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Yongguang Yang - One of the best experts on this subject based on the ideXlab platform.
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rapid dendritic cell activation and resistance to allotolerance induction in anti CD154 treated mice receiving cd47 deficient donor specific transfusion
Cell Transplantation, 2014Co-Authors: Yuantao Wang, Hui Wang, Roderick T Bronson, Yongguang YangAbstract:CD47-SIRPα signaling plays an important role in regulating macrophage and dendritic cell (DC) activation. Here we investigated the role of CD47 expression on donor cells in tolerance induction by combined treatment with donor-specific transfusion (DST) plus anti-CD154 mAb in a mouse model of fully MHC-mismatched heart allotransplantation. The majority of BALB/c recipient mice that received anti-CD154 and CD47(+/+) B6 splenocytes (DST) showed indefinite donor heart survival (median survival time, MST > 150 days). Donor heart survival was improved in anti-CD154-treated BALB/c mice that received CD47(+/-) (MST = 90 days) or CD47(-/-) B6 DST (MST = 42 days) when compared to the nontreated (MST = 7 days) and anti-CD154 alone-treated (MST = 15 days) controls, but significantly reduced when compared to mice receiving anti-CD154 plus CD47(+/+) B6 DST. Recipient mice treated with anti-CD154 plus CD47(-/-) or CD47(+/-) DST also showed significantly increased antidonor, but not anti-third-party, MLR responses compared to those receiving anti-CD154 and CD47(+/+) DST. Furthermore, CD47(-/-) DST induced rapid activation of CD11c(hi)SIRPα(hi)CD8α(-) DCs via a mechanism independent of donor alloantigens. These results demonstrated that CD47 expression on donor cells is essential to the success of tolerance induction by combined therapy with DST and CD40/CD154 blockade.
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rapid dendritic cell activation and resistance to allotolerance induction in anti CD154 treated mice receiving cd47 deficient donor specific transfusion
Cell Transplantation, 2014Co-Authors: Yuantao Wang, Hui Wang, Roderick T Bronson, Yongguang YangAbstract:CD47-SIRPα signaling plays an important role in regulating macrophage and dendritic cell (DC) activation. Here, we investigated the role of CD47 expression on donor cells in tolerance induction by combined treatment with donor-specific transfusion (DST) plus anti-CD154 mAb in a mouse model of fully MHC-mismatched heart allotransplantation. The majority of BALB/c recipient mice that received anti-CD154 and CD47+/+ B6 splenocytes (DST) showed indefinite donor heart survival (median survival time, MST>150d). Although donor heart survival was improved compared to non-treated (MST=7d) and anti-CD154 alone (MST=15d) controls, the graft survival time was significantly reduced in anti-CD154-treated BALB/c mice that received CD47+/− (MST=90d) or CD47−/− B6 DST (MST=42d) compared to those receiving CD47+/+ B6 DST. Recipient mice treated with anti-CD154 plus CD47−/− or CD47+/− DST also showed significantly increased anti-donor, but not anti-3rd-party, MLR responses compared to those receiving anti-CD154 and CD47+/+ DST. Furthermore, CD47−/− DST induced rapid activation of CD11chiSIRPαhiCD8α− DCs via a mechanism independent of donor alloantigens. These results demonstrate that CD47 expression on donor cells is essential to the success of tolerance induction by combined therapy with DST and CD40/CD154 blockade.
Chethan Ashokkumar - One of the best experts on this subject based on the ideXlab platform.
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Increased monocyte expression of sialoadhesin during acute cellular rejection and other enteritides after intestine transplantation in children.
Transplantation, 2012Co-Authors: Chethan Ashokkumar, George V Mazariegos, Mylarappa Ningappa, Qing Sun, Anna Gabriellan, Rakesh SindhiAbstract:BACKGROUND Sialoadhesin (CD169) facilitates T-cell priming when overexpressed on inflammatory monocytes. Monocyte-derived macrophages prime acute cellular rejection after intestine transplantation (ITx).The purpose of this study was to evaluate whether CD169-expressing activated monocytes associate with or predict ITx rejection. METHODS After informed consent (ClinicalTrials.gov NCT No. 01163578), activated CD169+CD14+monocytes were measured by flow cytometry in five normal healthy adult volunteers (group A), and 56 children with ITx sampled cross-sectionally (group B, 26), longitudinally (group C, 18), or during infection/inflammation without rejection (group D: acute enteritis, 9; Helicobacter pylori, 1; Streptococcal pharyngitis 1; and posttransplant lymphoma, 1). Activated monocytes were tested for correlations with donor-specific alloreactivity in simultaneous mixed lymphocyte co-cultures. RESULTS Median age was 3 years (range 0.5-21 yr), and distribution of ITx-alone:combined liver-ITx was 25:31. Higher frequencies (%) of activated monocytes were seen during rejection in group B and infection/inflammation without rejection in group D (58 ± 28 and 73 ± 26), compared with nonrejectors or normal controls (10.6 ± 7.9 or 10.7 ± 6.5, P=0.001). In longitudinal monitoring, rejectors also showed higher activated monocyte frequencies (%) before ITx (64 ± 26 vs. 13.4 ± 8.6, P=0.0007) and during acute cellular rejection (55 ± 28 vs. 22.4 ± 15, P=0.006) when compared with nonrejectors. Activated monocytes correlated significantly with allospecific CD154+T-cytotoxic memory cells (Spearman r=0.688, P=7.1E-05) and CD154+B cells (r=0.518, P=0.005) in ITx recipients without inflammation/infection but not in group D. CONCLUSIONS Monocytes overexpress sialoadhesin nonspecifically during ITx rejection and systemic or enteritic inflammatory states. When combined with allospecific T and B cells, this information may differentiate between rejection and other enteritides.
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increased expression of peripheral blood leukocyte genes implicate cd14 tissue macrophages in cellular intestine allograft rejection
American Journal of Pathology, 2011Co-Authors: Chethan Ashokkumar, Mylarappa Ningappa, Brandon W Higgs, Sarangarajan Ranganathan, Lori Schmitt, Sara Snyder, Jennifer Dobberstein, Maria F BrancaAbstract:Recurrent rejection shortens graft survival after intestinal transplantation (ITx) in children, most of whom also experience early acute cellular rejection (rejectors). To elucidate mechanisms common to early and recurrent rejection, we used a test cohort of 20 recipients to test the hypothesis that candidate peripheral blood leukocyte genes that trigger rejection episodes would be evident late after ITx during quiescent periods in genome-wide gene expression analysis and would achieve quantitative real-time PCR replication pre-ITx (another quiescent period) and in the early post-ITx period during first rejection episodes. Eight genes were significantly up-regulated among rejectors in the late post-ITx and pre-ITx periods, compared with nonrejectors: TBX21 , CCL5 , GNLY , SLAMF7 , TGFBR3 , NKG7 , SYNE1 , and GK5 . Only CCL5 was also up-regulated in the early post-ITx period. Among resting peripheral blood leukocyte subsets in randomly sampled nonrejectors, CD14 + monocytes expressed the CCL5 protein maximally. Compared with nonrejectors, rejectors demonstrated higher counts of both circulating CCL5 + CD14 + monocytes and intragraft CD14 + monocyte-derived macrophages in immunohistochemistry of postperfusion and early post-ITx biopsies from the test and an independent replication cohort. Donor-specific alloreactivity measured with CD154 + T-cytotoxic memory cells correlated with the CCL5 gene and intragraft CD14 + monocyte-derived macrophages at graft reperfusion and early post-ITx. CCL5 gene up-regulation and CD14 + macrophages likely prime cellular ITx rejection. Infiltration of reperfused intestine allografts with CD14 + macrophages may predict rejection events.
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increased expression of peripheral blood leukocyte genes implicate cd14 tissue macrophages in cellular intestine allograft rejection
American Journal of Pathology, 2011Co-Authors: Chethan Ashokkumar, Mylarappa Ningappa, Brandon W Higgs, Sarangarajan Ranganathan, Lori Schmitt, Qing Sun, Sara SnyderAbstract:Recurrent rejection shortens graft survival after intestinal transplantation (ITx) in children, most of whom also experience early acute cellular rejection (rejectors). To elucidate mechanisms common to early and recurrent rejection, we used a test cohort of 20 recipients to test the hypothesis that candidate peripheral blood leukocyte genes that trigger rejection episodes would be evident late after ITx during quiescent periods in genome-wide gene expression analysis and would achieve quantitative real-time PCR replication pre-ITx (another quiescent period) and in the early post-ITx period during first rejection episodes. Eight genes were significantly up-regulated among rejectors in the late post-ITx and pre-ITx periods, compared with nonrejectors: TBX21 , CCL5 , GNLY , SLAMF7 , TGFBR3 , NKG7 , SYNE1 , and GK5 . Only CCL5 was also up-regulated in the early post-ITx period. Among resting peripheral blood leukocyte subsets in randomly sampled nonrejectors, CD14 + monocytes expressed the CCL5 protein maximally. Compared with nonrejectors, rejectors demonstrated higher counts of both circulating CCL5 + CD14 + monocytes and intragraft CD14 + monocyte-derived macrophages in immunohistochemistry of postperfusion and early post-ITx biopsies from the test and an independent replication cohort. Donor-specific alloreactivity measured with CD154 + T-cytotoxic memory cells correlated with the CCL5 gene and intragraft CD14 + monocyte-derived macrophages at graft reperfusion and early post-ITx. CCL5 gene up-regulation and CD14 + macrophages likely prime cellular ITx rejection. Infiltration of reperfused intestine allografts with CD14 + macrophages may predict rejection events.
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allospecific CD154 t cells identify rejection prone recipients after pediatric small bowel transplantation
Surgery, 2009Co-Authors: Chethan Ashokkumar, George V Mazariegos, Kyle Soltys, Mylarappa Ningappa, Brandon W Higgs, Tamara Fazzolare, Lisa Remaley, Geoffrey J Bond, Ankit Gupta, Kareem AbuelmagdAbstract:Background Up to 70% of children with small bowel transplantation (SBTx) experience acute cellular rejection (ACR). Allospecific CD154+ T cells predict liver ACR in children in a novel, 16-hour mixed leukocyte response (MLR) assay, but remain untested in SBTx. Methods The expression of CD154 was measured in 4 subsets—naive (N) and memory (M) CD154+ T-helper (Th) and T-cytotoxic (Tc) cells (ie, CD154+ ThN, CD154+ ThM, CD154+ TcN, and CD154+ TcM, respectively)—in the MLR of single blood samples obtained from 32 children with SBTx within 60 days of SBTx biopsy. Children showing ACR in these biopsies were termed Rejectors. The ratio of donor-induced to third-party–induced CD154+ T cells was called the immunoreactivity index (IR). We hypothesized that IR >1 denoted increased donor-specific alloreactivity and increased risk of rejection; in contrast, IR Results Rejectors showed significantly greater numbers of donor-specific CD154+ T-cell subsets. Logistic regression analysis and leave-one-out cross validation followed by receiver operating characteristic analysis showed that, among the 4 subsets, IR ≥1.23 for CD154+ TcM identified Rejectors with a sensitivity and specificity of 93% and 88%. Also, a significant negative correlation was observed between CD154 expression and CTLA4 expression in allospecific Tc (Spearman's rho = –0.616, P = .006) but not in Th. Conclusion Allospecific CD154+ TcM identify rejection-prone children with SBTx.
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Allospecific CD154+ T-cells associate with rejection risk after pediatric liver transplantation
American Journal of Transplantation, 2008Co-Authors: Chethan Ashokkumar, George V Mazariegos, Brandon W Higgs, Anjan Talukdar, Qing Sun, Janine E. Janosky, Patrick Wilson, Ronald Jaffe, Anthony J. Demetris, Jennifer DobbersteinAbstract:Antigen-specific T-cells, which express CD154 rapidly, but remain untested in alloimmunity, were measured with flow cytometry in 16-hour MLR of 58 identically-immunosuppressed children with liver transplantation (LTx), to identify Rejectors (who had experienced biopsyproven rejection within 60 days post-transplantation). Thirty one children were sampled once, cross-sectionally. Twenty seven children were sampled longitudinally, pre-LTx, and at 1–60 and 61–200 days after LTx. Results were correlated with proliferative alloresponses measured by CFSE-dye dilution (n=23), and CTLA4, a negative T-cell costimulator, which antagonizes CD154-mediated effects (n=31). In cross-sectional observations, logistic regression and leave-oneout cross-validation identified donor-specific, CD154+T-cytotoxic (Tc)-memory cells as best associated with rejection outcomes. In the longitudinal cohort, 1) the association between CD154+Tc-memory cells and rejection outcomes was replicated with sensitivity/specificity 92.3%/84.6% for observations at 1–60 days, and 2) elevated pre-LTx CD154+Tc-memory cell responses were associated with significantly increased incidence (p=0.02) and hazard (HR=7.355) of rejection in survival/proportional hazard analysis. CD154 expression correlated with proliferative alloresponses (r=0.835, p=7.1e-07), and inversely with CTLA4 expression of allospecific CD154+Tc-memory cells (r=−0.706, p=3.0e-05). Allospecific CD154+T-helpermemory cells, not CD154+Tc-memory, were inhibited by increasing Tacrolimus concentrations (p=0.026). Collectively, allospecific CD154+T-cells provide an estimate of rejection risk in children with LTx.
Yuantao Wang - One of the best experts on this subject based on the ideXlab platform.
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rapid dendritic cell activation and resistance to allotolerance induction in anti CD154 treated mice receiving cd47 deficient donor specific transfusion
Cell Transplantation, 2014Co-Authors: Yuantao Wang, Hui Wang, Roderick T Bronson, Yongguang YangAbstract:CD47-SIRPα signaling plays an important role in regulating macrophage and dendritic cell (DC) activation. Here we investigated the role of CD47 expression on donor cells in tolerance induction by combined treatment with donor-specific transfusion (DST) plus anti-CD154 mAb in a mouse model of fully MHC-mismatched heart allotransplantation. The majority of BALB/c recipient mice that received anti-CD154 and CD47(+/+) B6 splenocytes (DST) showed indefinite donor heart survival (median survival time, MST > 150 days). Donor heart survival was improved in anti-CD154-treated BALB/c mice that received CD47(+/-) (MST = 90 days) or CD47(-/-) B6 DST (MST = 42 days) when compared to the nontreated (MST = 7 days) and anti-CD154 alone-treated (MST = 15 days) controls, but significantly reduced when compared to mice receiving anti-CD154 plus CD47(+/+) B6 DST. Recipient mice treated with anti-CD154 plus CD47(-/-) or CD47(+/-) DST also showed significantly increased antidonor, but not anti-third-party, MLR responses compared to those receiving anti-CD154 and CD47(+/+) DST. Furthermore, CD47(-/-) DST induced rapid activation of CD11c(hi)SIRPα(hi)CD8α(-) DCs via a mechanism independent of donor alloantigens. These results demonstrated that CD47 expression on donor cells is essential to the success of tolerance induction by combined therapy with DST and CD40/CD154 blockade.
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rapid dendritic cell activation and resistance to allotolerance induction in anti CD154 treated mice receiving cd47 deficient donor specific transfusion
Cell Transplantation, 2014Co-Authors: Yuantao Wang, Hui Wang, Roderick T Bronson, Yongguang YangAbstract:CD47-SIRPα signaling plays an important role in regulating macrophage and dendritic cell (DC) activation. Here, we investigated the role of CD47 expression on donor cells in tolerance induction by combined treatment with donor-specific transfusion (DST) plus anti-CD154 mAb in a mouse model of fully MHC-mismatched heart allotransplantation. The majority of BALB/c recipient mice that received anti-CD154 and CD47+/+ B6 splenocytes (DST) showed indefinite donor heart survival (median survival time, MST>150d). Although donor heart survival was improved compared to non-treated (MST=7d) and anti-CD154 alone (MST=15d) controls, the graft survival time was significantly reduced in anti-CD154-treated BALB/c mice that received CD47+/− (MST=90d) or CD47−/− B6 DST (MST=42d) compared to those receiving CD47+/+ B6 DST. Recipient mice treated with anti-CD154 plus CD47−/− or CD47+/− DST also showed significantly increased anti-donor, but not anti-3rd-party, MLR responses compared to those receiving anti-CD154 and CD47+/+ DST. Furthermore, CD47−/− DST induced rapid activation of CD11chiSIRPαhiCD8α− DCs via a mechanism independent of donor alloantigens. These results demonstrate that CD47 expression on donor cells is essential to the success of tolerance induction by combined therapy with DST and CD40/CD154 blockade.
Roderick T Bronson - One of the best experts on this subject based on the ideXlab platform.
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rapid dendritic cell activation and resistance to allotolerance induction in anti CD154 treated mice receiving cd47 deficient donor specific transfusion
Cell Transplantation, 2014Co-Authors: Yuantao Wang, Hui Wang, Roderick T Bronson, Yongguang YangAbstract:CD47-SIRPα signaling plays an important role in regulating macrophage and dendritic cell (DC) activation. Here we investigated the role of CD47 expression on donor cells in tolerance induction by combined treatment with donor-specific transfusion (DST) plus anti-CD154 mAb in a mouse model of fully MHC-mismatched heart allotransplantation. The majority of BALB/c recipient mice that received anti-CD154 and CD47(+/+) B6 splenocytes (DST) showed indefinite donor heart survival (median survival time, MST > 150 days). Donor heart survival was improved in anti-CD154-treated BALB/c mice that received CD47(+/-) (MST = 90 days) or CD47(-/-) B6 DST (MST = 42 days) when compared to the nontreated (MST = 7 days) and anti-CD154 alone-treated (MST = 15 days) controls, but significantly reduced when compared to mice receiving anti-CD154 plus CD47(+/+) B6 DST. Recipient mice treated with anti-CD154 plus CD47(-/-) or CD47(+/-) DST also showed significantly increased antidonor, but not anti-third-party, MLR responses compared to those receiving anti-CD154 and CD47(+/+) DST. Furthermore, CD47(-/-) DST induced rapid activation of CD11c(hi)SIRPα(hi)CD8α(-) DCs via a mechanism independent of donor alloantigens. These results demonstrated that CD47 expression on donor cells is essential to the success of tolerance induction by combined therapy with DST and CD40/CD154 blockade.
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rapid dendritic cell activation and resistance to allotolerance induction in anti CD154 treated mice receiving cd47 deficient donor specific transfusion
Cell Transplantation, 2014Co-Authors: Yuantao Wang, Hui Wang, Roderick T Bronson, Yongguang YangAbstract:CD47-SIRPα signaling plays an important role in regulating macrophage and dendritic cell (DC) activation. Here, we investigated the role of CD47 expression on donor cells in tolerance induction by combined treatment with donor-specific transfusion (DST) plus anti-CD154 mAb in a mouse model of fully MHC-mismatched heart allotransplantation. The majority of BALB/c recipient mice that received anti-CD154 and CD47+/+ B6 splenocytes (DST) showed indefinite donor heart survival (median survival time, MST>150d). Although donor heart survival was improved compared to non-treated (MST=7d) and anti-CD154 alone (MST=15d) controls, the graft survival time was significantly reduced in anti-CD154-treated BALB/c mice that received CD47+/− (MST=90d) or CD47−/− B6 DST (MST=42d) compared to those receiving CD47+/+ B6 DST. Recipient mice treated with anti-CD154 plus CD47−/− or CD47+/− DST also showed significantly increased anti-donor, but not anti-3rd-party, MLR responses compared to those receiving anti-CD154 and CD47+/+ DST. Furthermore, CD47−/− DST induced rapid activation of CD11chiSIRPαhiCD8α− DCs via a mechanism independent of donor alloantigens. These results demonstrate that CD47 expression on donor cells is essential to the success of tolerance induction by combined therapy with DST and CD40/CD154 blockade.
Hui Wang - One of the best experts on this subject based on the ideXlab platform.
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rapid dendritic cell activation and resistance to allotolerance induction in anti CD154 treated mice receiving cd47 deficient donor specific transfusion
Cell Transplantation, 2014Co-Authors: Yuantao Wang, Hui Wang, Roderick T Bronson, Yongguang YangAbstract:CD47-SIRPα signaling plays an important role in regulating macrophage and dendritic cell (DC) activation. Here we investigated the role of CD47 expression on donor cells in tolerance induction by combined treatment with donor-specific transfusion (DST) plus anti-CD154 mAb in a mouse model of fully MHC-mismatched heart allotransplantation. The majority of BALB/c recipient mice that received anti-CD154 and CD47(+/+) B6 splenocytes (DST) showed indefinite donor heart survival (median survival time, MST > 150 days). Donor heart survival was improved in anti-CD154-treated BALB/c mice that received CD47(+/-) (MST = 90 days) or CD47(-/-) B6 DST (MST = 42 days) when compared to the nontreated (MST = 7 days) and anti-CD154 alone-treated (MST = 15 days) controls, but significantly reduced when compared to mice receiving anti-CD154 plus CD47(+/+) B6 DST. Recipient mice treated with anti-CD154 plus CD47(-/-) or CD47(+/-) DST also showed significantly increased antidonor, but not anti-third-party, MLR responses compared to those receiving anti-CD154 and CD47(+/+) DST. Furthermore, CD47(-/-) DST induced rapid activation of CD11c(hi)SIRPα(hi)CD8α(-) DCs via a mechanism independent of donor alloantigens. These results demonstrated that CD47 expression on donor cells is essential to the success of tolerance induction by combined therapy with DST and CD40/CD154 blockade.
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rapid dendritic cell activation and resistance to allotolerance induction in anti CD154 treated mice receiving cd47 deficient donor specific transfusion
Cell Transplantation, 2014Co-Authors: Yuantao Wang, Hui Wang, Roderick T Bronson, Yongguang YangAbstract:CD47-SIRPα signaling plays an important role in regulating macrophage and dendritic cell (DC) activation. Here, we investigated the role of CD47 expression on donor cells in tolerance induction by combined treatment with donor-specific transfusion (DST) plus anti-CD154 mAb in a mouse model of fully MHC-mismatched heart allotransplantation. The majority of BALB/c recipient mice that received anti-CD154 and CD47+/+ B6 splenocytes (DST) showed indefinite donor heart survival (median survival time, MST>150d). Although donor heart survival was improved compared to non-treated (MST=7d) and anti-CD154 alone (MST=15d) controls, the graft survival time was significantly reduced in anti-CD154-treated BALB/c mice that received CD47+/− (MST=90d) or CD47−/− B6 DST (MST=42d) compared to those receiving CD47+/+ B6 DST. Recipient mice treated with anti-CD154 plus CD47−/− or CD47+/− DST also showed significantly increased anti-donor, but not anti-3rd-party, MLR responses compared to those receiving anti-CD154 and CD47+/+ DST. Furthermore, CD47−/− DST induced rapid activation of CD11chiSIRPαhiCD8α− DCs via a mechanism independent of donor alloantigens. These results demonstrate that CD47 expression on donor cells is essential to the success of tolerance induction by combined therapy with DST and CD40/CD154 blockade.