Janus tyrosine kinases and signal transducers and activators of transcription regulate critical functions of T cells in allograft rejection and transplantation tolerance

Transplantation

Volumn 82, Issue 3, 2006, Pages 295-303

  Stepkowski, Stanislaw M ^a   Kirken, Robert A ^b  

^a UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^b UNIVERSITY OF TEXAS AT EL PASO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 (4 HYDROXYANILINO) 6,7 DIMETHOXYQUINAZOLINE; 4 [N [1 (2 CYANO 1 OXOETHYL) 4 METHYL 3 PIPERIDINYL] N METHYLAMINO]PYRROLO[2,3 D]PYRIMIDINE; CALCINEURIN INHIBITOR; CYCLOSPORIN; CYTOKINE; CYTOKINE RECEPTOR; IMMUNOSUPPRESSIVE AGENT; JANUS KINASE; JANUS KINASE 3 INHIBITOR; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; N BENZYL 2 CYANO 3 (3,4 DIHYDROXYPHENYL)ACRYLAMIDE; NC 1153; PNU 156804; PRODIGIOSIN; RAPAMYCIN; STAT PROTEIN; TYRPHOSTIN; UNCLASSIFIED DRUG;

ABSENCE OF SIDE EFFECTS; ANTIGEN PRESENTING CELL; AUTOIMMUNE DISEASE; B LYMPHOCYTE; CELL DEATH; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL SURVIVAL; DRUG TARGETING; GRAFT REJECTION; HEMATOPOIESIS; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; KNOCKOUT MOUSE; LIPID METABOLISM; LYMPHATIC SYSTEM TUMOR; LYMPHOCYTE FUNCTION; NEPHROTOXICITY; NONHUMAN; PRIORITY JOURNAL; PROTEIN FAMILY; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; TRANSPLANTATION TOLERANCE;

ANIMALS; GRAFT REJECTION; HUMANS; PROTEIN-TYROSINE KINASES; SIGNAL TRANSDUCTION; STAT TRANSCRIPTION FACTORS; T-LYMPHOCYTES; TRANSPLANTATION TOLERANCE; TRANSPLANTATION, HOMOLOGOUS;

EID: 33747102044     PISSN: 00411337     EISSN: None     Source Type: Journal    
DOI: 10.1097/01.tp.0000228903.03118.be     Document Type: Review

References (116)

1. Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U S A 1990; 87: 6934.
2. Battle TE, Frank DA. The role of STATs in apoptosis. Curr Mol Med 2002; 2: 381.
3. Boutin Y, Leitenberg D, Tao X, Bottomly K. Distinct biochemical signals characterize agonist- and altered peptide ligand-induced differentiation of naive CD4+ T cells into Th1 and Th2 subsets. J Immunol 1997; 159: 5802.
4. Kuo CT, Leiden JM. Transcriptional regulation of T lymphocyte development and function. Annu Rev Immunol 1999; 17: 149.
5. Appleman LJ, Boussiotis VA. T cell anergy and costimulation. Immunol Rev 2003; 192: 161.
6. Leonard WJ. STA. Ts and cytokine specificity. Nat Med 1996; 2: 968.
7. Nelson BH, Willerford DM. Biology of the interleukin-2 receptor. Adv Immunol 1998; 70: 1.
8. Ihle JN, Witthuhn BA, Quelle FW, et al. Signaling through the hematopoietic cytokine receptors. Annu Rev Immunol 1995; 13: 369.
9. Zhou YJ, Hanson EP, Chen YQ, et al. Distinct tyrosine phosphorylation sites in JAK3 kinase domain positively and negatively regulate its enzymatic activity. Proc Natl Acad Sci U S A 1997; 94: 13850.
10. Boggon TJ, Li Y, Manley PW, Eck MJ. Crystal structure of the Jak3 kinase domain in complex with a staurosporine analogue. Blood 2005.
11. Kurzer JH, Argetsinger LS, Zhou YJ, et al. Tyrosine 813 is a site of JAK2 autophosphorylation critical for activation of JAK2 by SH2-B beta. Mol Cell Biol 2004; 24: 4557.
12. Darnell JE Jr. STATs and gene regulation. Science 1997; 277: 1630.
13. Leonard WJ, O'Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol 1998; 16: 293.
14. Shuai K, Horvath CM, Huang LH, et al. Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell 1994; 76: 821.
15. Decker T, Kovarik P. Serine phosphorylation of STATs. Oncogene 2000; 19: 2628.
16. Zhang Y, Turkson J, Carter-Su C, et al. Activation of Stat3 in v-Src-transformed fibroblasts requires cooperation of Jak1 kinase activity. J Biol Chem 2000; 275: 24935.
17. Turkson J, Bowman T, Adnane J, et al. Requirement for Ras/Rac1-mediated p38 and c-Jun N-terminal kinase signaling in Stat3 transcriptional activity induced by the Src oncoprotein. Mol Cell Biol 1999; 19: 7519.
18. Zhang X, Blenis J, Li HC, et al. Requirement of serine phosphorylation for formation of STAT-promoter complexes. Science 1995; 267: 1990.
19. Wen Z, Zhong Z, Darnell JE Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 1995; 82: 241.
20. Ng J, Cantrell D. STAT3 is a serine kinase target in T lymphocytes. Interleukin 2 and T cell antigen receptor signals converge upon serine 727. J Biol Chem 1997; 272: 24542.
21. Gamero AM, Larner AC. Signaling via the T cell antigen receptor induces phosphorylation of Stat1 on serine 727. J Biol Chem 2000; 275: 16574.
22. Lafont V, Decker T, Cantrell D. Antigen receptor signal transduction: activating and inhibitory antigen receptors regulate STAT1 serine phosphorylation. Eur J Immunol 2000; 30: 1851.
23. Winston LA, Hunter T. Intracellular signalling: putting JAKs on the kinase MAP. Curr Biol 1996; 6: 668.
24. David M, Petricoin E 3rd, Benjamin C, et al. Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. Science 1995; 269: 1721.
25. Chung J, Uchida E, Grammer TC, Blenis J. STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol Cell Biol 1997; 17: 6508.
26. Nagy ZS, Wang Y, Erwin-Cohen RA, et al. Interleukin-2 family cytokines stimulate phosphorylation of the Pro-Ser-Pro motif of Stat5 transcription factors in human T cells: resistance to suppression of multiple serine kinase pathways. J Leukoc Biol 2002; 72: 819.
27. Kuroki M, O'Flaherty JT. Extracellular signal-regulated protein kinase (ERK)-dependent and ERK-independent pathways target STAT3 on serine-727 in human neutrophils stimulated by chemotactic factors and cytokines. Biochem J 1999; 341(Pt 3): 691.
28. Yokogami K, Wakisaka S, Avruch J, Reeves SA. Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR. Curr Biol 2000; 10: 47.
29. Lim CP, Cao X. Serine phosphorylation and negative regulation of Stat3 by JNK. J Biol Chem 1999; 274: 31055.
30. Morinobu A, Gadina M, Strober W, et al. STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proc Natl Acad Sci U S A 2002; 99: 12281.
31. Kirken RA, Malabarba MG, Xu J, et al. Two discrete regions of interleukin-2 (IL2) receptor beta independently mediate IL2 activation of a PD98059/rapamycin/wortmannin-insensitive Stat5a/b serine kinase. J Biol Chem 1997; 272: 15459.
32. Wang Y, Malabarba MG, Nagy ZS, Kirken RA. Interleukin 4 regulates phosphorylation of serine 756 in the transactivation domain of Stat6. Roles for multiple phosphorylation sites and Stat6 function. J Biol Chem 2004; 279: 25196.
33. Yamashita H, Xu J, Erwin RA, et al. Differential control of the phosphorylation state of proline-juxtaposed serine residues Ser725 of Stat5a and Ser730 of Stat5b in prolactin-sensitive cells. J Biol Chem 1998; 273: 30218.
34. Clark DE, Williams CC, Duplessis TT, et al. ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events. J Biol Chem 2005; 280: 24175.
35. Ryan JJ, McReynolds LJ, Keegan A, et al. Growth and gene expression are predominantly controlled by distinct regions of the human IL-4 receptor. Immunity 1996; 4: 123.
36. Wang HY, Paul WE, Keegan AD. IL-4 function can be transferred to the IL-2 receptor by tyrosine containing sequences found in the IL-4 receptor alpha chain. Immunity 1996; 4: 113.
37. Woetmann A, Brockdorff J, Lovato P, et al. Protein phosphatase 2A (PP2A) regulates interleukin-4-mediated STAT6 signaling. J Biol Chem 2003; 278: 2787.
38. Wick KR, Berton MT. IL-4 induces serine phosphorylation of the STAT6 transactivation domain in B lymphocytes. Mol Immunol 2000; 37: 641.
39. Rodig SJ, Meraz MA, White JM, et al. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell 1998; 93: 373.
40. Parganas E, Wang D, Stravopodis D, et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell 1998; 93: 385.
41. Ihle JN, Thierfelder W, Teglund S, et al. Signaling by the cytokine receptor superfamily. Ann N Y Acad Sci 1998; 865: 1.
42. Aringer M, Hofmann SR, Frucht DM, et al. Characterization and analysis of the proximal Janus kinase 3 promoter. J Immunol 2003; 170: 6057.
43. Tortolani PJ, Lal BK, Riva A, et al. Regulation of JAK3 expression and activation in human B cells and B cell malignancies. J Immunol 1995; 155: 5220.
44. Yamaoka K, Min B, Zhou YJ, et al. Jak3 negatively regulates dendritic cell cytokine production and survival. Blood 2005; 106: 3227.
45. Li XC, Ima A, Li Y, Zheng XX, Malek TR, Strom TB. Blocking the common gamma-chain of cytokine receptors induces T cell apoptosis and long-term islet allograft survival. J Immunol 2000; 164: 1193.
46. Wen R, Wang D, McKay C, et al. Jak3 selectively regulates Bax and Bcl-2 expression to promote T-cell development. Mol Cell Biol 2001; 21: 678.
47. Noguchi M, Yi H, Rosenblatt HM, et al. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 1993; 73: 147.
48. Macchi P, Villa A, Giliani S, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 1995; 377: 65.
49. Russell SM, Tayebi N, Nakajima H, et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 1995; 270: 797.
50. Leonard WJ. The molecular basis of X-linked severe combined immunodeficiency: defective cytokine receptor signaling. Annu Rev Med 1996; 47: 229.
51. Cacalano NA, Migone TS, Bazan F, et al. Autosomal SCID caused by a point mutation in the N-terminus of Jak3: mapping of the Jak3-receptor interaction domain. EMBO J 1999; 18: 1549.
52. Candotti F, Oakes SA, Johnston JA, et al. Structural and functional basis for JAK3-deficient severe combined immunodeficiency. Blood 1997; 90: 3996.
53. Bunting KD, Sangster MY, Ihle JN, Sorrentino BP. Restoration of lymphocyte function in Janus kinase 3-deficient mice by retroviral-mediated gene transfer. Nat Med 1998; 4: 58.
54. Roberts JL, Lengi A, Brown SM, et al. Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation. Blood 2004; 103: 2009.
55. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 2000; 288: 669.
56. Shimoda K, Kato K, Aoki K, et al. Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function. Immunity 2000; 13: 561.
57. Karaghiosoff M, Neubauer H, Lassnig C, et al. Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity 2000; 13: 549.
58. Shimoda K, Kamesaki K, Numata A, et al. Cutting edge: tyk2 is required for the induction and nuclear translocation of Daxx which regulates IFN-alpha-induced suppression of B lymphocyte formation. J Immunol 2002; 169: 4707.
59. Durbin JE, Hackenmiller R, Simon MC, Levy DE. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 1996; 84: 443.
60. Meraz MA, White JM, Sheehan KC, et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 1996; 84: 431.
61. Lee CK, Smith E, Gimeno R, et al. STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-gamma. J Immunol 2000; 164: 1286.
62. Nishibori T, Tanabe Y, Su L, David M. Impaired development of CD4+ CD25+ regulatory T cells in the absence of STAT1: increased susceptibility to autoimmune disease. J Exp Med 2004; 199: 25.
63. Park C, Li S, Cha E, Schindler C. Immune response in Stat2 knockout mice. Immunity 2000; 13: 795.
64. Kaneko S, Suzuki N, Koizumi H, et al. Rescue by cytokines of apoptotic cell death induced by IL-2 deprivation of human antigen-specific T cell clones. Clin Exp Immunol 1997; 109: 185.
65. Takeda K, Noguchi K, Shi W, et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci U S A 1997; 94: 3801.
66. Takeda K, Kaisho T, Yoshida N, et al. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J Immunol 1998; 161: 4652.
67. Berenson LS, Ota N, Murphy KM. Issues in T-helper 1 development-resolved and unresolved. Immunol Rev 2004; 202: 157.
68. Kaplan MH, Sun YL, Hoey T, Grusby MJ. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 1996; 382: 174.
69. O'Shea JJ. Jaks, STATs, cytokine signal transduction, and immunoregulation: are we there yet? Immunity 1997; 7: 1.
70. Liu X, Robinson GW, Wagner KU, et al. Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev 1997; 11: 179.
71. Udy GB, Towers RP, Snell RG, et al. Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci U S A 1997; 94: 7239.
72. Moriggl R, Topham DJ, Teglund S, et al. Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 1999; 10: 249.
73. Chai SK, Nichols GL, Rothman P. Constitutive activation of JAKs and STATs in BCR-Abl-expressing cell lines and peripheral blood cells derived from leukemic patients. J Immunol 1997; 159: 4720.
74. Behbod F, Nagy ZS, Stepkowski SM, et al. Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumorderived lymphoid cells. J Immunol 2003; 171: 3919.
75. Snow JW, Abraham N, Ma MC, et al. Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5B-deficient mice. J Immunol 2003; 171: 5042.
76. Zhang Y, Kirken RA, Furian L, et al. Allograft rejection requires STAT5a/b-regulated antiapoptotic activity in T cells but not B cells. J Immunol 2006; 176: 128.
77. Antov A, Yang L, Vig M, et al. Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance. J Immunol 2003; 171: 3435.
78. Bensinger SJ, Walsh PT, Zhang J, et al. Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol 2004; 172: 5287.
79. Weber-Nordt RM, Egen C, Wehinger J, et al. Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein-Barr virus (EBV)-related lymphoma cell lines. Blood 1996; 88: 809.
80. Lord JD, McIntosh BC, Greenberg PD, Nelson BH. The IL-2 receptor promotes proliferation, bcl-2 and bcl-x induction, but not cell viability through the adapter molecule Shc. J Immunol 1998; 161: 4627.
81. Matikainen S, Sareneva T, Ronni T, et al. Interferon-alpha activates multiple STAT proteins and upregulates proliferation-associated IL-2Ralpha, c-myc, and pim-1 genes in human T cells. Blood 1999; 93: 1980.
82. Burchill MA, Goetz CA, Prlic M, et al. Distinct effects of STAT5 activation on CD4+ and CD8+ T cell homeostasis: development of CD4+CD25+ regulatory T cells versus CD8+ memory T cells. J Immunol 2003; 171: 5853.
83. Shimoda K, van Deursen J, Sangster MY, et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 1996; 380: 630.
84. Zhu J, Cote-Sierra J, Guo L, Paul WE. Stat5 activation plays a critical role in Th2 differentiation. Immunity 2003; 19: 739.
85. Hilton DJ. Negative regulators of cytokine signal transduction. Cell Mol Life Sci 1999; 55: 1568.
86. Greenhalgh CJ, Hilton DJ. Negative regulation of cytokine signaling. J Leukoc Biol 2001; 70: 348.
87. Endo TA, Masuhara M, Yokouchi M, et al.A new protein containing an SH2 domain that inhibits JAK kinases. Nature 1997; 387: 921.
88. Nicholson SE, Willson TA, Farley A, et al. Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. EMBO J 1999; 18: 375.
89. Yoshimura A. The CIS family: negative regulators of JAK-STAT signaling. Cytokine Growth Factor Rev 1998; 9: 197.
90. Naka T, Matsumoto T, Narazaki M, et al. Accelerated apoptosis of lymphocytes by augmented induction of Bax in SSI-1 (STAT-induced STAT inhibitor-1) deficient mice. Proc Natl Acad Sci U S A 1998; 95: 15577.
91. Alexander WS, Starr R, Fenner JE, et al. SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 1999; 98: 597.
92. Marine JC, McKay C, Wang D, et al. SOCS3 is essential in the regulation of fetal liver erythropoiesis. Cell 1999; 98: 617.
93. Kamizono S, Hanada T, Yasukawa H, et al. The SOCS box of SOCS-1 accelerates ubiquitin-dependent proteolysis of TEL-JAK2. J Biol Chem 2001; 276: 12530.
94. Fujimoto M, Naka T, Nakagawa R, et al. Defective thymocyte development and perturbed homeostasis of T cells in STAT-induced STAT inhibitor-1/ suppressors of cytokine signaling-1 transgenic mice. J Immunol 2000; 165: 1799.
95. Seki Y, Hayashi K, Matsumoto A, et al. Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation. Proc Natl Acad Sci U S A 2002; 99: 13003.
96. Egwuagu CE, Yu CR, Zhang M, et al. Suppressors of cytokine signaling proteins are differentially expressed in Th1 and Th2 cells: implications for Th cell lineage commitment and maintenance. J Immunol 2002; 168: 3181.
97. Seki Y, Inoue H, Nagata N, et al. SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses. Nat Med 2003; 9: 1047.
98. Yu CR, Mahdi RM, Ebong S, et al. Cell proliferation and STAT6 pathways are negatively regulated in T cells by STAT1 and suppressors of cytokine signaling. J Immunol 2004; 173: 737.
99. Ye Z, Kirken R, Janczewska S, et al. SOCS3 and C-maf are involved in generation and maintenance of Th2 regulatory cells in transplantation tolerance (Abstract 540). Am J Transplant 2003.
100. You-Ten KE, Muise ES, Itie A, et al. Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice. J Exp Med 1997; 186: 683.
101. Byth KF, Conroy LA, Howlett S, et al. CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation. J Exp Med 1996; 183: 1707.
102. Irie-Sasaki J, Sasaki T, Matsumoto W, et al. CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 2001; 409: 349.
103. Chung CD, Liao J, Liu B, et al. Specific inhibition of Stat3 signal transduction by PIAS3. Science 1997; 278: 1803.
104. Arora T, Liu B, He H, et al. PIASx is a transcriptional co-repressor of signal transducer and activator of transcription 4. J Biol Chem 2003; 278: 21327.
105. Liu B, Gross M, ten Hoeve J, Shuai K. A transcriptional corepressor of Stat1 with an essential LXXLL signature motif. Proc Natl Acad Sci U S A 2001; 98: 3203.
106. Pranada AL, Metz S, Herrmann A, et al. Real time analysis of STAT3 nucleocytoplasmic shuttling. J Biol Chem 2004; 279: 15114.
107. Yoshimura A, Nishinakamura H, Matsumura Y, Hanada T. Negative regulation of cytokine signaling and immune responses by SOCS proteins. Arthritis Res Ther 2005; 7: 100.
108. Sachdev S, Bruhn L, Sieber H, et al. PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes Dev 2001; 15: 3088.
109. Godfrey WR, Ge YG, Spoden DJ, et al. In vitro-expanded human CD4(+)CD25(+) T-regulatory cells can markedly inhibit allogeneic dendritic cell-stimulated MLR cultures. Blood 2004; 104: 453.
110. Kishimoto K, Dong VM, Issazadeh S, et al. The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo. J Clin Invest 2000; 106: 63.
111. Behbod F, Erwin-Cohen RA, Wang ME, et al. Concomitant inhibition of Janus kinase 3 and calcineurin-dependent signaling pathways synergistically prolongs the survival of rat heart allografts. J Immunol 2001; 166: 3724.
112. Stepkowski SM, Erwin-Cohen RA, Behbod F, et al. Selective inhibitor of Janus tyrosine kinase 3, PNU156804, prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin. Blood 2002; 99: 680.
113. Changelian PS, Flanagan ME, Ball DJ, et al. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 2003; 302: 875.
114. Uckun FM, Roers BA, Waurzyniak B, et al. Janus kinase 3 inhibitor WHI-P131/JANEX-1 prevents graft-versus-host disease but spares the graft-versus-leukemia function of the bone marrow allografts in a murine bone marrow transplantation model. Blood 2002; 99: 4192.
115. Stepkowski SM, Furian L, Janczewska S, et al. Jak3 inhibitor NC1153 induces apoptosis of T cells and donor-specific transplantation tolerance (Abstract 97). Am J Transplant 2004; 4.
116. Stepkowski SM, Kao J, Wang ME, et al. The Mannich base NC1153 promotes long-term allograft survival and spares the recipient from multiple toxicities. J Immunol 2005; 175: 4236.