| Objective:To investigate the clinical efficacy the the related HLA-haploidentical non T cell-depleted in vitro high dose peripheral hematopoietic stem cell transplantation(RH-PBSCT),in the treatment of hematologic malignancies,analyze immune reconstitution and its influencing factors after transplantation,and analyze clinical characteristics and influencing factors of acute graft-versus-host disease(a GVHD),and initially explored the relationship between B7 family and a GVHD,so as to preliminarily explore the mechanism of a GVHD,so as to establish our unique RH-PBSCT mode and optimize it.Methods:From July 2004 to December 2014,154 patients who underwent the RH-PBSCT(RH group)were enrolled to analyze the implantation,DFS,OS,GVHD,infection,NRM and relapse compared with 115 patients(MS group)who recieived the HLA-matched sibling non T cell-depleted in vitro PBSCT(MS-PBSCT)simultaneously in the same period.118 patients(78 patients in RH group,40 patients in MS group)detect lymphocyte subsets and the number of Treg cells using flow cytometry;detect Th1/Th2/Th17 cytokines and TGF-??B7 family by CBA and ELISA technique.Analysis of two groups of immune reconstruction and B7 family changes after transplantation and the effect of a GVHD on the immune reconstruction of RH patients and the changes of B7family were analyzed.Results:1.(1)In RH group,1 patients was not implanted,and all the patients in group MS were successfully implanted.There was no statistical difference between the two groups about DFS and OS in 3 years(P=0.109,P=0.159).(2)The cumulative in-cidence of a GVHD in the RH-PBSCT group was significantly higher than the MS-PBSCT group[(56.2±4.7)%vs(34±3.6)%,P<0.05],but the cumulative incidence of?-?and?-?grade a GVHD had no significant difference between the two groups[(39.5±2.9)%vs(21.2±5.4)%,P>0.05 and(12.6±4.1)%vs(10.8±2.4)%,P>0.05)];The cumulative incidence of the occurrence a GVHD was significantly higher in RH-PBSCT group than that in MS-PBSCT group[(42.3±3.2)%vs(17.5±2.3)%,P<0.05],the cumulative incidence of liver and gastrointestinal a GVHD between the two groups had no significant difference[(7.7±2.1)%vs(12.6±3.4)%,P>0.05,and(16.3±4.5)%vs(10.3±2.5)%,P>0.05];The accumulation of c GVHD and local c GVHD were not different between RH group and MS group[(59.2±4.4)%vs(69.4±4.8)%,P=0.731;(51.7±4.6)%vs(49±5.8)%,P=0.151],the incidence of extensive c GVHD in RH group was significantly lower than in MS Group[(14.3±4.2)%vs(42.1±6.3)%,P=0.01];a GVHD cumulative incidence that occured in the skin was significantly higher in RH group than MS group,and a GVHD cumulative incidence that occured in the liver and gastrointestinal have no difference between the two groups;The occurrence of c GVHD in RH group was mainly on the skin,and in MS group was mainly in the liver;HLA haplotype(P=0.003)and matched loci(P=0.002)were significantly correlated with a GVHD occurrence by univariate analysis.Multivariate analysis showed that only the HLA haplotype was a risk factor for a GVHD(HR=1.891,P=0.03);Multifactor analysis showed that HLA type,disease status,and a GVHD were risk factors for c GVHD.(3)The cumulative incidence of infection?NRM and relapse in RH group and MS group had no significant difference[(64.6±3.7)%to(40.3±4.2)%,P>0.05;P=0.120;P=0.820];hemorrhagic cystitis and herpes zoster cumulative incidence of RH was higher than MS group[(36.1±3.8)%to(17.7±3.3)%,P<0.05;(15.9±2.9)%to(8.5±2.4)%,P=0.049];interstitial pneumonia cumulative incidence have no significant difference between the two groups[(10.8±3)%to(12.2±2.9)%,P=0.832].There was no significant difference in cytomegalovirus antibody and DNA?EBV DNA between the two groups before and after transplantation(P=0.928,P=0.883,P=0.653);2.1 After transplantation,there was no difference in the recovery of CD3+T,D8+T,B cells and NK cells between RH group and MS group after transplantation.CD4~+T and CD4/CD8 ratio in the RH group recovered slowly after transplantation,and the difference was statistically significant compared with MS group.The levels of IL-2 and IFN-?were increased after transplantation,and the level and duration of the RH group were higher than those in the MS group,the difference between the two groups was statistically significant.The levels of IL-4 and IL-10 decreased after transplantation,IL-4 was not detected in RH group before and after transplantation,while MS group remained at a low level,the difference between the two groups was statistically significant.IL-10 level in RH group and MS group had no significant difference between the two groups.After transplantation,the levels of CD4~+CD25+Foxp3+Treg?IL-17 and TGF-?decreased significantly in group RH,but there was no significant change in MS group.The difference between the two groups was statistically significant(P<0.05).2 There was no significant difference in percentage ratio of CD3+,CD4+and CD8+T cells,CD4/CD8 ratio,total B cells and NK cells in RH group after a GVHD.There was no significant difference in total B cells and NK cells in those group without a GVHD.The serum levels of IL-4,IL-17,and TGF-?were higher than those without a GVHD.The number of Treg cells in the early stage of a GVHD was significantly lower than those without a GVHD patients(P=0.006).The level of IL-10 increased gradually in the patients without a GVHD,but decreased significantly in the patients with III-IV a GVHD(P<0.05).3.1 After transplantation,B7-1 levels increased gradually after transplantation and then decreased,the overall level of B7-1 in MS group is higher than that of RH group,the difference was statistically significant(P=0.049),after a GVHD,the B7-1 level in MS group with a GVHD is lower than the non GVHD group at 3,6,9 month after tansplantation,the difference was statistically significant difference(P<0.001).PD-1level increased in MS and RH groups after transplantation,there was no difference between the two groups.PD-1 level in RH group without a GVHD was significantly higher than that in a GVHD group,and the difference between them was significant(P=0.039).PD-L1 level decreased after transplantation,and RH group recovered faster than MS group.However,there was no difference between the two groups.After a GVHD,the PD-L1 level in MS groupa with a GVHD was higher than that in the non-a GVHD group,and the difference between them was significant(P=0.02).2 In RH group,the level of PD-1 in patients with a GVHD was lower than that in patients without a GVHD,while the level of TGF-?increased.Correlation analysis showed a negative correlation between them,and B7-1 level in patients with a GVHD was also lower than that in patients without a GVHD.Conclusion:Our unique RH-PBSCT achieved good clinical efficacy in treatment of malignant tumors,although the overall incidence of a GVHD was significantly higher than MS-PBSCT,but the incidence of severe a GVHD is not high,the main site was skin;Reconstitution of CD4~+T cells and its subsets are all delayed within 1 years after RH-PBSCT.Increased IL-4,IL-10,TGF-?serum levels and decreased Treg and IL-10level in RH group can help to establish the clinical diagnosis of a GVHD,and which is expected to provide a clinical basis for further target immunotherapy.The level of B7-1after RH-PBSCT without a GVHD was significantly lower than that of MS-PBSCT,while the level of B7-1 in patients with a GVHD had no difference in patients without a GVHD after RH-PBSCT,It shows that our unique RH-PBSCT pattern can reduce the incidence of severe a GVHD by regulation of a GVHD through the B7-1 in the B7 family. |
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