JP2015513403A5 - - Google Patents
Download PDFInfo
- Publication number
- JP2015513403A5 JP2015513403A5 JP2014560106A JP2014560106A JP2015513403A5 JP 2015513403 A5 JP2015513403 A5 JP 2015513403A5 JP 2014560106 A JP2014560106 A JP 2014560106A JP 2014560106 A JP2014560106 A JP 2014560106A JP 2015513403 A5 JP2015513403 A5 JP 2015513403A5
- Authority
- JP
- Japan
- Prior art keywords
- treg
- donor
- cells
- reactive
- sbc
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 210000004027 cell Anatomy 0.000 claims description 77
- 210000003289 regulatory T cell Anatomy 0.000 claims description 75
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 claims description 62
- 230000001965 increasing effect Effects 0.000 claims description 56
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 45
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 40
- 230000014509 gene expression Effects 0.000 claims description 22
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 21
- 229960002930 sirolimus Drugs 0.000 claims description 21
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 21
- 210000000056 organ Anatomy 0.000 claims description 20
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 claims description 19
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 claims description 19
- 210000003491 skin Anatomy 0.000 claims description 17
- 108010029697 CD40 Ligand Proteins 0.000 claims description 16
- 102100032937 CD40 ligand Human genes 0.000 claims description 16
- 210000004185 liver Anatomy 0.000 claims description 16
- 238000001943 fluorescence-activated cell sorting Methods 0.000 claims description 14
- 238000002650 immunosuppressive therapy Methods 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 10
- 230000001939 inductive effect Effects 0.000 claims description 9
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 8
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 8
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 8
- 210000003734 kidney Anatomy 0.000 claims description 8
- 210000004072 lung Anatomy 0.000 claims description 8
- 210000000496 pancreas Anatomy 0.000 claims description 8
- 230000003319 supportive effect Effects 0.000 claims description 8
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 claims description 7
- 229960004866 mycophenolate mofetil Drugs 0.000 claims description 7
- 102000006395 Globulins Human genes 0.000 claims description 6
- 108010044091 Globulins Proteins 0.000 claims description 6
- 108010002350 Interleukin-2 Proteins 0.000 claims description 6
- 102000000588 Interleukin-2 Human genes 0.000 claims description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 claims description 6
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims description 6
- 230000001154 acute effect Effects 0.000 claims description 6
- 230000001494 anti-thymocyte effect Effects 0.000 claims description 6
- 238000012258 culturing Methods 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 229960001967 tacrolimus Drugs 0.000 claims description 6
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 claims description 6
- 102100027207 CD27 antigen Human genes 0.000 claims description 5
- 229930105110 Cyclosporin A Natural products 0.000 claims description 5
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 5
- 108010036949 Cyclosporine Proteins 0.000 claims description 5
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 claims description 5
- 102000004388 Interleukin-4 Human genes 0.000 claims description 5
- 108090000978 Interleukin-4 Proteins 0.000 claims description 5
- 102000004338 Transferrin Human genes 0.000 claims description 5
- 108090000901 Transferrin Proteins 0.000 claims description 5
- 210000004698 lymphocyte Anatomy 0.000 claims description 5
- 238000011272 standard treatment Methods 0.000 claims description 5
- 239000012581 transferrin Substances 0.000 claims description 5
- 101001018097 Homo sapiens L-selectin Proteins 0.000 claims description 4
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 claims description 4
- 102000004877 Insulin Human genes 0.000 claims description 4
- 108090001061 Insulin Proteins 0.000 claims description 4
- 102100033467 L-selectin Human genes 0.000 claims description 4
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 claims description 4
- 206010052779 Transplant rejections Diseases 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- 229960001265 ciclosporin Drugs 0.000 claims description 4
- 229940125396 insulin Drugs 0.000 claims description 4
- 210000000936 intestine Anatomy 0.000 claims description 4
- 208000032839 leukemia Diseases 0.000 claims description 4
- 238000003501 co-culture Methods 0.000 claims description 3
- 238000004132 cross linking Methods 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 229940028885 interleukin-4 Drugs 0.000 claims description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 3
- 229960004618 prednisone Drugs 0.000 claims description 3
- 230000006052 T cell proliferation Effects 0.000 claims description 2
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 claims 4
- 238000003556 assay Methods 0.000 description 32
- 230000000735 allogeneic effect Effects 0.000 description 28
- 238000002054 transplantation Methods 0.000 description 28
- 239000011324 bead Substances 0.000 description 23
- 206010062016 Immunosuppression Diseases 0.000 description 21
- 230000001506 immunosuppresive effect Effects 0.000 description 21
- 230000000961 alloantigen Effects 0.000 description 20
- 230000000638 stimulation Effects 0.000 description 19
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 description 15
- 238000000684 flow cytometry Methods 0.000 description 15
- 238000011194 good manufacturing practice Methods 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 13
- 238000007799 mixed lymphocyte reaction assay Methods 0.000 description 13
- 230000005855 radiation Effects 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
- 239000012636 effector Substances 0.000 description 12
- 108020004414 DNA Proteins 0.000 description 11
- 102000053602 DNA Human genes 0.000 description 11
- JGPOSNWWINVNFV-UHFFFAOYSA-N carboxyfluorescein diacetate succinimidyl ester Chemical compound C=1C(OC(=O)C)=CC=C2C=1OC1=CC(OC(C)=O)=CC=C1C2(C1=C2)OC(=O)C1=CC=C2C(=O)ON1C(=O)CCC1=O JGPOSNWWINVNFV-UHFFFAOYSA-N 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 11
- 102100037796 Zinc finger protein Helios Human genes 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 238000001802 infusion Methods 0.000 description 10
- 102000004127 Cytokines Human genes 0.000 description 9
- 108090000695 Cytokines Proteins 0.000 description 9
- 102100027581 Forkhead box protein P3 Human genes 0.000 description 9
- 101000861452 Homo sapiens Forkhead box protein P3 Proteins 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 230000035755 proliferation Effects 0.000 description 9
- 230000001629 suppression Effects 0.000 description 9
- 238000011161 development Methods 0.000 description 8
- 230000018109 developmental process Effects 0.000 description 8
- 210000005259 peripheral blood Anatomy 0.000 description 8
- 239000011886 peripheral blood Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 102220595529 Mitochondrial ubiquitin ligase activator of NFKB 1_K40L_mutation Human genes 0.000 description 7
- 210000000612 antigen-presenting cell Anatomy 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 230000003389 potentiating effect Effects 0.000 description 7
- 102000006354 HLA-DR Antigens Human genes 0.000 description 6
- 108010058597 HLA-DR Antigens Proteins 0.000 description 6
- 101000599037 Homo sapiens Zinc finger protein Helios Proteins 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 210000000952 spleen Anatomy 0.000 description 6
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 5
- 101100193633 Danio rerio rag2 gene Proteins 0.000 description 5
- 101100059511 Homo sapiens CD40LG gene Proteins 0.000 description 5
- 101100193635 Mus musculus Rag2 gene Proteins 0.000 description 5
- 238000001574 biopsy Methods 0.000 description 5
- 230000006058 immune tolerance Effects 0.000 description 5
- 230000036039 immunity Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 210000000265 leukocyte Anatomy 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 230000009257 reactivity Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 229920001917 Ficoll Polymers 0.000 description 4
- 208000009329 Graft vs Host Disease Diseases 0.000 description 4
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 4
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 description 4
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 4
- 238000011529 RT qPCR Methods 0.000 description 4
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 4
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 230000003190 augmentative effect Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 208000024908 graft versus host disease Diseases 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 238000012317 liver biopsy Methods 0.000 description 4
- 230000001717 pathogenic effect Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 102100037850 Interferon gamma Human genes 0.000 description 3
- 108010074328 Interferon-gamma Proteins 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 3
- 238000000692 Student's t-test Methods 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000003416 augmentation Effects 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 239000003246 corticosteroid Substances 0.000 description 3
- 230000017858 demethylation Effects 0.000 description 3
- 238000010520 demethylation reaction Methods 0.000 description 3
- 210000004443 dendritic cell Anatomy 0.000 description 3
- 230000002500 effect on skin Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 238000009169 immunotherapy Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000012353 t test Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 2
- 239000012103 Alexa Fluor 488 Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 2
- 206010057573 Chronic hepatic failure Diseases 0.000 description 2
- 208000010334 End Stage Liver Disease Diseases 0.000 description 2
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 2
- 102000013691 Interleukin-17 Human genes 0.000 description 2
- 108050003558 Interleukin-17 Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 2
- 108020004682 Single-Stranded DNA Proteins 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 208000011444 chronic liver failure Diseases 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- 239000012595 freezing medium Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000011577 humanized mouse model Methods 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 102000007236 involucrin Human genes 0.000 description 2
- 108010033564 involucrin Proteins 0.000 description 2
- PGHMRUGBZOYCAA-UHFFFAOYSA-N ionomycin Natural products O1C(CC(O)C(C)C(O)C(C)C=CCC(C)CC(C)C(O)=CC(=O)C(C)CC(C)CC(CCC(O)=O)C)CCC1(C)C1OC(C)(C(C)O)CC1 PGHMRUGBZOYCAA-UHFFFAOYSA-N 0.000 description 2
- PGHMRUGBZOYCAA-ADZNBVRBSA-N ionomycin Chemical compound O1[C@H](C[C@H](O)[C@H](C)[C@H](O)[C@H](C)/C=C/C[C@@H](C)C[C@@H](C)C(/O)=C/C(=O)[C@@H](C)C[C@@H](C)C[C@@H](CCC(O)=O)C)CC[C@@]1(C)[C@@H]1O[C@](C)([C@@H](C)O)CC1 PGHMRUGBZOYCAA-ADZNBVRBSA-N 0.000 description 2
- 210000002510 keratinocyte Anatomy 0.000 description 2
- 210000005228 liver tissue Anatomy 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000003752 polymerase chain reaction Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000275 quality assurance Methods 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000003757 reverse transcription PCR Methods 0.000 description 2
- 229920002477 rna polymer Polymers 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 229940104230 thymidine Drugs 0.000 description 2
- 239000013598 vector Substances 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- 238000002689 xenotransplantation Methods 0.000 description 2
- IQFYYKKMVGJFEH-OFKYTIFKSA-N 1-[(2r,4s,5r)-4-hydroxy-5-(tritiooxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@@H](CO[3H])O[C@H]1N1C(=O)NC(=O)C(C)=C1 IQFYYKKMVGJFEH-OFKYTIFKSA-N 0.000 description 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- 239000012114 Alexa Fluor 647 Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 102100028972 HLA class I histocompatibility antigen, A alpha chain Human genes 0.000 description 1
- 102100028976 HLA class I histocompatibility antigen, B alpha chain Human genes 0.000 description 1
- 102100028971 HLA class I histocompatibility antigen, C alpha chain Human genes 0.000 description 1
- 108010075704 HLA-A Antigens Proteins 0.000 description 1
- 108010058607 HLA-B Antigens Proteins 0.000 description 1
- 108010052199 HLA-C Antigens Proteins 0.000 description 1
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 1
- 101000797623 Homo sapiens Protein AMBP Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- 108091054438 MHC class II family Proteins 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241001272996 Polyphylla fullo Species 0.000 description 1
- 102100032859 Protein AMBP Human genes 0.000 description 1
- 206010040844 Skin exfoliation Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 206010053692 Wound complication Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 238000002617 apheresis Methods 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 238000005422 blasting Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 238000005138 cryopreservation Methods 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 206010052015 cytokine release syndrome Diseases 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000000432 density-gradient centrifugation Methods 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- BFMYDTVEBKDAKJ-UHFFFAOYSA-L disodium;(2',7'-dibromo-3',6'-dioxido-3-oxospiro[2-benzofuran-1,9'-xanthene]-4'-yl)mercury;hydrate Chemical compound O.[Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(Br)=C([O-])C([Hg])=C1OC1=C2C=C(Br)C([O-])=C1 BFMYDTVEBKDAKJ-UHFFFAOYSA-L 0.000 description 1
- 230000019975 dosage compensation by inactivation of X chromosome Effects 0.000 description 1
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- -1 eBioscience) Proteins 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000010230 functional analysis Methods 0.000 description 1
- 238000003500 gene array Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 231100000226 haematotoxicity Toxicity 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 210000002767 hepatic artery Anatomy 0.000 description 1
- 201000004108 hypersplenism Diseases 0.000 description 1
- 238000011502 immune monitoring Methods 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 239000011325 microbead Substances 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000008823 permeabilization Effects 0.000 description 1
- 208000007232 portal hypertension Diseases 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000009696 proliferative response Effects 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000004988 splenocyte Anatomy 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 230000003614 tolerogenic effect Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 238000007492 two-way ANOVA Methods 0.000 description 1
- 239000012808 vapor phase Substances 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Images
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261606329P | 2012-03-02 | 2012-03-02 | |
| US61/606,329 | 2012-03-02 | ||
| PCT/US2013/028734 WO2013131045A1 (en) | 2012-03-02 | 2013-03-01 | Expansion of alloantigen-reactive regulatory t cells |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2015513403A JP2015513403A (ja) | 2015-05-14 |
| JP2015513403A5 true JP2015513403A5 (https=) | 2017-08-10 |
| JP6422344B2 JP6422344B2 (ja) | 2018-11-14 |
Family
ID=49083363
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2014560106A Active JP6422344B2 (ja) | 2012-03-02 | 2013-03-01 | 同種抗原反応性の制御性ｔ細胞を増大させる方法 |
Country Status (8)
| Country | Link |
|---|---|
| US (2) | US9801911B2 (https=) |
| EP (2) | EP2820125B1 (https=) |
| JP (1) | JP6422344B2 (https=) |
| CN (1) | CN104245923B (https=) |
| AU (2) | AU2013225721B2 (https=) |
| CA (1) | CA2866116C (https=) |
| ES (1) | ES2675317T3 (https=) |
| WO (1) | WO2013131045A1 (https=) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101697473B1 (ko) | 2014-11-26 | 2017-01-18 | 주식회사 녹십자랩셀 | T 세포를 이용한 자연살해세포의 배양방법 |
| IL258935B2 (en) * | 2015-10-28 | 2024-08-01 | Life Tech As | Selective expansion of different subpopulations of t cells by the alteration of cell surfacing signals and signal ratio |
| CN105420190B (zh) * | 2016-01-08 | 2018-07-31 | 无锡药明生基医药科技有限公司 | B27添加剂及其类似物在利用无血清培养基培养淋巴细胞中的应用 |
| EP3216861A1 (en) * | 2016-03-11 | 2017-09-13 | Fropharm GmbH | Immunoregulatory cells and methods for their production |
| EP3633029A4 (en) | 2017-05-26 | 2021-06-09 | Green Cross Lab Cell Corporation | METHOD OF DEVELOPING A NATURAL KILLER CELL USING A T-CELL |
| WO2018231803A1 (en) * | 2017-06-12 | 2018-12-20 | The Trustees Of Columbia University In The City Of New York | Methods for generating polyclonal regulatory t cells |
| TWI793151B (zh) | 2017-08-23 | 2023-02-21 | 瑞士商諾華公司 | 3-(1-氧異吲哚啉-2-基)之氫吡啶-2,6-二酮衍生物及其用途 |
| KR102232321B1 (ko) * | 2018-03-23 | 2021-03-26 | 주식회사 녹십자랩셀 | 자연살해세포의 제조방법 |
| BR122022012697B1 (pt) | 2018-07-10 | 2023-04-04 | Novartis Ag | Usos de derivados de 3-(5-hidróxi-1-oxoisoindolin-2-il)piperidina-2,6- diona, e kit |
| AR116109A1 (es) | 2018-07-10 | 2021-03-31 | Novartis Ag | Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6-diona y usos de los mismos |
| AU2019381526B2 (en) | 2018-11-14 | 2023-02-23 | Green Cross Lab Cell Corporation | Method for culturing cord blood-derived natural killer cells using transformed T-cells |
| MX2021013227A (es) * | 2019-04-30 | 2022-01-06 | Univ California | Expansion ex-vivo sin microesferas de celulas t reguladoras humanas. |
| CN110195041B (zh) * | 2019-06-20 | 2023-04-25 | 威海正生生物科技有限公司 | 利用ASC三维培养体系获得高活性Tregs细胞的方法 |
| WO2021007396A2 (en) | 2019-07-09 | 2021-01-14 | The Children's Mercy Hospital | Engineered regulatory t cells |
| PL238336B1 (pl) * | 2019-08-22 | 2021-08-09 | Gdanski Univ Medyczny | Sposób otrzymywania in vitro antygenowo-specyficznych limfocytów T regulatorowych |
| WO2022182763A1 (en) * | 2021-02-23 | 2022-09-01 | KSQ Therapeutics, Inc. | Methods for expanding regulatory t cells |
| WO2025081193A1 (en) * | 2023-10-13 | 2025-04-17 | Northwestern University | Antigen specific expansion of regulatory t cells |
| JP7627920B1 (ja) | 2023-12-11 | 2025-02-07 | 浩 宮内 | 移植材料の評価方法 |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5540926A (en) | 1992-09-04 | 1996-07-30 | Bristol-Myers Squibb Company | Soluble and its use in B cell stimulation |
| US7541184B2 (en) | 2000-02-24 | 2009-06-02 | Invitrogen Corporation | Activation and expansion of cells |
| US7572631B2 (en) | 2000-02-24 | 2009-08-11 | Invitrogen Corporation | Activation and expansion of T cells |
| AU2001253400B2 (en) | 2000-04-11 | 2007-03-01 | University Of Southern California | A method to prevent graft rejection using tgf-beta to induce t suppressor cells |
| US6746670B2 (en) | 2000-08-15 | 2004-06-08 | Schering Corporation | Regulatory T cells; methods |
| US6670146B2 (en) | 2000-10-04 | 2003-12-30 | Schering Corporation | Regulatory T cells; methods |
| US7745140B2 (en) | 2002-01-03 | 2010-06-29 | The Trustees Of The University Of Pennsylvania | Activation and expansion of T-cells using an engineered multivalent signaling platform as a research tool |
| US7494812B2 (en) | 2003-04-01 | 2009-02-24 | University Of Southern California | Generation of human regulatory T cells by bacterial toxins for the treatment of inflammatory disorders |
| US7651855B2 (en) | 2003-04-17 | 2010-01-26 | The Trustees Of The University Of Pennsylvania | Regulatory T cells and their use in immunotherapy and suppression of autoimmune responses |
| FR2856700B1 (fr) | 2003-06-24 | 2007-06-08 | Txcell | Procede d'identification de lymphocytes tr1 regulateurs par la presence et la surexpression de molecules specifiques et ses applications |
| AU2005206746B2 (en) | 2004-01-08 | 2008-08-28 | Regents Of The University Of California | Regulatory t cells suppress autoimmunity |
| ES2686593T3 (es) * | 2006-05-31 | 2018-10-18 | The Regents Of The University Of California | Expresión de CD127 que correlaciona inversamente con FoxP3 y la función supresora de Treg CD4+ |
| CA2706458A1 (en) | 2007-11-30 | 2009-06-11 | Therakos, Inc. | Process for reducing effects of graft versus host disease using ex vivo expanded cd4+cd25+ regulatory t cells |
| US8658159B2 (en) | 2008-06-30 | 2014-02-25 | Versitech Limited | Method to induce and expand therapeutic alloantigen-specific human regulatory T cells in large-scale |
| WO2010129770A1 (en) | 2009-05-07 | 2010-11-11 | The University Of Utah Research Foundation | Methods for expanding human t regulatory cells and uses of same |
-
2013
- 2013-03-01 JP JP2014560106A patent/JP6422344B2/ja active Active
- 2013-03-01 CA CA2866116A patent/CA2866116C/en active Active
- 2013-03-01 US US14/382,537 patent/US9801911B2/en active Active
- 2013-03-01 AU AU2013225721A patent/AU2013225721B2/en not_active Ceased
- 2013-03-01 WO PCT/US2013/028734 patent/WO2013131045A1/en not_active Ceased
- 2013-03-01 CN CN201380021317.7A patent/CN104245923B/zh not_active Expired - Fee Related
- 2013-03-01 ES ES13754740.2T patent/ES2675317T3/es active Active
- 2013-03-01 EP EP13754740.2A patent/EP2820125B1/en active Active
- 2013-03-01 EP EP18156148.1A patent/EP3366768B1/en active Active
-
2017
- 2017-09-29 US US15/721,439 patent/US20180036345A1/en not_active Abandoned
-
2018
- 2018-08-20 AU AU2018219968A patent/AU2018219968B2/en not_active Ceased
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6422344B2 (ja) | 同種抗原反応性の制御性ｔ細胞を増大させる方法 | |
| JP2015513403A5 (https=) | ||
| Blazar et al. | Immune regulatory cell infusion for graft-versus-host disease prevention and therapy | |
| CN1981031B (zh) | 调节性t细胞及它们在免疫治疗和抑制自身免疫反应中的应用 | |
| KR102768442B1 (ko) | CD8+CD45RClow TREGS의 신규한 아집단 및 이들의 용도 | |
| EP1715889A2 (en) | Regulatory t cells suppress autoimmunity | |
| US20090304659A1 (en) | Anti-cd8 antibodies block priming of cytotoxic effectors and lead to generation of regulatory cd8+ t cells | |
| CA2529941C (fr) | Procede d'identification de lymphocytes tr1 regulateurs par la presence et la surexpression de molecules specifiques et ses applications | |
| Mathew et al. | Cellular and functional biomarkers of clinical transplant tolerance | |
| Ma et al. | Combined therapy of CD4+ CD25+ regulatory T cells with low-dose sirolimus, but not calcineurin inhibitors, preserves suppressive function of regulatory T cells and prolongs allograft survival in mice | |
| WO2010129770A1 (en) | Methods for expanding human t regulatory cells and uses of same | |
| Peters et al. | Immunotherapy with regulatory T cells in transplantation | |
| WO2016182944A1 (en) | Cell culture systems for producing il-33 induced t9 cells and methods of using the cells | |
| EP4101925A1 (en) | Method for isolating autologous tumor antigen-reactive cd8 t cell by using cd71, and application thereof | |
| Shao et al. | Combination of monoclonal antibodies with DST inhibits accelerated rejection mediated by memory T cells to induce long-lived heart allograft acceptance in mice | |
| Romano | In vitro characterisation and expansion of human regulatory T cells for their in vivo application in the induction of tolerance in haematopoietic stem cell and solid organ transplantation | |
| Battaglia | Induction of tolerance via T regulatory cells. A clinical reality or just a nice experiment in mice? | |
| Smith | Mechanisms of Thymic Involution and Therapies to Prevent or Treat the loss of Thymic Epithelial Cells | |
| Sirkiä | Small-molecules as regulatory T cell modulators–A pilot | |
| HK1155467A (en) | Anti-cd8 antibodies block priming of cytotoxic effectors and lead to generation of regulatory cd8+t cells |