0 8 Evidence evidence NN 9 13 that that IN 14 25 calcineurin calcineurin NN 26 28 is be VBZ 29 42 rate-limiting rate-limiting JJ 43 46 for for IN 47 54 primary primary JJ 55 60 human human JJ 61 71 lymphocyte lymphocyte NN 72 82 activation activation NN 82 83 . . . 85 97 Cyclosporine cyclosporine NN 98 99 ( ( ( 99 102 CsA CsA NNP 102 103 ) ) ) 104 106 is be VBZ 107 111 both both CC 112 113 a a DT 114 122 clinical clinical JJ 123 140 immunosuppressive immunosuppressive JJ 141 145 drug drug NN 146 149 and and CC 150 151 a a DT 152 157 probe probe NN 158 160 to to TO 161 168 dissect dissect VB 169 182 intracellular intracellular JJ 183 192 signaling signaling NN 193 201 pathways pathway NNS 201 202 . . . 203 205 In in FW 206 211 vitro vitro FW 211 212 , , , 213 216 CsA CsA NNP 217 225 inhibits inhibit VBZ 226 236 lymphocyte lymphocyte NN 237 241 gene gene NN 242 252 activation activation NN 253 255 by by IN 256 266 inhibiting inhibit VBG 267 270 the the DT 271 282 phosphatase phosphatase NN 283 291 activity activity NN 292 294 of of IN 295 306 calcineurin calcineurin NN 307 308 ( ( ( 308 310 CN CN NNP 310 311 ) ) ) 311 312 . . . 313 315 In in IN 316 324 clinical clinical JJ 325 328 use use NN 328 329 , , , 330 333 CsA CsA NNP 334 343 treatment treatment NN 344 352 inhibits inhibit VBZ 353 358 50-75 50-75 CD 358 359 % % NN 360 362 of of IN 363 365 CN cn NN 366 374 activity activity NN 375 377 in in IN 378 389 circulating circulate VBG 390 400 leukocytes leukocyte NNS 400 401 . . . 402 404 We we PRP 405 412 modeled model VBD 413 417 this this DT 418 424 degree degree NN 425 427 of of IN 428 430 CN cn NN 431 441 inhibition inhibition NN 442 444 in in IN 445 452 primary primary JJ 453 458 human human JJ 459 469 leukocytes leukocyte NNS 470 472 in in FW 473 478 vitro vitro FW 479 481 in in IN 482 487 order order NN 488 490 to to TO 491 496 study study VB 497 500 the the DT 501 507 effect effect NN 508 510 of of IN 511 518 partial partial JJ 519 521 CN cn NN 522 532 inhibition inhibition NN 533 535 on on IN 536 539 the the DT 540 550 downstream downstream JJ 551 560 signaling signaling NN 561 567 events event NNS 568 572 that that WDT 573 577 lead lead VBP 578 580 to to TO 581 585 gene gene NN 586 596 activation activation NN 596 597 . . . 598 600 In in IN 601 612 CsA-treated csa-treated JJ 613 623 leukocytes leukocyte NNS 624 634 stimulated stimulate VBN 635 637 by by IN 638 645 calcium calcium NN 646 655 ionophore ionophore NN 655 656 , , , 657 660 the the DT 661 667 degree degree NN 668 670 of of IN 671 680 reduction reduction NN 681 683 in in IN 684 686 CN cn NN 687 695 activity activity NN 696 699 was be VBD 700 711 accompanied accompany VBN 712 714 by by IN 715 716 a a DT 717 724 similar similar JJ 725 731 degree degree NN 732 734 of of IN 735 745 inhibition inhibition NN 746 748 of of IN 749 753 each each DT 754 759 event event NN 760 766 tested test VBN 766 767 : : : 768 785 dephosphorylation dephosphorylation NN 786 788 of of IN 789 796 nuclear nuclear JJ 797 803 factor factor NN 804 806 of of IN 807 816 activated activate VBN 817 818 T t NN 819 823 cell cell NN 824 832 proteins protein NNS 832 833 , , , 834 841 nuclear nuclear JJ 842 845 DNA dna NN 846 853 binding binding NN 853 854 , , , 855 865 activation activation NN 866 868 of of IN 869 870 a a DT 871 882 transfected transfecte VBN 883 891 reporter reporter NN 892 896 gene gene NN 897 906 construct construct NN 906 907 , , , 908 917 IFN-gamma IFN-gamma NNP 918 921 and and CC 922 926 IL-2 il-2 NN 927 931 mRNA mrna NN 932 944 accumulation accumulation NN 944 945 , , , 946 949 and and CC 950 959 IFN-gamma IFN-gamma NNP 960 970 production production NN 970 971 . . . 972 983 Furthermore furthermore RB 983 984 , , , 985 988 the the DT 989 995 degree degree NN 996 998 of of IN 999 1001 CN cn NN 1002 1012 inhibition inhibition NN 1013 1016 was be VBD 1017 1026 reflected reflect VBN 1027 1029 by by IN 1030 1031 a a DT 1032 1039 similar similar JJ 1040 1046 degree degree NN 1047 1049 of of IN 1050 1059 reduction reduction NN 1060 1062 in in IN 1063 1073 lymphocyte lymphocyte NN 1074 1087 proliferation proliferation NN 1088 1091 and and CC 1092 1101 IFN-gamma IFN-gamma NNP 1102 1112 production production NN 1113 1115 in in IN 1116 1119 the the DT 1120 1130 allogeneic allogeneic JJ 1131 1136 mixed mixed JJ 1137 1147 lymphocyte lymphocyte NN 1148 1156 cultures culture NNS 1156 1157 . . . 1158 1163 These these DT 1164 1168 data datum NNS 1169 1176 support support VBP 1177 1180 the the DT 1181 1191 conclusion conclusion NN 1192 1196 that that IN 1197 1199 CN cn NN 1200 1208 activity activity NN 1209 1211 is be VBZ 1212 1225 rate-limiting rate-limiting JJ 1226 1229 for for IN 1230 1233 the the DT 1234 1244 activation activation NN 1245 1247 of of IN 1248 1255 primary primary JJ 1256 1261 human human JJ 1262 1263 T t NN 1264 1275 lymphocytes lymphocyte NNS 1275 1276 . . . 1277 1281 Thus thus RB 1281 1282 , , , 1283 1286 the the DT 1287 1296 reduction reduction NN 1297 1299 of of IN 1300 1302 CN cn NN 1303 1311 activity activity NN 1312 1320 observed observe VBN 1321 1323 in in IN 1324 1335 CsA-treated csa-treated JJ 1336 1344 patients patient NNS 1345 1347 is be VBZ 1348 1359 accompanied accompany VBN 1360 1362 by by IN 1363 1364 a a DT 1365 1372 similar similar JJ 1373 1379 degree degree NN 1380 1382 of of IN 1383 1392 reduction reduction NN 1393 1395 in in IN 1396 1406 lymphocyte lymphocyte NN 1407 1411 gene gene NN 1412 1422 activation activation NN 1422 1423 , , , 1424 1427 and and CC 1428 1436 accounts account VBZ 1437 1440 for for IN 1441 1444 the the DT 1445 1462 immunosuppression immunosuppression NN 1463 1471 observed observe VBN 1471 1472 . . .