| Background and Objection:Allogeneic hematopoietic stem cell transplantation(allo-HSCT)has been considerd the most important therapy for mang hematologic diseases and other diseases.However,viral infections,especially Epstein-Barr virus(EBV)and cytomegalovirus,(CMV)infection/reactivation and associated diseases remain common complications in recipients of HSCT.EBV and CMV belong to the family of gamma-herpes virus and cause an asymptomatic lifelong persistent infection in 90%of the world population.EBV and CMV may be re-active when the antiviral immunity is impaired,leading to severe end-organ diseases and malignance.With the development of prophylaxis and pre-emptive strategy of post-transplant CMV infection/reactivation,the incidence of CMV-associated diseases after HSCT decreases.EBV infection/reactivation following allo-HSCT can cause deadly post-transplant lymphoproliferative disorders(PTLD)and other EBV-associated diseases which are not well treated at present.Risk factors for viral infections include HLA-mismatch or unrelated stem cell donors,anti-thymocyte globulin(ATG)as the standard prophylaxis of graft versus host disease(GVHD)and so on.Nowaday,genetic heterogeneity of the recipients is considered to be related with EBV and CMV infections.The association between gene polymorphism and many diseases has been reported.The most well-studied genes about viral infections include human leukocyte antigen(HLA)genes and innate immunity-related genes.Both these two kinds of gene play important roles in the mechanism of viral infections.Therefore,polymorphism in HLA gene and innate immunity-related genes may affect the viral infections.Many researchers have reported the association between HLA gene polymorphism and nasopharyngeal carcinoma which is caused by EBV.The relation between HLA gene polymorphism and PLTD after solid organ transplantation has also been proven in several studies.Besides,HLA gene polymorphism is considered to affect the development of CMV infection/reactivation and diseases in recipients of HSCT.Cytokine gene is the most important gene among innate immunity-related genes.Single nucleotide polymorphism(SNP)in cytokine gene is considered to be related with PTLD and post-tranplant CMV infections.Since population of allo-HSCT is small,the reports of large samples which is about the association between gene polymorphism and EBV or CMV infections after HSCT are rare.In addition,the mechanism of how polymorphism affect EBV or CMV infections remains unclear.It is presumed to be related with virus-specific cytotoxic T cell(CTL).In this study,the association between polymorphisms,including HLA and cytokine gene polymorphism,and EBV or CMV infection/reactivation or diseases in recipients undergoing allo-HSCT was evaluated.Besides,relation between polymorphism and EBV-CTL was analyzed.Methods:1 Association of HLA polymorphisms with EBV and CMV infections after allo-HSCT:A total of 504 patients who received allo-HSCT between July 2008 to January 2015 were enrolled in this study.Polymorphism in HLA-A,-B,-DRB1,-C and-DQB1 loci of these patients and their donors were analyzed.The frequencies of HLA loci in patients with or without EBV or CMV infection/reactivation and associated diseases were compared.Besides,the risk factors for EBV or CMV infection/reactivation and associated diseases were studied.2 Association of cytokine gene polymorphisms with EBV and CMV infections after allo-HSCT:A total of 233 patients who received allo-HSCT between March 2012 to December 2014 were enrolled in this study.Ten SNPs,including IL-1-511 rs16944,IL-1RN+11100 rs315952,IL-2-330 rs2069762,IL-4-590 rs2243250,IL-10-592 rs1800872,IL-12+1188 rs3212227,TNF-α-308 rs1800629,TGF-β1-509 rs1800469,TGF-β1+869 rs1800470,IFN-y +874 rs2430561 were tested.The SNPs genotypes in patients with or without EBV or CMV infection/reactivation and associated diseases were compared.Besides,the risk factors for EBV or CMV infection/reactivation were studied.3 Reconstruction of EBV-CTL in allo-HSCT recipients early after transplantation:Thirty patients undergoing allo-HSCT between November 2013 to September 2014 were enrolled in this study.Enzyme-linked immunospot assay(ELISPOT)was used to test EBV-CTL in 30,90,180 days after transplantation and when EBV infection/reactivation and associated diseases occurred.Besides,HLA-restricted EBV peptide tetramer was used to test EBV-CTL in patients who developed EBV-associated diseases.Statistical analysis:SPSS 13.0 statistical package was used for analysis.Pearson’s chi-square test and Fisher’s exact test were used to compare the frequencies of HLA and cytokine gene polymorphism genotypes between two groups.Kaplan-Meier were used for culumative incidences of EBV and CMV infection/reactivation and diseases and Cox proportional hazards model was used for analysis of risk factors.EBV-CTL count in different periods,SNPs genotpyes,patients with or withour EBV infection/reactivation were compared using the non-parametric analysis.P<0.05 was considered statistically significant.Results:1 Association of HLA polymorphisms with EBV and CMV infections after allo-HSCT:(1)166 patients developed EBV infection/reactivation and 51 developed EBV-associated diseases.The 1-year cumulative incidence of EBV infection/reactivation and EBV-associated diseases were 35.0±2.2%and 11.2±1.5%,respectively.279 patients developed CMV infection/reactivation and 7 developed EBV-associated diseases.The 1-year cumulative incidence of EBV infection/reactivation and EBV-associated diseases were 56.1±2.3%and 1.5±0.6%,respectively.(2)The frequencies of both recipient and donor HLA-B44 were higher in patients with EBV infection/reactivation than those without(donor B44:4.22%vs 1.18%,p=0.046;recipient B44:4.24%vs 1.18%,p=0.046).Recipient HLA-B44(p=0.008,HR-2.809,95%CI=1.303-6.056)was risk factor for post-transplant EBV infection/reactivation.The frequencies of recipient HLA-B44,donor HLA-B46 and recipient HLA-C05 were higher in patients with EBV-associated diseases than those without(7.84%vs 1.55%,p=0.018;42.00%vs 26.71%,p=0.023;5.00%vs 0%,p=0.011)while the frequency of donor HLA-C03 in patients with EBV-associated diseases was lower than those without(32.43%vs 50.16%,p=0.041).In multivariate analysis,recipient HLA-B44(p<0.001,HR=8.163,95%CI =2.786-23.916)and donor HLA-B46(p=0.038,HR=1.816,95%CI=1.033-3.192)were risk factors for EBV-associated diseases in allo-HSCT recipients.(3)The frequencies of both recipient and donor HLA-B46 were higher in patients with CMV infection/reactivation than those without(donor B46:32.26%vs 21.78%,p=0.009;recipient B46:32.73%vs 22.67%,p=0.013)while the frequencies of recipient HLA-B*48,donor HLA-B*48,recipient HLA-DR*03,donor HLA-DR*03,donor HLA-DR*16,recipient HLA-C*08,donor HLA-C*12 in patients with CMV infection/reactivation were lower than those without(1.43%vs 5.78%,p=0.007;1.44%vs 6.22%,p=0.004;10.39%vs 17.33%,p=0.023;10.43%vs 17.78%,p=0.017;7.19%vs 13.33%,p=0.022;11.98%vs 20.48%,p=0.023;5.31%vs 14.39%,p=0.004).In multivariate analysis,donor HLA-B46(p=0.020,HR=1.355,95%CI=1.049-1.749)was risk factors for CMV infection/reactivation while donor HLA-B*48(p=0.027,HR=0.326,95%CI=0.121-0.878)and donor HLA-DR*03(p=0.026,HR=0.642,95%CI=0.435-0.948)were protective factors for post-transplant CMV infection/reactivation.2 Association of cytokine gene polymorphisms with EBV and CMV infections after allo-HSCT:(1)74 patients developed EBV infection/reactivation and 21 developed EBV-associated diseases.135 patients developed CMV infection/reactivation and 5 developed EBV-associated diseases.(2)The frequencies of donor IL-1β-511 TT genotype,donor IL-4-590 TT genotype and recipient TNF-α-308 GG genotype were higher in patients with EBV infection/reactivation than those without(31.1%vs 17.6%,p=0.021;74.3%vs 54.7%,p=0.004;90.5%vs 78.0%,p=0.020)while the frequencies of donor IL-1β-511 CC genotype,donor IL-1RN+11100 TT genotype,donor IL-2-330 TT genotype,donor IL-4-590 CC genotype and recipient TNF-a-308 GA genotype in patients with EBV infection/reactivation were lower than those without(17.6%vs 30.2%,p=0.041;21.6%vs 35.8%,p=0.029;5.4%vs 19.5%,p=0.005;0%vs 7.5%,p=0.011;9.5%vs 20.1%,p=0.042).And donor IL-4-590TT genotype(p=0.016,HR=1.907,95%CI=1.130-3.218)and recipient TNF-a-308GG genotype(p=0.002,HR=3.550,95%CI=1.613-7.812)were risk factors for post-transplant EBV infection/reactivation while donor IL-1RN+11100TT genotype(p=0.001,HR=0.382,95%CI=0.218-0.670)was protective factors for post-transplant EBV infection/reactivation.The frequencies of donor IFN-y +874 AT genotype were higher in patients with EBV-associated diseases than those without(42.9%vs 20.3%,p=0.027)while the frequencies of donor IL-1β-511 CC genotype,donor IL-10-592 AA genotype,donor IL-12+1188 AA genotype and donor IFN-y +874 AA genotypein patients with EBV-associated diseases were lower than those without(4.8%vs 28.3%,p=0.019;23.8%vs 50.9%,p=0.018;9.5%vs 34.9%,p=0.018;52.4%vs 77.8%,p=0.010).(3)The frequencies of donor IL-1β-511 TT genotype,donor IL-12+1188 CC genotype and donor TGF-β1-509 CC genotype were higher in patients with CMV infection/reactivation than those without(28.1%vs 13.3%,p=0.007;22.2%vs 5.1%,p<0.001;37.8%vs 23.5%,p=0.021)while the frequency of donor IL-12+1188 CA genotype in patients with EBV infection/reactivation was lower than those without(45.2%vs 62.2%,p=0.010).And donor IL-12+1188CC genotype(p=0.012,HR=1.698,95%CI=1.123-2.568)and recipient TGF-β1-509 TT genotype(p=0.004,HR=1.676,95%CI=1.180-2.381)were risk factors for post-transplant CMV infection/reactivation.3 Reconstruction of EBV-CTL in allo-HSCT recipients early after transplantation:(1)EBV-CTL count in +90d after HSCT was significantly higher than +30d in patients who had response for peptide FLY(Z=-2.272,p=0.023)and CLG(Z=-2.572,p=0.010)as well as IVF(Z=-2.600,p=0.009).(2)The patients with EBV infection/reactivation had higher EBV-CTL response for peptide CLG than those without in +90d after HSCT(Z=-2.722,p=0.004).(3)No significant difference in EBV-CTL reconstruction was found among the patiens with HLA-A*0201,*0203,*0207 genotype.(4)The patients with recipient IL-1β-511 TT genotype had higher EBV-CTL response for peptide FLY and SSC than those without recipient IL-1β-511 TT genotypein +90d after HSCT(FLY:Z=-2.041,p= 0.048;SSC:Z=-2.042,p= 0.048).The patients with donor IL-1RN+11100 TT genotype had lowerEBV-CTL response for peptide SSC than those withoutin +90d after HSCT(Z=-2.042,p=0.048).The patients with recipient IL-2-330 GG genotype had higher EBV-CTL response for peptide FLY,SSC,IVF than those withoutin +90d after HSCT(FLY:Z=-2.4571,p= 0.012;SSC:Z=-2.042,p= 0.048;IVF:Z=-2.652,p= 0.006).The patients with donor IL-2-330 GG genotype had higher EBV-CTL response for peptide IVF than those withoutin +90d after HSCT(Z=-2.652,p= 0.006).The patients with recipient IL-10-592 AA genotype had higher EBV-CTL response for peptide CLG than those withoutin +90d after HSCT(Z=-2.268,p= 0.024).The patients with recipient IL-1RN+11100 TT genotype had higher EBV-CTL response for peptide FLY than those withoutin+180d after HSCT(Z=-2.241,p= 0.026).The patients with donor IL-2-330 TT genotype had lower EBV-CTL response for peptide FLY than those withoutin +180d after HSCT(Z=-2.148,p= 0.030).The patients with recipient TGF-β1 +869 CC genotype had higherEBV-CTL response for peptide FLY than those withoutin +180d after HSCT(Z=-2.038,p= 0.048).Conclusion:1 HLA-B*44 and-B*46 might be associated with EBV infection/reactivation or EBV-associated diseases in recipients of allo-HSCT.HLA-B*46,-B*48 and-DR*03 might be related to the development of post-tranplant CMV infection/reactivation.2 SNPs in IL-1RN +11100TT,IL-4-590 and TNF-a-308 might be associated with EBV infection/reactivation or EBV-associated diseases in recipients of allo-HSCT.SNPs in IL-12 +1188 and TGF-β1-509 might be related to the development of post-tranplant CMV infection/reactivation.However,these association should be studied further.3 EBV-CTL response could be tested in +30d after HSCT and some patients might achieve reconstruction of EBV-CTL in +90d.IL-1β-511,IL-1RN +11100,IL-2-330,IL-10-592 and TGF-β1+869 SNPs might be related to the reconstruction of EBV-CTL,which should be studied further. |
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