Assessment and reduction of risk of graft-versus-host disease

Abstract

Methods of assessing and reducing risk of graft versus host disease (GVHD) based on gene expression profiling are described, as well as methods of selecting a suitable transplant donor. Corresponding reagents and kits are also described.

1 - 23 . (canceled) 
     
     
         24 . A method of assessing risk, of a candidate transplant donor, of inducing graft versus host disease (GVHD) in a transplant recipient, said method comprising:
 (a) comparing a candidate gene expression profile derived from a biological sample from said candidate transplant donor to a corresponding reference gene expression profile, wherein said candidate gene expression profile comprises a candidate expression value for one or more gene(s) selected from the group consisting of CXCR6, SMAD1, FAF1, SH3KBP1, HDAC2, IL1R1, CDC42, GADD45G, IFNAR2, IFRD1, IGFBP2, IRF3, LIG4, MAP2K1, MME, RASGRP1, STAT1, TFRC, TRIM22, TFAP2C, CDC25A, GSR, PRF1, BCAP31, RANBP2, SNRPN, SOCS5, ANXA5, CD63, CD81, CKS2, CPE, MAD, MYCL1, PDCD8, RHOA, SKP2, YWHAQ, GAPD, PPIE, RAN, FOSB, MAP2K6, SERPINB2, TLR4, CD3D, GAB2, MAPK8IP1, SMO, CD151, EP300, FNBP3, IL6R, NMI, PDK2, PPP1R16B, SIL, SNRP70, STK38, TCIRG1, CD1A, IL15RA, IL2RG, ILF1, LAT, MGMT, TLR1, RGS13, THBS1, NFAT5, PIAS4, ADD1, BAG3, VEGF, YY1, AKT2, FURIN, ATBF1, CCND1, CHERP, CSDA, DOK2, FOXJ1, HEXA, LAMP2, MCAM, NFKB2, PTGER4, DAD1, ILF3, RFXANK, SMAD3, TNFRSF1B, VIM, CD24, DAP, HLA-DRB1, HSPB1, PRKACA, HDAC5, CDC25B, TGIF and TGFBI;   
       wherein said reference gene expression profile comprises a reference expression value for said one or more gene(s), said reference expression profile being derived from a comparison of:
 (i) a GVHD+ expression profile comprising a GVHD+ expression value for one or more gene(s) derived from a biological sample obtained from a transplant donor known to have induced GVHD in a transplant recipient with 
 (ii) a GVHD− expression profile comprising a GVHD− expression value for one or more gene(s) derived from a biological sample obtained from a transplant donor known to have not induced GVHD in a transplant recipient, 
 
       whereby said reference expression value is determined as being (A) the level of expression midway between said GVHD+ and GVHD− expression values whereby said midway level separates a GVHD+ class comprising said GVHD+ expression value from a GVHD− class comprising said GVHD− expression value; (B) the level of expression between said GVHD+ and GVHD− expression values defined as separating expression values into GVHD+ and GVHD− classes on the basis of discriminatory analysis; or (C) both (A) and (B); and
 (b) assessing risk of said candidate transplant donor of inducing graft versus host disease (GVHD) in a transplant recipient in accordance with said comparison of said candidate gene expression profile with said reference gene expression profile. 
 
     
     
         25 . The method of  claim 24 , wherein said expression value is obtained by determining the level of expression of a nucleic acid or polypeptide encoded thereby comprising a sequence selected from SEQ ID NOs: 1-206. 
     
     
         26 . The method of  claim 24 , wherein said reference expression value is determined as being (a) the level of expression midway between said GVHD+ and GVHD− expression values. 
     
     
         27 . The method of  claim 24 , wherein a candidate expression value within said GVHD+ class is indicative that said candidate transplant donor has an increased risk of inducing GVHD in a transplant recipient. 
     
     
         28 . The method of  claim 24 , wherein a candidate expression value within said GVHD− class is indicative that said candidate transplant donor has a reduced risk of inducing GVHD in a transplant recipient. 
     
     
         29 . The method of  claim 24 , wherein said gene is selected from TCIRG1, SMAD3, ATBF1, AKT2, CD24, CD151, TGIF, SIL, PRF1, FNBP3, TGFBI, EP300, SH3KBP1, NMI, FURIN and NFAT5. 
     
     
         30 . The method of  claim 24 , wherein the expression value of said one or more gene(s) is determined by determining the level of expression of a nucleic acid or polypeptide encoded thereby comprising a sequence selected from SEQ ID NOs: 7-8, 45-46, 99-104, 107-108, 113-114, 119-120, 139-140, 151-156, 183-184, 189-190 and 203-206. 
     
     
         31 . The method of  claim 24 , wherein said one or more gene(s) is selected from the group consisting of SH3KBP1, PRF1, CD151, EP300, FNBP3, NMI, SIL, TCIRG1, NFAT5, AKT2, FURIN, ATBF1, SMAD3, CD24, TGIF and TGFBI. 
     
     
         32 . The method of  claim 24 , wherein said one or more gene(s) is one or more gene pair(s) selected from the group consisting of (a) SH3KBP1 and NFAT5; (b) PRF1 and NFAT5; (c) PRF1 and TCIRG1; and (d) CD151 and SIL. 
     
     
         33 . The method of  claim 24 , wherein the reference gene expression profile is contained within a database. 
     
     
         34 . The method of  claim 24 , wherein said comparing is carried out using a computer algorithm. 
     
     
         35 . The method of  claim 24 , wherein the biological sample is selected from a cell, a tissue and a body fluid. 
     
     
         36 . The method of  claim 35 , where the cell is selected from a CD4 +  and a CD8 +  T cell. 
     
     
         37 . The method of  claim 24 , wherein said biological sample is a CD4 +  T cell and wherein said one or more gene(s) is selected from CD151, EP300, FNBP3, NMI, SIL, TCIRG1, AKT2, FURIN, ATBF1, SMAD3, TGIF and TGFBI. 
     
     
         38 . The method of  claim 24 , wherein said biological sample is a CD8 +  T cell and wherein said one or more gene pair(s) is selected from SH3KBP1-NFAT5, PRF1-NFAT5 and PRF1-TCIRG1. 
     
     
         39 . The method of  claim 24 , wherein said biological sample is a CD4 +  T cell and wherein said one or more gene(s) is selected from RAN, FOSB, MAP2K6, SERPINB2, TLR4, CD3D, GAB2, MAPK8IP1, SMO, CD151, EP300, FNBP3, IL6R, NMI, PDK2, PPP1R16B, SIL, SNRP70, STK38, TCIRG1, PIAS4, ADD1, BAGS, VEGF, YY1, AKT2, FURIN, ATBF1, CCND1, CHERP, CSDA, DOK2, FOXJ1, HEXA, LAMP2, MCAM, NFKB2, PTGER4, RFXANK, SMAD3, VIM, CDC25B, TGIF and TGFBI. 
     
     
         40 . The method of  claim 39 , wherein said one or more gene(s) is selected from TCIRG1, SMAD3, ATBF1, AKT2, CD151, SIL, FNBP3, EP300, NMI, FURIN, TGIF and TGFBI. 
     
     
         41 . The method of  claim 24 , wherein said biological sample is a CD8 +  T cell and wherein said one or more gene(s) is selected from CD3D, CD1A, IL15RA, IL2RG, ILF1, LAT, MGMT, TLR1, RGS13, THBS1, TCIRG1, PIAS4, NFAT5, BA G3, VEGF, YY1, FURIN, CCND1, CHERP, CSDA, DOK2, FOXJ1, MCAM, NFKB2, PTGER4, DAD1, ILF3, RFXANK, SMAD3, TNFRSF1B, VIM, CD24, DAP, HLA-DRB1, HSPB1, PRKACA, HDAC5 and CDC25B. 
     
     
         42 . The method of  claim 41 , wherein said one or more gene(s) is selected from CD24, NFAT5 and TCIRG1. 
     
     
         43 . The method of  claim 24 , wherein said biological sample is a CD4 +  T cell and wherein said one or more gene(s) is selected from CXCR6, SMAD1, FAF1, BCAP31, RANBP2, SNRPN, SOCS5, ANXA5, CD63, CD81, CKS2, CPE, MAD, MYCL1, PDCD8, RHOA, SKP2 and YWHAQ.