JP2020535847A - 免疫細胞型及び免疫応答の機能状況の決定 - Google Patents
免疫細胞型及び免疫応答の機能状況の決定 Download PDFInfo
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Abstract
Description
本出願は、2017年10月2日に出願され、「免疫診断法」と題される、米国特許仮出願第62/566,755号、及び2018年6月12日に出願され、「免疫診断法」と題される、米国特許仮出願第62/683,710号の優先権を主張するものであり、それらの明細書、特許請求の範囲、及び図面の全体が、全ての目的で、参照により本明細書に組み込まれる。
好中球において、休止状況が、支持状況より高度のPI3K経路、低度のNFκB経路、低度のTGF−β経路、低度のJAK−STAT1/2経路、低度のJAK−STAT3経路、低度のWnt経路、及び低度のNotch経路により特徴づけられること;
単球において、休止状況が、支持状況より高度のPI3K経路、低度のNFκB経路、低度のTGF−β経路、低度のNotch経路、及び低度のJAK−STAT3経路により特徴づけられること;
樹状細胞において、休止状況が、支持状況より低度のPI3K経路、低度のNFκB経路、低度のJAK−STAT1/2経路、低度のTGF−β経路、及び低度のJAK−STAT3経路により特徴づけられること;
樹状細胞において、休止状況が、抑制状況より低度のPI3K経路、高度のNFκB経路、及び低度のJAK−STAT1/2経路により特徴づけられること;
樹状細胞において、支持状況が、抑制状況より高度のPI3K経路、高度のNFκB経路、高度のJAK−STAT1/2経路、及び高度のTGF−β経路により特徴づけられること;
マクロファージにおいて、休止状況が、支持状況より低度のNFκB経路、低度のNotch経路、低度のJAK−STAT1/2経路、及び低度のJAK−STAT3経路により特徴づけられること;
CD4+ T細胞において、休止状況が、支持状況より高度のPI3K経路、低度のNFκB経路、低度のJAK−STAT3経路、低度のNotch経路、及び低度のJAK−STAT1/2経路により特徴づけられること;
CD4+ T細胞において、休止状況が、抑制状況より低度のPI3K経路、低度のNFκB経路、低度のJAK−STAT3経路、及び低度のTGF−β経路により特徴づけられること;
CD4+ T細胞において、支持状況が、抑制状況より低度のPI3K経路、高度のNFκB経路、高度のJAK−STAT3経路、低度のTGF−β経路、及び低度のJAK−STAT1/2経路により特徴づけられること;
CD4+ Th1細胞が、CD4+ Th2細胞より低度のPI3K経路、高度のNFκB経路、高度のTGF−β経路、及び高度のJAK−STAT1/2経路により特徴づけられること;
T−reg細胞において、休止状況が、抑制状況より低度のPI3K経路、低度のNFκB経路、低度のJAK−STAT3経路、低度のTGF−β経路、及び低度のNotch経路により特徴づけられること;
CD8+ T細胞において、休止状況が、支持状況より低度のPI3K経路、低度のNFκB経路、低度のJAK−STAT3経路、低度のTGF−β経路、低度のNotch経路、及び低度のJAK−STAT1/2経路により特徴づけられること;
メモリーT細胞が、ナイーブT細胞より高度のPI3K経路、高度のNFκB経路、及び高度のTGF−β経路により特徴づけられること;
Bリンパ球において、休止状況が、支持状況より高度のPI3K経路、低度のNFκB経路、及び低度のJAK−STAT3経路により特徴づけられること
に基づき決定される。
AR:KLK2、PMEPA1、TMPRSS2、NKX3 1、ABCC4、KLK3、FKBP5、ELL2、UGT2B15、DHCR24、PPAP2A、NDRG1、LRIG1、CREB3L4、LCP1、GUCY1A3、AR及びEAF2(WO 2013/011479、WO 2014/102668);KLK2、PMEPA1、TMPRSS2、NKX3 1、ABCC4、KLK3、FKBP5、ELL2、UGT2B15、DHCR24、PPAP2A、NDRG1、LRIG1、CREB3L4、LCP1、GUCY1A3、AR、及びEAF2(WO 2014/174003);
ER:CDH26、SGK3、PGR、GREBl、CA12、XBP1、CELSR2、WISP2、DSCAM、ERBB2、CTSD、TFF1及びNRIPl(WO 2013/011479、WO 2014/102668);GREB1、PGR、XBP1、CA12、SOD1、CTSD、IGFBP4、TFF1、SGK3、NRIP1、CELSR2、WISP2、及びAP1B1(WO 2014/174003);AP1B1、ATP5J、COL18A1、COX7A2L、CTSD、DSCAM、EBAG9、ESRl、HSPBl、KRT19、NDUFV3、NRIPI、PGR、PISD、PRDM15、PTMA、RARA、SODl、TFFl、TRIM25、XBPl、GREBl、IGFBP4、MYC、SGK3、WISP2、ERBB2、CA12、CDH26、及びCELSR2(WO 2016/062892、WO 2016/062893);
HH:GLI1、PTCH1、PTCH2、IGFBP6、SPP1、CCND2、FST、FOXL1、CFLAR、TSC22D1、RAB34、S100A9、S100A7、MYCN、FOXM1、GLI3、TCEA2、FYN及びCTSL1(WO 2013/011479、WO 2014/102668、WO 2014/174003);GLI1、PTCH1、PTCH2、HHIP、SPP1、TSC22D1、CCND2、HI 9、IGFBP6、TOM1、JUP、FOXA2、MYCN、NKX2−2、NKX2−8、RAB34、MIF、GLI3、FST、BCL2、CTSL1、TCEA2、MYLK、FYN、PITRM1、CFLAR、IL1R2、S100A7、S100A9、CCNDl、JAG2、FOXM1、FOXF1、及びFOXL1(WO 2016/062892、WO 2016/062893);
JAK−STAT1/2:BID、GNAZ、IRF1、IRF7、IRF8、IRF9、LGALS1、NCF4、NFAM1、OAS1、PDCD1、RAB36、RBX1、RFPL3、SAMM50、SMARCB1、SSTR3、ST13、STAT1、TRMT1、UFD1L、USP18、及びZNRF3、好ましくは、IRF1、IRF7、IRF8、IRF9、OAS1、PDCD1、ST13、STAT1、及びUSP18(EP17194291.5、前出)からなるグループから;
JAK−STAT3:AKT1、BCL2、BCL2L1、BIRC5、CCND1、CD274、CDKN1A、CRP、FGF2、FOS、FSCN1、FSCN2、FSCN3、HIF1A、HSP90AA1、HSP90AB1、HSP90B1、HSPA1A、HSPA1B、ICAM1、IFNG、IL10、JunB、MCL1、MMP1、MMP3、MMP9、MUC1、MYC、NOS2、POU2F1、PTGS2、SAA1、STAT1、TIMP1、TNFRSF1B、TWIST1、VIM及びZEB1(EP17194293.1、前出);
MAPK−AP−1:BCL2L11、CCND1、DDIT3、DNMT1、EGFR、ENPP2、EZR、FASLG、FIGF、GLRX、IL2、IVL、LOR、MMP1、MMP3、MMP9、SERPINE1、PLAU、PLAUR、PTGS2、SNCG、TIMP1、TP53及びVIM(EP17209053.2、前出);
NFkB:BCL2L1、BIRC3、CCL2、CCL3、CCL4、CCL5、CCL20、CCL22、CX3CL1、CXCL1、CXCL2、CXCL3、ICAM1、IL1B、IL6、IL8、IRF1、MMP9、NFKB2、NFKBIA、NFKB IE、PTGS2、SELE、STAT5A、TNF、TNFAIP2、TNIP1、TRAF1及びVCAM1(WO 2017/029215);
Notch:CD28、CD44、DLGAP5、DTX1、EPHB3、FABP7、GFAP、GIMAP5、HES1、HES4、HES5、HES7、HEY1、HEY2、HEYL、KLF5、MYC、NFKB2、NOX1、NRARP、PBX1、PIN1、PLXND1、PTCRA、SOX9及びTNC(EP 17194288.1、前出);
PI3K:AGRP、BCL2L11、BCL6、BNIP3、BTG1、CAT、CAV1、CCND1、CCND2、CCNG2、CDK 1A、CDK 1B、ESRl、FASLG、FBX032、GADD45A、INSR、MXIl、NOS3、PCKl、POMC、PPARGCIA、PRDX3、RBL2、SOD2及びTNFSF10(WO 2015/101635);ATP8A1、BCL2L11、BNIP3、BTGl、ClOorflO、CAT、CBLB、CCNDl、CCND2、CDKNIB、DDB1、DYRK2、ERBB3、EREG、ESRl、EXT1、FASLG、FGFR2、GADD45A、IGF1R、IGFBP1、IGFBP3、INSR、LGMN、MXI1、PPM1D、SEMA3C、SEPP1、SESN1、SLC5A3、SMAD4、SOD2、TLE4、及びTNFSF10(WO 2016/062892、WO 2016/062893);SOD2、BNIP3、MXI1、PCK1、PPARGC1A及びCAT(EP16200697.7、前出);
TGF−β:ANGPTL4、CDC42EP3、CDKNIA、CDKN2B、CTGF、GADD45A、GADD45B、HMGA2、ID1、IL11、SERPINE1、INPP5D、JUNB、MMP2、MMP9、NKX2−5、OVOL1、PDGFB、PTHLH、SGK1、SKIL、SMAD4、SMAD5、SMAD6、SMAD7、SNAI1、SNAI2、TIMP1及びVEGFA(WO 2016/062891、WO 2016/062893);
Wnt:KIAA1199、AXIN2、RNF43、TBX3、TDGF1、SOX9、ASCL2、IL8、SP5、ZNRF3、KLF6、CCND1、DEFA6、及びFZD7(WO2013/011479、WO2014/102668、WO2014/174003);ADRA2C、ASCL2、AXIN2、BMP7、CCNDl、CD44、COL18A1、DEFA6、DKKl、EPHB2、EPHB3、FAT1、FZD7、GLUL、HNF1A、CXCL8(旧称:IL8)、CEMIP(旧称:KIAAl199)、KLF6、LECT2、LEF1、LGR5、MYC、NKD1、OAT、PPARG、REGIB、RNF43、SLC1A2、SOX9、SP5、TBX3、TCF7L2、TDGF1、及びZNRF3(WO2016/062892、WO2016/062893)。
自然免疫系状況、獲得免疫系状況、及び/又は全免疫系状況が、支持状態にあるのか、休止状態にあるのか、免疫抑制状態にあるのかを決定又は予測するステップ;
全免疫系状況が、自然免疫系状況により、主に統御されているのかどうかを決定又は予測するステップ;
全免疫系状況が、獲得免疫系状況により、主に統御されているのかどうかを決定又は予測するステップ;
少なくとも1つの免疫細胞型が、異常な機能状況を有するのかどうかを決定又は予測するステップであって、前記決定又は予測するステップは、異常が、ある特定の事態において、与えられるべき機能状況であり、前記機能状況は、例えば、がんの場合、機能状況が、活性であるべきであり、自己免疫疾患の場合、機能状況が、不活性であるべきである機能状況とは別の機能状況を意味する、決定又は予測するステップ;
治療に対する応答を予測、モニタリング、又は決定するステップ;
治療の有効性を予測、モニタリング、又は決定するステップ;
腫瘍に対する免疫応答を予測、モニタリング、又は決定するステップ;
対象が治療に適合するのかどうかを決定又はモニタリングするステップ;
治療、投与量、及び/又は投与レジメンを決定するか、最適化させるか、又は調整するステップ;
疾患、特に、免疫媒介性疾患を診断又は亜型分類するステップ;
免疫媒介性疾患の活動性状況をモニタリングするステップ;
疾患時又は治療時の免疫応答状態をモニタリングするステップ;
治療の、免疫系状況に対する副作用を予測するステップ;
がんなどの疾患の高度の危険性についての、個体の診断又はスクリーニング;
免疫障害状態の診断;又は
過剰活性の免疫応答の診断をさらに含み;
この場合、決定するステップ、予測するステップ、モニタリングするステップ、最適化させるステップ、調整するステップ、又は診断するステップは、少なくとも1つの免疫細胞型の機能状況、少なくとも1つの自然免疫細胞型及び/又は少なくとも1つの獲得免疫細胞型の、機能的な免疫細胞活性に基づき、
治療は、好ましくは、免疫療法、特に、抗腫瘍免疫療法、化学療法、ターゲティング療法、放射線療法、免疫活性化療法、免疫調節療法、免疫抑制療法、ワクチン接種、in vivoワクチン接種、in vitro樹状細胞ワクチン接種、抗病原体療法又は抗感染療法、例えば、抗生剤又は抗ウイルス療法又は抗真菌療法のグループから選択される。
以下のシグナル伝達経路:
NFκB及びPI3K(転写因子:FOXO)
の各々の転写因子の標的遺伝子のうちの1つ、好ましくは、3つ又はこれを超える標的遺伝子の発現を定量するための構成要素
を含み;任意選択で、
以下のシグナル伝達経路:
AR、ER、HH、JAK−STAT1/2(転写因子:STAT1/2)、JAK−STAT3(転写因子:STAT3)、MAPK−AP−1(転写因子:AP−1)、Notch、TGF−β、及びWnt
の各々の標的遺伝子のうちの1つ、好ましくは、3つ又はこれを超える標的遺伝子の発現を定量するための構成要素
のうちの1つ又は複数を含む。
本明細書で記載される、本発明のキットと、
本明細書で記載される、本発明の装置、本明細書で記載される、本発明の非一時的記憶媒体、又は本明細書で記載される、本発明のコンピュータプログラムとを含む。
がん、自己免疫/免疫媒介性疾患、感染性疾患、炎症性疾患、免疫構成要素を伴う他の疾患のために、
免疫療法に対する応答/免疫活性化薬/免疫調節薬/免疫抑制薬/ワクチン接種/in vivoワクチン接種/in vitro樹状細胞ワクチン接種を予測する;
免疫療法に対する応答をモニタリングする;
免疫療法に対する応答を定量する;
樹状免疫細胞などの免疫細胞型からなる試料上で、細胞が、機能的に、休止状態にあるのか、活性化させられているのか、又は免疫抑制されているのかを同定する;
樹状免疫細胞からなる試料上で、細胞が、機能的に、休止状態にあるのか、活性化させられているのか、又は免疫抑制されているのかを同定する;
樹状細胞を含有する、臓器/組織に由来する組織試料上で、樹状細胞が、休止しているのか、活性であるのか、抑制されているのかを同定する;
樹状細胞を含有する、がん組織に由来する組織試料上で、樹状細胞が、休止しているのか、活性であるのか、抑制されているのかを同定する;
腫瘍流入領域リンパ節に由来する組織試料上で、樹状細胞が、休止しているのか、活性であるのか、抑制されているのかを同定する;
自己免疫疾患を伴う患者に由来する樹状細胞を含有する組織試料上で、樹状細胞が、休止しているのか、活性であるのか、抑制されているのかを同定する;
血液試料上で、樹状細胞が、休止しているのか、活性であるのか、抑制されているのかを同定する;
患者試料上で、免疫療法が、有効となるのかどうかを同定する;
血液試料上で、免疫療法が、有効となるのかどうかを同定する;
組織試料上で、免疫療法が、有効となるのかどうかを同定する;
試料に由来する樹状細胞上で、免疫療法が、有効となるのかどうかを同定する;
患者に由来する試料上で、導入された治療が、有効であるのかどうかを同定する;
患者に由来する試料上で、導入された免疫療法が、有効であるのかどうかを同定する;
血液試料上で、患者が、免疫活性化療法、とりわけ、樹状細胞活性化免疫療法又はワクチン接種療法に関して、適合性であるのかどうかを同定する;
がんを伴う患者に由来する試料上で、免疫活性化療法、とりわけ、樹状細胞活性化免疫療法が、有効となるのかどうかを同定する;
がんを伴う患者に由来する試料上で、樹状細胞活性化免疫療法が、有効となるのかどうかを同定する;
がんを伴う患者に由来する樹状細胞上で、樹状細胞活性化免疫療法が、有効となるのかどうかを同定する;
患者に由来する樹状細胞上で、in vivoワクチン接種が、有効となるのかどうかを同定する;
in vitroにおける活性化樹状細胞上で、後続の樹状細胞ワクチン接種が、有効となるのかどうかを同定する;
樹状細胞ワクチン接種療法後の血液に由来する樹状細胞上で、この療法が、有効であったのかどうかを同定する;
樹状細胞上で、STING経路活性化薬が、有効となるのかどうかを同定する;
樹状細胞上で、適用されたSTING経路活性化薬が、有効であった/であるのかどうかを同定する;
例えば、例えば、腫瘍内の免疫応答が、既に活性である場合、さらなる刺激は、有効ではないという仮定に基づき、免疫療法に対する応答を予測する;
抗原提示免疫細胞型、具体的に、樹状細胞の機能的免疫活性又は免疫抑制状態を特徴づけること;
抗原提示免疫細胞型、具体的に、樹状細胞型の機能的免疫活性又は免疫抑制状態に基づき、治療応答を予測すること;
抗原提示免疫細胞型、具体的に、樹状細胞型の機能的免疫活性又は免疫抑制状態に基づき、免疫調節療法の形態に対する応答を予測すること;
抗原提示免疫細胞型、具体的に、樹状細胞型の機能的免疫活性又は免疫抑制状態に基づき、免疫刺激療法に対する応答を予測すること;
抗原提示免疫細胞型、具体的に、樹状細胞型の機能的免疫活性又は免疫抑制状態に基づき、免疫抑制療法に対する応答を予測すること;
抗原提示免疫細胞型、具体的に、樹状細胞型の機能的免疫活性又は免疫抑制状態に基づく、治療(上記で言及された全て)の効能の評価;
抗原提示免疫細胞型、具体的に、樹状細胞型の機能的免疫活性又は免疫抑制状態に基づく、治療応答のモニタリング;
抗原提示免疫細胞型、具体的に、樹状細胞型の機能的免疫活性又は免疫抑制状態に基づく、治療適合性の評価又はモニタリング
のうちの少なくとも1つにおいて使用されても有利でありうる。
GEOデータセットのデータベース(https://www.ncbi.nlm.nih.gov/gds/)を使用して、多様な型の免疫細胞を、休止状態において、かつ、多様な活性状態の下で探索し、関与性のサイトカインで刺激し、かつ、刺激せずにおいた、臨床研究及び前臨床研究による試料に由来するAffymetrix 2.0Plusデータを、経路モデルを使用して、シグナル伝達経路の活性に関して解析した(図1〜12)。これは、休止状態にある異なる免疫細胞型について、特徴的な経路活性の組合せの同定を可能とし、活性状態又は免疫抑制状態、及び各免疫細胞型について、特徴的な免疫機能経路プロファイルを、活性化サイトカイン若しくは免疫抑制性サイトカイン又は他の因子への曝露と関連すると規定した。
a.単球:休止、免疫支持(較正:GSE28490+GSE43700/バリデーション:GSE72642+GSE16385)
b.マクロファージ:休止及び免疫支持(較正:GSE43596/バリデーション:GSE40885)
c.樹状細胞:休止及び免疫支持の2状態モデル(較正GSE18791/バリデーション52081);入力としての、それぞれ、3つ(較正:GSE23371/バリデーション:GSE13762+GSE56017)及び4つ(較正:GSE23371/バリデーション:GSE13762+GSE56017)のシグナル伝達経路活性についての、休止及び免疫支持及び免疫抑制の3状態モデル
d.好中球:休止、支持(較正:GSE22103/バリデーション:GSE28490)
B.獲得免疫応答
a.CD4+ T細胞:休止、免疫支持(較正:GSE36766/バリデーション:GSE11292)
b.CD4 Th1亜型:免疫支持及びCD4 Th2亜型:免疫抑制(較正:GSE71566/バリデーション:GSE32959)
c.CD8+ T細胞:休止、免疫支持、免疫抑制(較正:GSE26347/バリデーション:GSE72642)
d.Treg細胞:休止、免疫抑制(較正:GSE65010/バリデーション:GSE11292)
e.B細胞:休止、免疫支持(較正:GSE39411/バリデーション:GSE9119)
f.メモリーT:ナイーブ、メモリー(較正:GSE65010/バリデーション:GSE65010+GSE26495)
異なる免疫細胞型の経路解析は、各免疫細胞型について、多様な機能的免疫状態、すなわち、休止状態、免疫支持状態、又は免疫抑制状態にある、活性のシグナル伝達経路の特異的な組合せを明らかにした(図1〜図12)。
休止状態にある好中球(図1)は、免疫経路である、NFκB、JAK−STAT1/2(I型インターフェロン及びII型インターフェロン)、及びJAK−STAT3の低活性と関連する、PI3K経路の不活性又は低活性を指し示す、活性のFOXO転写因子を有し、Notch及びWntのいずれによる経路も、不活性であった。支持状態では、FOXO転写因子の活性が低下することから、PI3K経路活性の増大が指し示され、免疫経路の活性は増大し、Notch/Wntも活性となる。
獲得免疫応答の細胞型は、経路活性の機能及び使用が、自然免疫応答の細胞型と比較して大きく異なる。支持状態にあるCD4(図7)リンパ球は、免疫経路であるNFκB、JAK−STAT1/2、JAK−STAT3の活性の増大、及びTGF−β経路の活性の低減と組み合わされた、PI3K経路活性の増大を指し示す、低FOXO転写因子活性を示す。それぞれ、支持性及び抑制性である、CD4+リンパ球亜型Th1及びTh2(図8)は、FOXO転写因子活性(高度のPI3K経路活性を指し示す、免疫支持性Th1が最低である)と、Th1細胞内で高度である、NFκB、JAK−STAT1/2及びJAK−STAT3、並びにTGF−βによる経路とに基づき区別することができる。Treg細胞(図9)は、活性化すると、免疫抑制性(抑制性)となり、次いで、明らかに、FOXO、NFκB、Notch、JAK−STAT1/2、JAK−STAT3、及びTGF−βの活性プロファイルの強化を示す。
次いで、較正データセットの経路結果を、モデルを較正するための入力として使用して、免疫細胞型の各々について、複数のコンピュータモデルが生成された(図1〜12)。次いで、各モデルを凍結し、対応する独立のバリデーションデータセット上でバリデーションして、モデルの精度を調べた(図1〜12)。モデルを創出するために、免疫細胞の機能状態の決定において、既知の役割(学術文献)を果たすシグナル伝達経路の活性状況を使用した。
少なくとも2つの異なる免疫細胞型上で測定された、機能的な免疫細胞活性(本明細書ではまた、免疫細胞の機能状態/状況とも称する)から、免疫応答(本明細書ではまた、免疫系状況とも称する)の機能状況を予測するのに、3つのモデルを開発した。
免疫応答活性百分率=[(累計ポイント−6)/13]×100%
の通りに計算することができる。
免疫応答活性%−77=免疫活性状況
の通りとなり、式中、正の数は、免疫応答が活性であることを意味し、負の数は、免疫応答抑制性であることを意味する。
免疫活性百分率={[(累計ポイント−6)/13]×100%}−77
となる。
累計ポイントが10ポイントを超えるほど、免疫応答が、不活性/抑制ではないことを指し示し、累計ポイントが10ポイントを下回るほど、免疫応答が抑制状態にあることを指し示す(図15)
の通りに計算する。
図1〜図6は、自然免疫応答の細胞型についての結果を示す。図7〜図12は、獲得免疫応答の細胞型についての結果を示す。経路活性の結果(それぞれのコンピュータモデルに組み入れられたシグナル伝達経路)を、log2オッズとして示し、試料中の免疫細胞の機能状況を指し示し(休止性、支持性、抑制性、ナイーブ、メモリー)、モデルにより提示される機能状況スコアを、右側に示すが、正とは、正確な機能表示を意味し、誤とは、不正確な機能表示を意味する。図1B〜図12Bでは、2つの隣接する状態を、第1の状態の平均線形値及び第2の状態の平均線形値の総平均により決定される境界値により分離する。境界値は、以下の表に与える。
GEOデータセットのデータベース(https://www.ncbi.nlm.nih.gov/gds/)を使用して、樹状免疫細胞を、休止状態において、かつ、多様な活性状態及び寛容原性状態の下で探索し、関与性のサイトカインで刺激し、かつ、刺激せずにおいた、臨床研究及び前臨床研究による試料に由来するAffymetrix 2.0Plusデータを、経路モデルを使用して、シグナル伝達経路の活性に関して解析した。 これは、休止状態にある樹状細胞型について、特徴的な経路活性プロファイルの同定を可能とし、活性状態又は免疫抑制(寛容原性)状態、及び特徴的な免疫機能経路プロファイルを、活性化サイトカイン若しくは免疫抑制性サイトカイン又は他の因子への曝露と関連すると規定した。
(1)樹状細胞の休止状況と対比した活性状況についてのスコアを提供する(2Dモデルと呼ばれる)事態;
(2)樹状細胞の寛容原性状況と対比した休止状況と対比した活性状況についてのスコアを提供する(3Dモデルと呼ばれる)事態
についてのモデルを開発した。
2Dモデルは、樹状細胞の活性/支持状況についての、不活性/休止状況と対比したスコアを、log2オッズスケール上で提供する(図25A及び図25B)。現況技術に従って、活性/支持状態へと誘導されるか、又は不活性/休止状態に保たれた、末梢血由来の分化樹状細胞に由来するAffymetrix 2.0Plusデータを、経路活性について解析し、モデルを使用して、免疫活性スコアを、log2オッズとして提供した。較正試料結果を、左側に示し、図のキャプションにおいて、「較正」として指し示す。2Dベイジアンモデルを、データセットであるGSE18791上でバリデーションし、この/これらのデータセット内の試料の活性スコアを、正確に予測した。
線形モデルを、2Dモデルについて、データセットであるGSE18791上、及び3Dモデルについて、データセットであるGSE13672上及びGSE18791上でバリデーションしたところ、データセット内の試料の活性スコアを、正確に予測した(図22C及び図22D)。
重心モデルを、2状態モデルについて、データセットであるGSE18791上、及び3状態モデルについて、データセットであるGSE13672上及びGSE18791上でバリデーションしたところ、データセット内の試料の活性スコアを、正確に予測した(図23C及び図23D)。
Claims (15)
- 対象の少なくとも1例の試料中の少なくとも1つの免疫細胞型の機能状況を決定するための方法であって、前記方法は、
前記対象の前記少なくとも1例の試料中の前記少なくとも1つの免疫細胞型内の少なくとも1つのシグナル伝達経路の活性に基づき、前記少なくとも1つの免疫細胞型の前記機能状況を決定するステップと;任意選択で、
前記対象の前記少なくとも1例の試料中の前記少なくとも1つの免疫細胞型の前記機能状況を提供するステップと
を有する、方法。 - 前記少なくとも1つのシグナル伝達経路が、PI3K、NFκB、TGF−β、JAK−STAT3、JAK−STAT1/2、Notch、Wnt、MAPK−AP−1、AR、ER、及びHHシグナル伝達経路のグループから選択され、
前記少なくとも1つのシグナル伝達経路が、好ましくは、上記のグループから選択された、2つ又はこれを超えるシグナル伝達経路を含み、前記決定するステップが、前記2つ又はこれを超えるシグナル伝達経路の活性に基づく、
請求項1に記載の方法。 - 前記シグナル伝達経路が、好ましくは、PI3Kシグナル伝達経路及びNFκBシグナル伝達経路の少なくとも一方又は両方を含む、
請求項1又は2に記載の方法。 - 前記少なくとも1つの免疫細胞型の前記機能状況が、前記シグナル伝達経路の1つ又は複数の活性を、前記少なくとも1つの免疫細胞型の前記機能状況と関連付ける、較正された数学的モデルを査定することに基づき決定される、
請求項1から3のいずれか一項に記載の方法。 - 前記少なくとも1つの免疫細胞型内の前記少なくとも1つのシグナル伝達経路の前記活性が、
前記少なくとも1つのシグナル伝達経路の1つの標的遺伝子、好ましくは、3つ又はこれを超える標的遺伝子の発現レベルを受信するステップと、
前記3つ又はこれを超える標的遺伝子の転写を制御する、シグナル伝達経路と関連する転写因子(TF)エレメントの活性レベルを決定するステップであって、前記標的遺伝子の前記発現レベルを、前記少なくとも1つのシグナル伝達経路の前記活性レベルと関連付ける、較正された数学的経路モデルを査定することに基づく、決定するステップと、
前記少なくとも1つの免疫細胞型内の少なくとも1つのシグナル伝達経路の前記活性を、前記シグナル伝達経路と関連するTFエレメントの決定された活性レベルに基づき推測するステップと
を有する方法により推測可能であり、
前記較正された数学的経路モデルが、好ましくは、重心モデル若しくは線形モデル、又は条件付き確率に基づく、ベイジアンネットワークモデルである、
請求項1から4のいずれか一項に記載の方法。 - 前記少なくとも1つの免疫細胞型の前記機能状況が、休止状況、支持状況、抑制状況、ナイーブ状況、又はメモリー状況を有することが決定される、
請求項1から5のいずれか一項に記載の方法。 - 前記少なくとも1例の試料が、組織、リンパ節、血液、気管支吸引物、骨髄吸引物、及び体腔試料からなるグループから選択され、かつ/又は
前記少なくとも1つの免疫細胞型が、
自然免疫細胞、特にナチュラルキラー(NK)細胞、多形核白血球(PMN)、特に好中球、マクロファージ、単球、骨髄樹状細胞、形質細胞様樹状細胞、及び古典的樹状細胞を含む樹状細胞、末梢血単核細胞(PBMC)、並びに
獲得免疫細胞、特にBリンパ球、Tリンパ球、及びこれらの亜型、特にCD4+ T細胞、CD4+ Th1細胞、CD4+ Th2細胞、CD4+調節性T(T−reg)細胞、CD4+メモリーT細胞、CD8+ T細胞、及びCD8+メモリーT細胞
からなるグループから選択される、
請求項1から6のいずれか一項に記載の方法。 - 前記少なくとも1つの免疫細胞型の前記機能状況の決定が、前記少なくとも1つの免疫細胞型の2つ又は3つの機能状態を識別することを含み、前記識別が、免疫細胞型1つ当たり以下の関係:
好中球において、休止状況が、支持状況より高度のPI3K経路、低度のNFκB経路、低度のTGF−β経路、低度のJAK−STAT1/2経路、低度のJAK−STAT3経路、低度のWnt経路、及び低度のNotch経路により特徴づけられること;
単球において、休止状況が、支持状況より高度のPI3K経路、低度のNFκB経路、低度のTGF−β経路、低度のNotch経路、及び低度のJAK−STAT3経路により特徴づけられること;
樹状細胞において、休止状況が、支持状況より低度のPI3K経路、低度のNFκB経路、低度のJAK−STAT1/2経路、低度のTGF−β経路、及び低度のJAK−STAT3経路により特徴づけられること;
樹状細胞において、休止状況が、抑制状況より低度のPI3K経路、高度のNFκB経路、及び低度のJAK−STAT1/2経路により特徴づけられること;
樹状細胞において、支持状況が、抑制状況より高度のPI3K経路、高度のNFκB経路、高度のJAK−STAT1/2経路、及び高度のTGF−β経路により特徴づけられること;
マクロファージにおいて、休止状況が、支持状況より低度のNFκB経路、低度のNotch経路、低度のJAK−STAT1/2経路、及び低度のJAK−STAT3経路により特徴づけられること;
CD4+ T細胞において、休止状況が、支持状況より高度のPI3K経路、低度のNFκB経路、低度のJAK−STAT3経路、低度のNotch経路、及び低度のJAK−STAT1/2経路により特徴づけられること;
CD4+ T細胞において、休止状況が、抑制状況より低度のPI3K経路、低度のNFκB経路、低度のJAK−STAT3経路、及び低度のTGF−β経路により特徴づけられること;
CD4+ T細胞において、支持状況が、抑制状況より低度のPI3K経路、高度のNFκB経路、高度のJAK−STAT3経路、低度のTGF−β経路、及び低度のJAK−STAT1/2経路により特徴づけられること;
CD4+ Th1細胞が、CD4+ Th2細胞より低度のPI3K経路、高度のNFκB経路、高度のTGF−β経路、及び高度のJAK−STAT1/2経路により特徴づけられること;
T−reg細胞において、休止状況が、抑制状況より低度のPI3K経路、低度のNFκB経路、低度のJAK−STAT3経路、低度のTGF−β経路、及び低度のNotch経路により特徴づけられること;
CD8+ T細胞において、休止状況が、支持状況より低度のPI3K経路、低度のNFκB経路、低度のJAK−STAT3経路、低度のTGF−β経路、低度のNotch経路、及び低度のJAK−STAT1/2経路により特徴づけられること;
メモリーT細胞が、ナイーブT細胞より高度のPI3K、高度のNFκB経路、及び高度のTGF−β経路により特徴づけられること;
Bリンパ球において、休止状況が、支持状況より高度のPI3K経路、低度のNFκB経路、及び低度のJAK−STAT3経路により特徴づけられること
のうちの少なくとも1つが当てはまる可能性に基づく、
請求項1から7のいずれか一項に記載の方法。 - 対象の自然免疫系活性状況又は獲得免疫系活性状況を決定するための方法であって、前記方法は、
前記対象の少なくとも1例の試料中の少なくとも1つの自然免疫細胞型の機能状況に基づき、前記自然免疫系活性状況を決定するステップ、及び任意選択で、
前記自然免疫系活性状況を提供するステップ、又は
前記対象の少なくとも1例の試料中の少なくとも1つの獲得免疫細胞型の機能状況に基づき、前記獲得免疫系活性状況を決定するステップ、及び任意選択で、
前記対象の前記獲得免疫系活性状況を提供するステップ
を有し、
前記少なくとも1つの自然免疫細胞型又は獲得免疫細胞型の前記機能状況が、好ましくは、請求項1から8のいずれか一項に記載の方法により決定可能である、方法。 - 対象の全免疫系活性状況を決定するための方法であって、前記方法は、
前記対象の自然免疫系状態及び獲得免疫系状態に基づき、前記全免疫系活性状況を決定するステップであって、前記自然免疫系活性状態及び/若しくは獲得免疫系活性状態が、請求項7に記載の方法により決定可能である、ステップ、又は
前記対象の少なくとも1例の試料中の少なくとも1つの自然免疫細胞型、及び少なくとも1つの獲得免疫細胞型の機能状態に基づき、前記全免疫系活性状況を決定するステップ、並びに任意選択で、
前記対象の前記全免疫系活性状況を提供するステップ
を含み、
前記少なくとも1つの自然免疫細胞型及び/又は前記少なくとも1つの獲得免疫細胞型の前記機能状態が、好ましくは、請求項1から8のいずれか一項に記載の方法により決定可能である、方法。 - 前記免疫系活性状況を決定するステップが、前記少なくとも1つの免疫細胞型の前記機能状態を、前記免疫系活性状況と関連付ける、較正された数学的モデルを査定することに基づき、
前記較正された数学的免疫モデルが、好ましくは、重心モデル若しくは線形モデル、又は条件付き確率に基づく、ベイジアンネットワークモデルである、
請求項9又は10に記載の方法。 - 請求項1から11のいずれか一項に記載の方法を実施するように構成された少なくとも1つのデジタルプロセッサを含む、装置。
- 請求項1から11のいずれか一項に記載の方法を実施するための、デジタル処理デバイスにより実行可能な命令を保存する、非一時的記憶媒体。
- デジタル処理デバイス上で実行される場合に、前記デジタル処理デバイスに、請求項1から11のいずれか一項に記載の方法を実施させるためのプログラムコード手段を含む、コンピュータプログラム。
- 請求項1から11のいずれか一項に記載の方法を実施するためのキットであって、
前記キットは、
3つ又はこれを超えるPI3K標的遺伝子の発現を定量するための構成要素と、
3つ又はこれを超えるNFκB標的遺伝子の発現を定量するための構成要素と
を含み、任意選択で、
3つ又はこれを超えるTGF−β標的遺伝子の発現を定量するための構成要素;
3つ又はこれを超えるSTAT3標的遺伝子の発現を定量するための構成要素;
3つ又はこれを超えるSTAT1/2標的遺伝子の発現を定量するための構成要素;
3つ又はこれを超えるNotch標的遺伝子の発現を定量するための構成要素;
3つ又はこれを超えるWnt標的遺伝子の発現を定量するための構成要素;
3つ又はこれを超えるAP−1標的遺伝子の発現を定量するための構成要素;
3つ又はこれを超えるAR標的遺伝子の発現を定量するための構成要素;
3つ又はこれを超えるER標的遺伝子の発現を定量するための構成要素;及び
3つ又はこれを超えるHH標的遺伝子の発現を定量するための構成要素
のうちの1又は複数を含み、
好ましくは、qPCR、多重qPCR、ddPCR、RNAseq、RNA発現アレイ、及び質量分析からなるグループから選択され、
好ましくは、請求項12に記載の装置、請求項13に記載の非一時的記憶媒体、又は請求項14に記載のコンピュータプログラムをさらに含む、キット。
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