach SE, Murray R. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. The Journal of experimental medicine. 1995;181(4):1519-26. PubMed PMID: 7699333; PMCID: PMC2191954.
10. Kuhn R, Rajewsky K, Muller W. Generation and analysis of interleukin-4 deficient mice. Science. 1991;254(5032):707-10. PubMed PMID: 1948049.
11. Noben-Trauth N, Kohler G, Burki K, Ledermann B. Efficient targeting of the IL-4 gene in a BALB/c embryonic stem cell line. Transgenic Res. 1996;5(6):487-91. PubMed PMID: 8840532.
12. Burstein HJ, Tepper RI, Leder P, Abbas AK. Humoral immune functions in IL-4 transgenic mice. Journal of immunology. 1991;147(9):2950-6. PubMed PMID: 1919000.
13. Tepper RI, Levinson DA, Stanger BZ, Campos-Torres J, Abbas AK, Leder P. IL-4 induces allergic-like inflammatory disease and alters T cell development in transgenic mice. Cell. 1990;62(3):457-67. PubMed PMID: 2116236.
14. Rich BE, Campos-Torres J, Tepper RI, Moreadith RW, Leder P. Cutaneous lymphoproliferation and lymphomas in interleukin 7 transgenic mice. The Journal of experimental medicine. 1993;177(2):305-16. PubMed PMID: 7678850; PMCID: PMC2190896.
15. Godfraind C, Louahed J, Faulkner H, Vink A, Warnier G, Grencis R, Renauld JC. Intraepithelial infiltration by mast cells with both connective tissue-type and mucosal-type characteristics in gut, trachea, and kidneys of IL-9 transgenic mice. Journal of immunology. 1998;160(8):3989-96. PubMed PMID: 9558107.
16. McLane MP, Haczku A, van de Rijn M, Weiss C, Ferrante V, MacDonald D, Renauld JC, Nicolaides NC, Holroyd KJ, Levitt RC. Interleukin-9 promotes allergen-induced eosinophilic inflammation and airway hyperresponsiveness in transgenic mice. American journal of respiratory cell and molecular biology. 1998;19(5):713-20. doi: 10.1165/ajrcmb.19.5.3457. PubMed PMID: 9806735.
17. Townsend JM, Fallon GP, Matthews JD, Smith P, Jolin EH, McKenzie NA. IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity. 2000;13(4):573-83. PubMed PMID: 11070175.
18. Brady J, Hayakawa Y, Smyth MJ, Nutt SL. IL-21 induces the functional maturation of murine NK cells. Journal of immunology. 2004;172(4):2048-58. PubMed PMID: 14764669.
19. Allard EL, Hardy MP, Leignadier J, Marquis M, Rooney J, Lehoux D, Labrecque N. Overexpression of IL-21 promotes massive CD8+ memory T cell accumulation. European journal of immunology. 2007;37(11):3069-77. doi: 10.1002/eji.200637017. PubMed PMID: 17918202.
20. Ohbo K, Suda T, Hashiyama M, Mantani A, Ikebe M, Miyakawa K, Moriyama M, Nakamura M, Katsuki M, Takahashi K, Yamamura K, Sugamura K. Modulation of hematopoiesis in mice with a truncated mutant of the interleukin-2 receptor gamma chain. Blood. 1996;87(3):956-67. PubMed PMID: 8562967.
21. Ikebe M, Miyakawa K, Takahashi K, Ohbo K, Nakamura M, Sugamura K, Suda T, Yamamura K, Tomita K. Lymphohaematopoietic abnormalities and systemic lymphoproliferative disorder in interleukin-2 receptor gamma chain-deficient mice. Int J Exp Pathol. 1997;78(3):133-48. PubMed PMID: 9306921; PMCID: PMC2694530.
22. Nata T, Basheer A, Cocchi F, van Besien R, Massoud R, Jacobson S, Azimi N, Tagaya Y. Targeting the binding interface on a shared receptor subunit of a cytokine family enables the inhibition of multiple member cytokines with selectable target spectrum. The Journal of biological chemistry. 2015;290(37):22338-51. doi: 10.1074/jbc.M115.661074. PubMed PMID: 26183780; PMCID: PMC4566211.
23. Osame M, Usuku K, Izumo S, Ijichi N, Amitani H, Igata A, Matsumoto M, Tara M. HTLV-I associated myelopathy, a new clinical entity. Lancet. 1986;1(8488):1031-2. PubMed PMID: 2871307.
24. Gessain A, Barin F, Vernant JC, Gout O, Maurs L, Calender A, de The G. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet. 1985;2(8452):407-10. PubMed PMID: 2863442.
25. Tendler CL, Greenberg SJ, Blattner WA, Manns A, Murphy E, Fleisher T, Hanchard B, Morgan O, Burton JD, Nelson DL, et al. Transactivation of IL2 and its receptor induces immune activation in human T-cell lymphotropic virus type I-associated myelopathy: pathogenic implications and a rationale for immunotherapy. Proceedings of the National Academy of Sciences of the United States of America. 1990;87(13):5218-22. PubMed PMID: 2367534; PMCID: 54293.
26. Tendler CL, Greenberg SJ, Burton JD, Danielpour D, Kim SJ, Blattner WA, Manns A, Waldmann TA. Cytokine induction in HTLV-I associated myelopathy and adult T-cell leukemia: alternate molecular mechanisms underlying retroviral pathogenesis. J Cell Biochem. 1991;46(4):302-11. doi: 10.1002/jcb.240460405. PubMed PMID: 1757474.
27. Azimi N, Jacobson S, Leist T, Waldmann TA. Involvement of IL-15 in the pathogenesis of human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis: implications for therapy with a monoclonal antibody directed to the IL-2/15R beta receptor. Journal of immunology. 1999;163(7):4064-72. PubMed PMID: 10491011.
28. Azimi N, Nagai M, Jacobson S, Waldmann TA. IL-15 plays a major role in the persistence of Tax-specific CD8 cells in HAM/TSP patients. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(25):14559-64. doi: 10.1073/pnas.251540598. PubMed PMID: 11717409; PMCID: 64721.
29. Ju W, Zhang M, Jiang JK, Thomas CJ, Oh U, Bryant BR, Chen J, Sato N, Tagaya Y, Morris JC, Janik JE, Jacobson S, Waldmann TA. CP-690,550, a therapeutic agent, inhibits cytokine-mediated Jak3 activation and proliferation of T cells from patients with ATL and HAM/TSP. Blood. 2011;117(6):1938-46. doi: 10.1182/blood-2010-09-305425. PubMed PMID: 21106989; PMCID: 3056641.
30. Massoud R, Enose-Akahata Y, Tagaya Y, Azimi N, Basheer A, Jacobson S. Common gamma-chain blocking peptide reduces in vitro immune activation markers in HTLV-1-associated myelopathy/tropical spastic paraparesis. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(35):11030-5. doi: 10.1073/pnas.1412626112. PubMed PMID: 26283355; PMCID: PMC4568234.
31. McInnes IB, Liew FY. Cytokine networks-towards new therapies for rheumatoid arthritis. Nature clinical practice Rheumatology. 2005;1(1):31-9. doi: 10.1038/ncprheum0020. PubMed PMID: 16932625.
32. Kishimoto T. IL-6: from its discovery to clinical applications. International immunology. 2010;22(5):347-52. doi: 10.1093/intimm/dxq030. PubMed PMID: 20410258.
33. Young DA, Hegen M, Ma HL, Whitters MJ, Albert LM, Lowe L, Senices M, Wu PW, Sibley B, Leathurby Y, Brown TP, Nickerson-Nutter C, Keith JC, Jr., Collins M. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis and rheumatism. 2007;56(4):1152-63. doi: 10.1002/art.22452. PubMed PMID: 17393408.
34. Jabri B, de Serre NP, Cellier C, Evans K, Gache C, Carvalho C, Mougenot JF, Allez M, Jian R, Desreumaux P, Colombel JF, Matuchansky C, Cugnenc H, Lopez-Botet M, Vivier E, Moretta A, Roberts AI, Ebert EC, Guy-Grand D, Brousse N, Schmitz J, Cerf-Bensussan N. Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease. Gastroenterology. 2000;118(5):867-79. PubMed PMID: 10784586.
35. Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, Raulet DH, Lanier LL, Groh V, Spies T, Ebert EC, Green PH, Jabri B. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity. 2004;21(3):357-66. doi: 10.1016/j.immuni.2004.06.020. PubMed PMID: 15357947.
36. Meresse B, Curran SA, Ciszewski C, Orbelyan G, Setty M, Bhagat G, Lee L, Tretiakova M, Semrad C, Kistner E, Winchester RJ, Braud V, Lanier LL, Geraghty DE, Green PH, Guandalini S, Jabri B. Reprogramming of CTLs into natural killer-like cells in celiac disease. The Journal of experimental medicine. 2006;203(5):1343-55. doi: 10.1084/jem.20060028. PubMed PMID: 16682498; PMCID: 2121214.
37. Bhagat G, Naiyer AJ, Shah JG, Harper J, Jabri B, Wang TC, Green PH, Manavalan JS. Small intestinal CD8+TCRgammadelta+NKG2A+ intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease. The Journal of clinical investigation. 2008;118(1):281-93. doi: 10.1172/JCI30989. PubMed PMID: 18064301; PMCID: 2117760.
38. Tang F, Chen Z, Ciszewski C, Setty M, Solus J, Tretiakova M, Ebert E, Han J, Lin A, Guandalini S, Groh V, Spies T, Green P, Jabri B. Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15. The Journal of experimental medicine. 2009;206(3):707-19. doi: 10.1084/jem.20071887. PubMed PMID: 19237603; PMCID: 2699120.
39. Abadie V, Discepolo V, Jabri B. Intraepithelial lymphocytes in celiac disease immunopathology. Seminars in immunopathology. 2012;34(4):551-66. doi: 10.1007/s00281-012-0316-x. PubMed PMID: 22660791.
40. Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, Antonopoulos DA, Jabri B, Chang EB. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. Nature. 2012;487(7405):104-8. doi: 10.1038/nature11225. PubMed PMID: 22722865; PMCID: 3393783.
41. Bodd M, Raki M, Tollefsen S, Fallang LE, Bergseng E, Lundin KE, Sollid LM. HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22. Mucosal immunology. 2010;3(6):594-601. doi: 10.1038/mi.2010.36. PubMed PMID: 20571486.
42. Naramura M, Hu RJ, Gu H. Mice with a fluorescent marker for interleukin 2 gene activation. Immunity. 1998;9(2):209-16. PubMed PMID: 9729041.
43. Bamford RN, DeFilippis AP, Azimi N, Kurys G, Waldmann TA. The 5' untranslated region, signal peptide, and the coding sequence of the carboxyl terminus of IL-15 participate in its multifaceted translational control. Journal of immunology. 1998;160(9):4418-26. PubMed PMID: 9574546.
44. Waldmann TA, Tagaya Y. The multifaceted regulation of IL-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens. Annual review of immunology. 1999;17:19-49. doi: 10.1146/annurev.immunol.17.1.19. PubMed PMID: 10358752.
45. Azimi N, Brown K, Bamford RN, Tagaya Y, Siebenlist U, Waldmann TA. Human T cell lymphotropic virus type I Tax protein trans-activates IL15 gene transcription through an NF-kappaB site. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(5):2452-7. PubMed PMID: 9482906; PMCID: 19372.
46. Kontermann RE, Brinkmann U. Bispecific antibodies. Drug Discov Today. 2015;20(7):838-47. doi: 10.1016/j.drudis.2015.02.008. PubMed PMID: 25728220.
47. Whitty A, Borysenko CW. Small molecule cytokine mimetics. Chem Biol. 1999;6(4):R107-18. doi: 10.1016/S1074-5521(99)80034-9. PubMed PMID: 10099129.
48. Nakamura Y, Russell SM, Mess SA, Friedmann M, Erdos M, Francois C, Jacques Y, Adelstein S, Leonard WJ. Heterodimerization of the IL-2 receptor beta- and gamma-chain cytoplasmic domains is required for signalling. Nature. 1994;369(6478):330-3. doi: 10.1038/369330a0. PubMed PMID: 8183373.
49. Tsudo M, Kitamura F, Miyasaka M. Characterization of the interleukin 2 receptor beta chain using three distinct monoclonal antibodies. Proceedings of the National Academy of Sciences of the United States of America. 1989;86(6):1982-6. PubMed PMID: 2467293; PMCID: PMC286829.
50. Waldmann TA, Conlon KC, Stewart DM, Worthy TA, Janik JE, Fleisher TA, Albert PS, Figg WD, Spencer SD, Raffeld M, Decker JR, Goldman CK, Bryant BR, Petrus MN, Creekmore SP, Morris JC. Phase 1 trial of IL-15 trans presentation blockade using humanized Mikbeta1 mAb in patients with T-cell large granular lymphocytic leukemia. Blood. 2013;121(3):476-84. doi: 10.1182/blood-2012-08-450585. PubMed PMID: 23212516; PMCID: 3548167.
51. Dubois S, Patel HJ, Zhang M, Waldmann TA, Muller JR. Preassociation of IL-15 with IL-15R alpha-IgG1-Fc enhances its activity on proliferation of NK and CD8+/CD44high T cells and its antitumor action. Journal of immunology. 2008;180(4):2099-106. PubMed PMID: 18250415.
52. Mortier E, Woo T, Advincula R, Gozalo S, Ma A. IL-15Ralpha chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation. The Journal of experimental medicine. 2008;205(5):1213-25. doi: 10.1084/jem.20071913. PubMed PMID: 18458113; PMCID: PMC2373851.
53. Bergamaschi C, Bear J, Rosati M, Beach RK, Alicea C, Sowder R, Chertova E, Rosenberg SA, Felber BK, Pavlakis GN. Circulating IL-15 exists as heterodimeric complex with soluble IL-15Ralpha in human and mouse serum. Blood. 2012;120(1):e1-8. doi: 10.1182/blood-2011-10-384362. PubMed PMID: 22496150; PMCID: 3390963.
54. Dubois S, Mariner J, Waldmann TA, Tagaya Y. IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells. Immunity. 2002;17(5):537-47. PubMed PMID: 12433361.
55. Chertova E, Bergamaschi C, Chertov O, Sowder R, Bear J, Roser JD, Beach RK, Lifson JD, Felber BK, Pavlakis GN. Characterization and favorable in vivo properties of heterodimeric soluble IL-15.IL-15Ralpha cytokine compared to IL-15 monomer. The Journal of biological chemistry. 2013;288(25):18093-103. doi: 10.1074/jbc.M113.461756. PubMed PMID: 23649624; PMCID: PMC3689953.
56. Li J, Valentin A, Ng S, Beach RK, Alicea C, Bergamaschi C, Felber BK, Pavlakis GN. Differential effects of IL-15 on the generation, maintenance and cytotoxic potential of adaptive cellular responses induced by DNA vaccination. Vaccine. 2015;33(9):1188-96. doi: 10.1016/j.vaccine.2014.12.046. PubMed PMID: 25559187.
57. Castillo EF, Acero LF, Stonier SW, Zhou D, Schluns KS. Thymic and peripheral microenvironments differentially mediate development and maturation of iNKT cells by IL-15 transpresentation. Blood. 2010;116(14):2494-503. doi: 10.1182/blood-2010-03-277103. PubMed PMID: 20581314; PMCID: PMC2953886.
58. Stonier SW, Ma LJ, Castillo EF, Schluns KS. Dendritic cells drive memory CD8 T-cell homeostasis via IL-15 transpresentation. Blood. 2008;112(12):4546-54. doi: 10.1182/blood-2008-05-156307. PubMed PMID: 18812469; PMCID: PMC2597127.
59. Huntington ND, Alves NL, Legrand N, Lim A, Strick-Marchand H, Mention JJ, Plet A, Weijer K, Jacques Y, Becker PD, Guzman C, Soussan P, Kremsdorf D, Spits H, Di Santo JP. IL-15 transpresentation promotes both human T-cell reconstitution and T-cell-dependent antibody responses in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(15):6217-22. doi: 10.1073/pnas.1019167108. PubMed PMID: 21444793; PMCID: PMC3076818.
60. Stoklasek TA, Colpitts SL, Smilowitz HM, Lefrancois L. MHC class I and TCR avidity control the CD8 T cell response to IL-15/IL-15Ralpha complex. Journal of immunology. 2010;185(11):6857-65. doi: 10.4049/jimmunol.1001601. PubMed PMID: 21041729; PMCID: PMC3150213.
61. Sandau MM, Schluns KS, Lefrancois L, Jameson SC. Cutting edge: transpresentation of IL-15 by bone marrow-derived cells necessitates expression of IL-15 and IL-15R alpha by the same cells. Journal of immunology. 2004;173(11):6537-41. PubMed PMID: 15557143.
62. Mortier E, Advincula R, Kim L, Chmura S, Barrera J, Reizis B, Malynn BA, Ma A. Macrophage- and dendritic-cell-derived interleukin-15 receptor alpha supports homeostasis of distinct CD8+ T cell subsets. Immunity. 2009;31(5):811-22. doi: 10.1016/j.immuni.2009.09.017. PubMed PMID: 19913445.
63. Terme M, Ullrich E, Delahaye NF, Chaput N, Zitvogel L. Natural killer cell-directed therapies: moving from unexpected results to successful strategies. Nature immunology. 2008;9(5):486-94. doi: 10.1038/ni1580. PubMed PMID: 18425105.
64. Burkett PR, Koka R, Chien M, Chai S, Boone DL, Ma A. Coordinate expression and trans presentation of interleukin (IL)-15Ralpha and IL-15 supports natural killer cell and memory CD8+ T cell homeostasis. The Journal of experimental medicine. 2004;200(7):825-34. doi: 10.1084/jem.20041389. PubMed PMID: 15452177; PMCID: PMC2213280.
65. Burkett PR, Koka R, Chien M, Chai S, Chan F, Ma A, Boone DL. IL-15R alpha expression on CD8+ T cells is dispensable for T cell memory. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(8):4724-9. doi: 10.1073/pnas.0737048100. PubMed PMID: 12671073; PMCID: PMC153623.
66. Koka R, Burkett P, Chien M, Chai S, Boone DL, Ma A. Cutting edge: murine dendritic cells require IL-15R alpha to prime NK cells. Journal of immunology. 2004;173(6):3594-8. PubMed PMID: 15356102.
67. Koka R, Burkett PR, Chien M, Chai S, Chan F, Lodolce JP, Boone DL, Ma A. Interleukin (IL)-15R[alpha]-deficient natural killer cells survive in normal but not IL-15R[alpha]-deficient mice. The Journal of experimental medicine. 2003;197(8):977-84. doi: 10.1084/jem.20021836. PubMed PMID: 12695489; PMCID: 2193874.
68. Lodolce J, Burkett P, Koka R, Boone D, Chien M, Chan F, Madonia M, Chai S, Ma A. Interleukin-15 and the regulation of lymphoid homeostasis. Mol Immunol. 2002;39(9):537-44. PubMed PMID: 12431387.
69. Lodolce JP, Burkett PR, Boone DL, Chien M, Ma A. T cell-independent IL15Ralpha signals are required for bystander proliferation. The Journal of experimental medicine. 2001;194(8):1187-94. PubMed PMID: 11602647; PMCID: 2193508.
70. Lodolce JP, Burkett PR, Koka RM, Boone DL, Ma A. Regulation of lymphoid homeostasis by interleukin-15. Cytokine Growth Factor Rev. 2002;13(6):429-39. PubMed PMID: 12401478.
71. Kawamura T, Koka R, Ma A, Kumar V. Differential roles for IL-15R alpha-chain in NK cell development and Ly-49 induction. Journal of immunology. 2003;171(10):5085-90. PubMed PMID: 14607906.
72. Sato N, Sabzevari H, Fu S, Ju W, Petrus MN, Bamford RN, Waldmann TA, Tagaya Y. Development of an IL-15-autocrine CD8 T-cell leukemia in IL-15-transgenic mice requires the cis expression of IL-15Ralpha. Blood. 2011;117(15):4032-40. doi: 10.1182/blood-2010-09-307504. PubMed PMID: 21304101; PMCID: 3087530.
73. Domingues H, Cregut D, Sebald W, Oschkinat H, Serrano L. Rational design of a GCN4-derived mimetic of interleukin-4. Nat Struct Biol. 1999;6(7):652-6. doi: 10.1038/10706. PubMed PMID: 10404222.
74. Mueller TD, Zhang JL, Sebald W, Duschl A. Structure, binding, and antagonists in the IL-4/IL-13 receptor system. Biochim Biophys Acta. 2002;1592(3):237-50. PubMed PMID: 12421669.
75. Walker BL, Leigh R. Use of biologicals as immunotherapy in asthma and related diseases. Expert Rev Clin Immunol. 2008;4(6):743-56. doi: 10.1586/1744666X.4.6.743. PubMed PMID: 20477124.
76. Zurawski SM, Vega F, Jr., Huyghe B, Zurawski G. Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction. The EMBO journal. 1993;12(7):2663-70. PubMed PMID: 8101483; PMCID: PMC413514.
77. Perugini M, Varelias A, Sadlon T, D'Andrea RJ. Hematopoietic growth factor mimetics: from concept to clinic. Cytokine Growth Factor Rev. 2009;20(1):87-94. doi: 10.1016/j.cytogfr.2009.01.002. PubMed PMID: 19223217.
78. Gutti U, Pasupuleti SR, Sahu I, Kotipalli A, Undi RB, Kandi R, Venakata Saladi RG, Gutti RK. Erythropoietin and thrombopoietin mimetics: Natural alternatives to erythrocyte and platelet disorders. Crit Rev Oncol Hematol. 2016;108:175-86. doi: 10.1016/j.critrevonc.2016.11.002. PubMed PMID: 27931836.
79. Spina P, Impera S, Todaro AM, Salerno M, Floridia PM, Castagna F, Consoli U. "On-demand" treatment with Thrombopoietin mimetics as "bridge to recovery" from chemotherapy in chronic immune thrombocytopenia patients with cancer. A single centre experience in nine patients. Br J Haematol. 2017. doi: 10.1111/bjh.14605. PubMed PMID: 28466471.
80. Ahmed CM, Johnson HM. Short peptide type I interferon mimetics: therapeutics for experimental allergic encephalomyelitis, melanoma, and viral infections. J Interferon Cytokine Res. 2014;34(10):802-9. doi: 10.1089/jir.2014.0041. PubMed PMID: 24811478; PMCID: PMC4186642.
81. Zhang H, Zou K, Tesseur I, Wyss-Coray T. Small molecule tgf-beta mimetics as potential neuroprotective factors. Curr Alzheimer Res. 2005;2(2):183-6. PubMed PMID: 15974916.
82. Ueki R, Ueki A, Kanda N, Sando S. Oligonucleotide-Based Mimetics of Hepatocyte Growth Factor. Angew Chem Int Ed Engl. 2016;55(2):579-82. doi: 10.1002/anie.201508572. PubMed PMID: 26592704.
83. Nedjai B, Li H, Stroke IL, Wise EL, Webb ML, Merritt JR, Henderson I, Klon AE, Cole AG, Horuk R, Vaidehi N, Pease JE. Small molecule chemokine mimetics suggest a molecular basis for the observation that CXCL10 and CXCL11 are allosteric ligands of CXCR3. Br J Pharmacol. 2012;166(3):912-23. doi: 10.1111/j.1476-5381.2011.01660.x. PubMed PMID: 21895630; PMCID: PMC3417418.
84. Fernandez-Botran R, Crespo FA, Sun X. Soluble cytokine receptors in biological therapy. Expert Opin Biol Ther. 2002;2(6):585-605. doi: 10.1517/14712598.2.6.585. PubMed PMID: 12171504.
85. Smerz-Bertling C, Duschl A. Both interleukin 4 and interleukin 13 induce tyrosine phosphorylation of the 140-kDa subunit of the interleukin 4 receptor. The Journal of biological chemistry. 1995;270(2):966-70. PubMed PMID: 7822337.
86. Maliszewski CR, Sato TA, Vanden Bos T, Waugh S, Dower SK, Slack J, Beckmann MP, Grabstein KH. Cytokine receptors and B cell functions. I. Recombinant soluble receptors specifically inhibit IL-1- and IL-4-induced B cell activities in vitro. Journal of immunology. 1990;144(8):3028-33. PubMed PMID: 2139075.
87. Steinke JW. Anti-IL-4 therapy. Immunology and allergy clinics of North America. 2004;24(4):599-614, vi. doi: 10.1016/j.iac.2004.06.008. PubMed PMID: 15474861.
88. Steinke JW. Current prospective of anti-IL-4, -IL-9, and -IL-13 therapies in allergic disease. Recent patents on inflammation & allergy drug discovery. 2010;4(3):222-30. PubMed PMID: 20807191.
89. Stark GR, Darnell JE, Jr. The JAK-STAT pathway at twenty. Immunity. 2012;36(4):503-14. doi: 10.1016/j.immuni.2012.03.013. PubMed PMID: 22520844; PMCID: PMC3909993.
90. O'Shea JJ, Husa M, Li D, Hofmann SR, Watford W, Roberts JL, Buckley RH, Changelian P, Candotti F. Jak3 and the pathogenesis of severe combined immunodeficiency. Mol Immunol. 2004;41(6-7):727-37. doi: 10.1016/j.molimm.2004.04.014. PubMed PMID: 15220007.
91. Bozzi F, Lefranc G, Villa A, Badolato R, Schumacher RF, Khalil G, Loiselet J, Bresciani S, O'Shea JJ, Vezzoni P, Notarangelo LD, Candotti F. Molecular and biochemical characterization of JAK3 deficiency in a patient with severe combined immunodeficiency over 20 years after bone marrow transplantation: implications for treatment. Br J Haematol. 1998;102(5):1363-6. PubMed PMID: 9753072.
92. Cacalano NA, Migone TS, Bazan F, Hanson EP, Chen M, Candotti F, O'Shea JJ, Johnston JA. Autosomal SCID caused by a point mutation in the N-terminus of Jak3: mapping of the Jak3-receptor interaction domain. The EMBO journal. 1999;18(6):1549-58. doi: 10.1093/emboj/18.6.1549. PubMed PMID: 10075926; PMCID: PMC1171243.
93. Candotti F, Oakes SA, Johnston JA, Giliani S, Schumacher RF, Mella P, Fiorini M, Ugazio AG, Badolato R, Notarangelo LD, Bozzi F, Macchi P, Strina D, Vezzoni P, Blaese RM, O'Shea JJ, Villa A. Structural and functional basis for JAK3-deficient severe combined immunodeficiency. Blood. 1997;90(10):3996-4003. PubMed PMID: 9354668.
94. Candotti F, O'Shea JJ, Villa A. Severe combined immune deficiencies due to defects of the common gamma chain-JAK3 signaling pathway. Springer Semin Immunopathol. 1998;19(4):401-15. PubMed PMID: 9618765.
95. Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, Ugazio AG, Johnston JA, Candotti F, O'Shea JJ, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. 1995;377(6544):65-8. doi: 10.1038/377065a0. PubMed PMID: 7659163.
96. Russell SM, Tayebi N, Nakajima H, Riedy MC, Roberts JL, Aman MJ, Migone TS, Noguchi M, Markert ML, Buckley RH, O'Shea JJ, Leonard WJ. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science. 1995;270(5237):797-800. PubMed PMID: 7481768.
97. Johnston JA, Kawamura M, Kirken RA, Chen YQ, Blake TB, Shibuya K, Ortaldo JR, McVicar DW, O'Shea JJ. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature. 1994;370(6485):151-3. doi: 10.1038/370151a0. PubMed PMID: 8022485.
98. Park SY, Saijo K, Takahashi T, Osawa M, Arase H, Hirayama N, Miyake K, Nakauchi H, Shirasawa T, Saito T. Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity. 1995;3(6):771-82. PubMed PMID: 8777722.
99. Cao X, Shores EW, Hu-Li J, Anver MR, Kelsall BL, Russell SM, Drago J, Noguchi M, Grinberg A, Bloom ET, et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity. 1995;2(3):223-38. PubMed PMID: 7697543.
100. Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, McBride OW, Leonard WJ. IL-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993;73(1):147-57. PubMed PMID: 8462096.
101. Changelian PS, Flanagan ME, Ball DJ, Kent CR, Magnuson KS, Martin WH, Rizzuti BJ, Sawyer PS, Perry BD, Brissette WH, McCurdy SP, Kudlacz EM, Conklyn MJ, Elliott EA, Koslov ER, Fisher MB, Strelevitz TJ, Yoon K, Whipple DA, Sun J, Munchhof MJ, Doty JL, Casavant JM, Blumenkopf TA, Hines M, Brown MF, Lillie BM, Subramanyam C, Shang-Poa C, Milici AJ, Beckius GE, Moyer JD, Su C, Woodworth TG, Gaweco AS, Beals CR, Littman BH, Fisher DA, Smith JF, Zagouras P, Magna HA, Saltarelli MJ, Johnson KS, Nelms LF, Des Etages SG, Hayes LS, Kawabata TT, Finco-Kent D, Baker DL, Larson M, Si MS, Paniagua R, Higgins J, Holm B, Reitz B, Zhou YJ, Morris RE, O'Shea JJ, Borie DC. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science. 2003;302(5646):875-8. doi: 10.1126/science.1087061. PubMed PMID: 14593182.
102. Furumoto Y, Smith CK, Blanco L, Zhao W, Brooks SR, Thacker SG, Zarzour A, Sciume G, Tsai WL, Trier AM, Nunez L, Mast L, Hoffmann V, Remaley AT, O'Shea JJ, Kaplan MJ, Gadina M. Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction. Arthritis Rheumatol. 2017;69(1):148-60. doi: 10.1002/art.39818. PubMed PMID: 27429362; PMCID: PMC5195893.
103. Ghoreschi K, Jesson MI, Li X, Lee JL, Ghosh S, Alsup JW, Warner JD, Tanaka M, Steward-Tharp SM, Gadina M, Thomas CJ, Minnerly JC, Storer CE, LaBranche TP, Radi ZA, Dowty ME, Head RD, Meyer DM, Kishore N, O'Shea JJ. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). Journal of immunology. 2011;186(7):4234-43. doi: 10.4049/jimmunol.1003668. PubMed PMID: 21383241; PMCID: 3108067.
104. Kremer J, Li ZG, Hall S, Fleischmann R, Genovese M, Martin-Mola E, Isaacs JD, Gruben D, Wallenstein G, Krishnaswami S, Zwillich SH, Koncz T, Riese R, Bradley J. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Annals of internal medicine. 2013;159(4):253-61. doi: 10.7326/0003-4819-159-4-201308200-00006. PubMed PMID: 24026258.
105. Okiyama N, Furumoto Y, Villarroel VA, Linton JT, Tsai WL, Gutermuth J, Ghoreschi K, Gadina M, O'Shea JJ, Katz SI. Reversal of CD8 T-cell-mediated mucocutaneous graft-versus-host-like disease by the JAK inhibitor tofacitinib. J Invest Dermatol. 2014;134(4):992-1000. doi: 10.1038/jid.2013.476. PubMed PMID: 24213371; PMCID: PMC3961527.
106. Onda M, Ghoreschi K, Steward-Tharp S, Thomas C, O'Shea JJ, Pastan IH, FitzGerald DJ. Tofacitinib suppresses antibody responses to protein therapeutics in murine hosts. Journal of immunology. 2014;193(1):48-55. doi: 10.4049/jimmunol.1400063. PubMed PMID: 24890727; PMCID: PMC4106678.
107. Sandborn WJ, Ghosh S, Panes J, Vranic I, Su C, Rousell S, Niezychowski W, Study AI. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. The New England journal of medicine. 2012;367(7):616-24. doi: 10.1056/NEJMoa1112168. PubMed PMID: 22894574.
108. Strober B, Buonanno M, Clark JD, Kawabata T, Tan H, Wolk R, Valdez H, Langley RG, Harness J, Menter A, Papp K. Effect of tofacitinib, a Janus kinase inhibitor, on haematological parameters during 12 weeks of psoriasis treatment. The British journal of dermatology. 2013;169(5):992-9. doi: 10.1111/bjd.12517. PubMed PMID: 23855761.
109. Wojciechowski D, Vincenti F. Tofacitinib in kidney transplantation. Expert opinion on investigational drugs. 2013;22(9):1193-9. doi: 10.1517/13543784.2013.811231. PubMed PMID: 23841583.
110. Yokoyama S, Perera PY, Waldmann TA, Hiroi T, Perera LP. Tofacitinib, a janus kinase inhibitor demonstrates efficacy in an IL-15 transgenic mouse model that recapitulates pathologic manifestations of celiac disease. Journal of clinical immunology. 2013;33(3):586-94. doi: 10.1007/s10875-012-9849-y. PubMed PMID: 23269601; PMCID: 3594487.
111. Kontzias A, Kotlyar A, Laurence A, Changelian P, O'Shea JJ. Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. Curr Opin Pharmacol. 2012;12(4):464-70. doi: 10.1016/j.coph.2012.06.008. PubMed PMID: 22819198; PMCID: PMC3419278.
112. Jiang JK, Ghoreschi K, Deflorian F, Chen Z, Perreira M, Pesu M, Smith J, Nguyen DT, Liu EH, Leister W, Costanzi S, O'Shea JJ, Thomas CJ. Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-y l)-3-oxopropanenitrile (CP-690,550). J Med Chem. 2008;51(24):8012-8. doi: 10.1021/jm801142b. PubMed PMID: 19053756; PMCID: PMC2660606.
113. Fleischmann R, Cutolo M, Genovese MC, Lee EB, Kanik KS, Sadis S, Connell CA, Gruben D, Krishnaswami S, Wallenstein G, Wilkinson BE, Zwillich SH. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis and rheumatism. 2012;64(3):617-29. doi: 10.1002/art.33383. PubMed PMID: 21952978.
114. Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, Krishnaswami S, Burgos-Vargas R, Wilkinson B, Zerbini CA, Zwillich SH. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis and rheumatism. 2009;60(7):1895-905. doi: 10.1002/art.24567. PubMed PMID: 19565475.
115. Kremer JM, Cohen S, Wilkinson BE, Connell CA, French JL, Gomez-Reino J, Gruben D, Kanik KS, Krishnaswami S, Pascual-Ramos V, Wallenstein G, Zwillich SH. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis and rheumatism. 2012;64(4):970-81. doi: 10.1002/art.33419. PubMed PMID: 22006202.
116. Tanaka Y, Suzuki M, Nakamura H, Toyoizumi S, Zwillich SH, Tofacitinib Study I. Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken). 2011;63(8):1150-8. doi: 10.1002/acr.20494. PubMed PMID: 21584942.
117. Thoma G, Druckes P, Zerwes HG. Selective inhibitors of the Janus kinase Jak3--Are they effective? Bioorg Med Chem Lett. 2014;24(19):4617-21. doi: 10.1016/j.bmcl.2014.08.046. PubMed PMID: 25217444.
118. Peschon JJ, Morrissey PJ, Grabstein KH, Ramsdell FJ, Maraskovsky E, Gliniak BC, Park LS, Ziegler SF, Williams DE, Ware CB, Meyer JD, Davison BL. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. The Journal of experimental medicine. 1994;180(5):1955-60. PubMed PMID: 7964471; PMCID: PMC2191751.
119. Puel A, Ziegler SF, Buckley RH, Leonard WJ. Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nat Genet. 1998;20(4):394-7. doi: 10.1038/3877. PubMed PMID: 9843216.
120. Parrish YK, Baez I, Milford TA, Benitez A, Galloway N, Rogerio JW, Sahakian E, Kagoda M, Huang G, Hao QL, Sevilla Y, Barsky LW, Zielinska E, Price MA, Wall NR, Dovat S, Payne KJ. IL-7 Dependence in human B lymphopoiesis increases during progression of ontogeny from cord blood to bone marrow. Journal of immunology. 2009;182(7):4255-66. doi: 10.4049/jimmunol.0800489. PubMed PMID: 19299724; PMCID: PMC2659466.
121. Ogasawara K, Hida S, Azimi N, Tagaya Y, Sato T, Yokochi-Fukuda T, Waldmann TA, Taniguchi T, Taki S. Requirement for IRF-1 in the microenvironment supporting development of natural killer cells. Nature. 1998;391(6668):700-3. doi: 10.1038/35636. PubMed PMID: 9490414.
122. Zenatti PP, Ribeiro D, Li W, Zuurbier L, Silva MC, Paganin M, Tritapoe J, Hixon JA, Silveira AB, Cardoso BA, Sarmento LM, Correia N, Toribio ML, Kobarg J, Horstmann M, Pieters R, Brandalise SR, Ferrando AA, Meijerink JP, Durum SK, Yunes JA, Barata JT. Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet. 2011;43(10):932-9. doi: 10.1038/ng.924. PubMed PMID: 21892159.
123. Shochat C, Tal N, Bandapalli OR, Palmi C, Ganmore I, te Kronnie G, Cario G, Cazzaniga G, Kulozik AE, Stanulla M, Schrappe M, Biondi A, Basso G, Bercovich D, Muckenthaler MU, Izraeli S. Gain-of-function mutations in interleukin-7 receptor-alpha (IL7R) in childhood acute lymphoblastic leukemias. The Journal of experimental medicine. 2011;208(5):901-8. doi: 10.1084/jem.20110580. PubMed PMID: 21536738; PMCID: PMC3092356.
124. Hanick NA, Rickert M, Varani L, Bankovich AJ, Cochran JR, Kim DM, Surh CD, Garcia KC. Elucidation of the IL-15 binding site on its alpha receptor by NMR. Biochemistry. 2007;46(33):9453-61. doi: 10.1021/bi700652f. PubMed PMID: 17655329.
125. LaPorte SL, Juo ZS, Vaclavikova J, Colf LA, Qi X, Heller NM, Keegan AD, Garcia KC. Molecular and structural basis of cytokine receptor pleiotropy in the IL-4/13 system. Cell. 2008;132(2):259-72. doi: 10.1016/j.cell.2007.12.030. PubMed PMID: 18243101; PMCID: 2265076.
126. Marquez A, Orozco G, Martinez A, Palomino-Morales R, Fernandez-Arquero M, Mendoza JL, Taxonera C, Diaz-Rubio M, Gomez-Garcia M, Nieto A, Lopez-Nevot MA, de la Concha EG, Martin J, Urcelay E. Novel association of the IL2-IL21 region with inflammatory bowel disease. The American journal of gastroenterology. 2009;104(8):1968-75. doi: 10.1038/ajg.2009.224. PubMed PMID: 19471255.
127. Rickert M, Wang X, Boulanger MJ, Goriatcheva N, Garcia KC. The structure of IL-2 complexed with its alpha receptor. Science. 2005;308(5727):1477-80. doi: 10.1126/science.1109745. PubMed PMID: 15933202.
128. Ring AM, Lin JX, Feng D, Mitra S, Rickert M, Bowman GR, Pande VS, Li P, Moraga I, Spolski R, Ozkan E, Leonard WJ, Garcia KC. Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. Nature immunology. 2012;13(12):1187-95. doi: 10.1038/ni.2449. PubMed PMID: 23104097; PMCID: 3501574.
129. Wang X, Rickert M, Garcia KC. Structure of the quaternary complex of IL-2 with its alpha, beta, and gammac receptors. Science. 2005;310(5751):1159-63. doi: 10.1126/science.1117893. PubMed PMID: 16293754.
130. Jacobson S, Shida H, McFarlin DE, Fauci AS, Koenig S. Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurological disease. Nature. 1990;348(6298):245-8. doi: 10.1038/348245a0. PubMed PMID: 2146511.
131. Azimi N, Shiramizu KM, Tagaya Y, Mariner J, Waldmann TA. Viral activation of IL-15: characterization of a virus-inducible element in the IL-15 promoter region. Journal of virology. 2000;74(16):7338-48. PubMed PMID: 10906187; PMCID: 112254.
132. Chen J, Petrus M, Bryant BR, Phuc Nguyen V, Stamer M, Goldman CK, Bamford R, Morris JC, Janik JE, Waldmann TA. Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism. Blood. 2008;111(10):5163-72. doi: 10.1182/blood-2007-09-113654. PubMed PMID: 18339896; PMCID: 2384140.
133. Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annual review of immunology. 2004;22:531-62. doi: 10.1146/annurev.immunol.21.120601.141122. PubMed PMID: 15032588.
134. Sakaguchi S, Vignali DA, Rudensky AY, Niec RE, Waldmann H. The plasticity and stability of regulatory T cells. Nature reviews Immunology. 2013;13(6):461-7. doi: 10.1038/nri3464. PubMed PMID: 23681097.
135. Yokohama A, Mishra A, Mitsui T, Becknell B, Johns J, Curphey D, Blaser BW, Vandeusen JB, Mao H, Yu J, Caligiuri MA. A novel mouse model for the aggressive variant of NK cell and T cell large granular lymphocyte leukemia. Leuk Res. 2010;34(2):203-9. doi: 10.1016/j.leukres.2009.06.031. PubMed PMID: 19660811; PMCID: PMC2814907.
136. Mishra A, Liu S, Sams GH, Curphey DP, Santhanam R, Rush LJ, Schaefer D, Falkenberg LG, Sullivan L, Jaroncyk L, Yang X, Fisk H, Wu LC, Hickey C, Chandler JC, Wu YZ, Heerema NA, Chan KK, Perrotti D, Zhang J, Porcu P, Racke FK, Garzon R, Lee RJ, Marcucci G, Caligiuri MA. Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation. Cancer Cell. 2012;22(5):645-55. doi: 10.1016/j.ccr.2012.09.009. PubMed PMID: 23153537; PMCID: PMC3627362.
137. Mishra A, Sullivan L, Caligiuri MA. Molecular pathways: interleukin-15 signaling in health and in cancer. Clin Cancer Res. 2014;20(8):2044-50. doi: 10.1158/1078-0432.CCR-12-3603. PubMed PMID: 24737791; PMCID: PMC3989546.
138. Blaser BW, Roychowdhury S, Kim DJ, Schwind NR, Bhatt D, Yuan W, Kusewitt DF, Ferketich AK, Caligiuri MA, Guimond M. Donor-derived IL-15 is critical for acute allogeneic graft-versus-host disease. Blood. 2005;105(2):894-901. doi: 10.1182/blood-2004-05-1687. PubMed PMID: 15374888.
139. Blaser BW, Schwind NR, Karol S, Chang D, Shin S, Roychowdhury S, Becknell B, Ferketich AK, Kusewitt DF, Blazar BR, Caligiuri MA. 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. 2006;108(7):2463-9. doi: 10.1182/blood-2006-04-019059. PubMed PMID: 16757683; PMCID: PMC1895554.
140. Roychowdhury S, Blaser BW, Freud AG, Katz K, Bhatt D, Ferketich AK, Bergdall V, Kusewitt D, Baiocchi RA, Caligiuri MA. IL-15 but not IL-2 rapidly induces lethal xenogeneic graft-versus-host disease. Blood. 2005;106(7):2433-5. doi: 10.1182/blood-2005-04-1597. PubMed PMID: 15976176; PMCID: PMC1895258.
141. Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K, Li W, Lopez R, McWilliam H, Remmert M, Soding J, Thompson JD, Higgins DG. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 2011;7:539. doi: 10.1038/msb.2011.75. PubMed PMID: 21988835; PMCID: PMC3261699.
142. Andrusier N, Nussinov R, Wolfson HJ. FireDock: fast interaction refinement in molecular docking. Proteins. 2007;69(1):139-59. doi: 10.1002/prot.21495. PubMed PMID: 17598144.
143. Schneidman-Duhovny D, Inbar Y, Nussinov R, Wolfson HJ. PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res. 2005;33(Web Server issue):W363-7. doi: 10.1093/nar/gki481. PubMed PMID: 15980490; PMCID: PMC1160241.