0 10 Tyrphostin Tyrphostin NNP 11 17 AG-490 AG-490 NNP 18 26 inhibits inhibit VBZ 27 44 cytokine-mediated cytokine-mediated JJ 45 58 JAK3/STAT5a/b JAK3/STAT5a/b NNP 59 65 signal signal NN 66 78 transduction transduction NN 79 82 and and CC 83 91 cellular cellular JJ 92 105 proliferation proliferation NN 106 108 of of IN 109 126 antigen-activated antigen-activated JJ 127 132 human human JJ 133 134 T t NN 135 140 cells cell NNS 140 141 . . . 143 148 Janus Janus NNP 149 155 kinase kinase NNP 156 157 3 3 CD 158 159 ( ( ( 159 163 JAK3 jak3 NN 163 164 ) ) ) 165 167 is be VBZ 168 169 a a DT 170 181 cytoplasmic cytoplasmic JJ 182 190 tyrosine tyrosine NN 191 197 kinase kinase NNP 198 206 required require VBN 207 210 for for IN 211 212 T t NN 213 217 cell cell NN 218 229 development development NN 230 233 and and CC 234 243 activated activate VBN 244 246 by by IN 247 256 cytokines cytokine NNS 257 261 that that WDT 262 269 utilize utilize VBP 270 273 the the DT 274 287 interleukin-2 interleukin-2 NN 288 289 ( ( ( 289 293 IL-2 il-2 NN 293 294 ) ) ) 295 303 receptor receptor NN 304 310 common common JJ 311 316 gamma gamma NN 317 322 chain chain NN 323 324 ( ( ( 324 333 gamma(c)) gamma(c)) NNP 333 334 . . . 335 342 Genetic genetic JJ 343 355 inactivation inactivation NN 356 358 of of IN 359 363 JAK3 JAK3 NNP 364 366 is be VBZ 367 377 manifested manifest VBN 378 380 as as IN 381 387 severe severe JJ 388 396 combined combined JJ 397 413 immunodeficiency immunodeficiency NN 414 421 disease disease NN 422 423 ( ( ( 423 427 SCID SCID NNP 427 428 ) ) ) 429 431 in in IN 432 438 humans human NNS 439 442 and and CC 443 447 mice mouse NNS 447 448 . . . 449 454 These these DT 455 463 findings finding NNS 464 468 have have VBP 469 478 suggested suggest VBN 479 483 that that IN 484 488 JAK3 JAK3 NNP 489 499 represents represent VBZ 500 501 a a DT 502 517 pharmacological pharmacological JJ 518 524 target target NN 525 527 to to TO 528 535 control control VB 536 543 certain certain JJ 544 560 lymphoid-derived lymphoid-derived JJ 561 569 diseases disease NNS 569 570 . . . 571 575 Here here RB 576 578 we we PRP 579 586 provide provide VBP 587 592 novel novel JJ 593 601 evidence evidence NN 602 606 that that IN 607 613 AG-490 AG-490 NNP 614 622 potently potently RB 623 631 inhibits inhibit VBZ 632 635 the the DT 636 646 autokinase autokinase NNP 647 655 activity activity NN 656 658 of of IN 659 663 JAK3 jak3 NN 664 667 and and CC 668 676 tyrosine tyrosine NN 677 692 phosphorylation phosphorylation NN 693 696 and and CC 697 700 DNA dna NN 701 708 binding binding NN 709 711 of of IN 712 718 signal signal NN 719 729 transducer transducer NN 730 733 and and CC 734 743 activator activator NN 744 746 of of IN 747 760 transcription transcription NN 761 763 5a 5a NN 764 767 and and CC 768 770 5b 5b NN 771 772 ( ( ( 772 780 STAT5a/b STAT5a/b NNP 780 781 ) ) ) 781 782 . . . 783 790 Similar similar JJ 791 801 inhibitory inhibitory JJ 802 809 effects effect NNS 810 814 were be VBD 815 823 observed observe VBN 824 828 with with IN 829 834 other other JJ 835 844 cytokines cytokine NNS 845 849 that that WDT 850 853 use use VBP 854 862 gamma(c) gamma(c) NN 862 863 . . . 864 870 AG-490 AG-490 NNP 871 875 also also RB 876 885 inhibited inhibit VBD 886 899 IL-2-mediated il-2-mediated JJ 900 913 proliferative proliferative JJ 914 920 growth growth NN 921 923 in in IN 924 929 human human JJ 930 931 T t NN 932 937 cells cell NNS 938 942 with with IN 943 945 an an DT 946 950 IC50 ic50 NN 950 951 ) ) ) 952 953 = = SYM 954 956 25 25 CD 957 963 microM microm NN 964 968 that that WDT 969 972 was be VBD 973 982 partially partially RB 983 994 recoverable recoverable JJ 994 995 . . . 996 1004 Moreover moreover RB 1004 1005 , , , 1006 1008 we we PRP 1009 1020 demonstrate demonstrate VBP 1021 1025 that that IN 1026 1030 this this DT 1031 1040 inhibitor inhibitor NN 1041 1050 prevented prevent VBD 1051 1058 tetanus tetanus NN 1059 1065 toxoid toxoid JJ 1066 1082 antigen-specific antigen-specific JJ 1083 1084 T t NN 1085 1089 cell cell NN 1090 1103 proliferation proliferation NN 1104 1107 and and CC 1108 1117 expansion expansion NN 1118 1121 but but CC 1122 1128 failed fail VBD 1129 1131 to to TO 1132 1137 block block VB 1138 1148 activation activation NN 1149 1151 of of IN 1152 1157 Zap70 zap70 NN 1158 1160 or or CC 1161 1167 p56Lck p56lck NN 1168 1173 after after IN 1174 1182 anti-CD3 anti-cd3 JJ 1183 1194 stimulation stimulation NN 1195 1197 of of IN 1198 1203 human human JJ 1204 1205 T t NN 1206 1211 cells cell NNS 1211 1212 . . . 1213 1218 Taken take VBN 1219 1227 together together RB 1227 1228 , , , 1229 1234 these these DT 1235 1243 findings finding NNS 1244 1251 suggest suggest VBP 1252 1256 that that IN 1257 1263 AG-490 ag-490 NN 1264 1272 inhibits inhibit VBZ 1273 1276 the the DT 1277 1290 JAK3-mediated jak3-mediated JJ 1291 1295 Type Type NNP 1296 1298 II ii CD 1299 1308 signaling signaling NN 1309 1316 pathway pathway NN 1317 1320 but but CC 1321 1324 not not RB 1325 1328 the the DT 1329 1330 T t NN 1331 1335 cell cell NN 1336 1352 receptor-derived receptor-derived JJ 1353 1357 Type Type NNP 1358 1359 I i CD 1360 1367 pathway pathway NN 1368 1371 and and CC 1372 1381 possesses possess VBZ 1382 1393 therapeutic therapeutic JJ 1394 1403 potential potential NN 1404 1407 for for IN 1408 1409 T t NN 1410 1422 cell-derived cell-derived JJ 1423 1434 pathologies pathology NNS 1435 1439 such such JJ 1440 1442 as as IN 1443 1460 graft-versus-host graft-versus-host JJ 1461 1468 disease disease NN 1468 1469 , , , 1470 1477 allergy allergy NN 1477 1478 , , , 1479 1482 and and CC 1483 1493 autoimmune autoimmune JJ 1494 1503 disorders disorder NNS 1503 1504 . . .