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Acute response of peripheral blood cell to autologous hematopoietic stem cell transplantation in type 1 diabetic patient.

Zhang X, Ye L, Hu J, Tang W, Liu R, Yang M, Hong J, Wang W, Ning G, Gu W - PLoS ONE (2012)

Bottom Line: We found six patients obtained insulin free (IF group) and three remained insulin dependent (ID group); C-peptide production was significantly higher in IF group compared to ID group.The acute responses in lymphocytes at six-month follow-up include declined CD3(+)CD4(+), CD3(+)CD8(+) T cell population and recovered B cell, NK cell population in both groups but with no significant differences between the two groups; most immune-related genes and pathways were up-regulated in peripheral blood mononuclear cell (PBMC) of both groups while none of transcription factors for immune regulatory component were significantly changed; the IF group demonstrated more AHST-modified genetic events than the ID group and distinct pattern of top pathways, co-expression network as well as 'hub' genes (eg, TCF7 and GZMA) were associated with each group.AHST could improve the islet function in newly diagnosed T1D patients and elimination of the islet specific autoreactive T cells might be one of the mechanisms involved; T1D patients responded differently to AHST possibly due to the distinct transcriptional events occurring in PBMC.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Key Laboratory for Endocrine Tumors, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, School of Medicine, Shanghai Jiaotong University, Ruijin Hospital, Shanghai, People's Republic of China.

ABSTRACT

Objective: Autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) was the first therapeutic approach that can improve β cell function in type 1 diabetic (T1D) patients. This study was designed to investigate the potential mechanisms involved.

Design and methods: We applied AHST to nine T1D patients diagnosed within six months and analyzed the acute responses in peripheral blood for lymphocyte subpopulation as well as for genomic expression profiling at the six-month follow-up.

Results: We found six patients obtained insulin free (IF group) and three remained insulin dependent (ID group); C-peptide production was significantly higher in IF group compared to ID group. The acute responses in lymphocytes at six-month follow-up include declined CD3(+)CD4(+), CD3(+)CD8(+) T cell population and recovered B cell, NK cell population in both groups but with no significant differences between the two groups; most immune-related genes and pathways were up-regulated in peripheral blood mononuclear cell (PBMC) of both groups while none of transcription factors for immune regulatory component were significantly changed; the IF group demonstrated more AHST-modified genetic events than the ID group and distinct pattern of top pathways, co-expression network as well as 'hub' genes (eg, TCF7 and GZMA) were associated with each group.

Conclusions: AHST could improve the islet function in newly diagnosed T1D patients and elimination of the islet specific autoreactive T cells might be one of the mechanisms involved; T1D patients responded differently to AHST possibly due to the distinct transcriptional events occurring in PBMC.

Trial registration: ClinicalTrials.gov NCT00807651.

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Workflow of the genomic expression profiling of the PMBC in patients with type 1 diabetes.Differentially expressed genes (pre-treatment vs post-treatment) meet the criterion p<0.05 and FDR<0.05. Up, genes with higher expression after AHST. Down, genes with lower expression after AHST. Other, genes that were up-regulated in IF group and down-regulated in ID group.
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pone-0031887-g002: Workflow of the genomic expression profiling of the PMBC in patients with type 1 diabetes.Differentially expressed genes (pre-treatment vs post-treatment) meet the criterion p<0.05 and FDR<0.05. Up, genes with higher expression after AHST. Down, genes with lower expression after AHST. Other, genes that were up-regulated in IF group and down-regulated in ID group.

Mentions: Given the limited signature that can be obtained by lymphocyte population profiling we opted to additionally perform transcriptome analysis. For both the responding (IF) and non-responding (ID) patient groups, we observed that most immune-related genes were up-regulated (Table S1) and the number of significantly regulated genes was greater in the IF group compared to ID group (Figure 2). A majority of the pathway categories were observed in both IF and ID groups, but group-specific pathways also existed. These findings are summarized in Table S2, which shows the top 20 pathways commonly and differentially modified in each group. Top two pathway categories commonly identified in the two groups included (1) selective expression of chemokine receptors during T-cell polarization and (2) IL12 and Stat4 dependent signaling pathway in Th1 development. These two pathways indicated that T cell was differentiated to Th1 subset after AHST. Of interest, the IFN-γ signaling pathway was the top ranked differential pathway in the ID group. Co-expression network analysis was performed based on combined differential genes in pre-treatment and post-treatment of IF and ID group respectively. As shown in Figure S1, AHST induced a less packed co-expression network in IF group compared to ID group, shown as a significant reduced pattern of connectivity post- than pre-transplantation in IF group. The derivation of co-expression networks based on coefficient correlations of all differently modified genes identified a total of 77 and 52 ‘hub’ genes in the IF and ID groups respectively (Figure 3). The top 20 ‘hub’ genes for each group are summarized in Table S3.


Acute response of peripheral blood cell to autologous hematopoietic stem cell transplantation in type 1 diabetic patient.

Zhang X, Ye L, Hu J, Tang W, Liu R, Yang M, Hong J, Wang W, Ning G, Gu W - PLoS ONE (2012)

Workflow of the genomic expression profiling of the PMBC in patients with type 1 diabetes.Differentially expressed genes (pre-treatment vs post-treatment) meet the criterion p<0.05 and FDR<0.05. Up, genes with higher expression after AHST. Down, genes with lower expression after AHST. Other, genes that were up-regulated in IF group and down-regulated in ID group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3285188&req=5

pone-0031887-g002: Workflow of the genomic expression profiling of the PMBC in patients with type 1 diabetes.Differentially expressed genes (pre-treatment vs post-treatment) meet the criterion p<0.05 and FDR<0.05. Up, genes with higher expression after AHST. Down, genes with lower expression after AHST. Other, genes that were up-regulated in IF group and down-regulated in ID group.
Mentions: Given the limited signature that can be obtained by lymphocyte population profiling we opted to additionally perform transcriptome analysis. For both the responding (IF) and non-responding (ID) patient groups, we observed that most immune-related genes were up-regulated (Table S1) and the number of significantly regulated genes was greater in the IF group compared to ID group (Figure 2). A majority of the pathway categories were observed in both IF and ID groups, but group-specific pathways also existed. These findings are summarized in Table S2, which shows the top 20 pathways commonly and differentially modified in each group. Top two pathway categories commonly identified in the two groups included (1) selective expression of chemokine receptors during T-cell polarization and (2) IL12 and Stat4 dependent signaling pathway in Th1 development. These two pathways indicated that T cell was differentiated to Th1 subset after AHST. Of interest, the IFN-γ signaling pathway was the top ranked differential pathway in the ID group. Co-expression network analysis was performed based on combined differential genes in pre-treatment and post-treatment of IF and ID group respectively. As shown in Figure S1, AHST induced a less packed co-expression network in IF group compared to ID group, shown as a significant reduced pattern of connectivity post- than pre-transplantation in IF group. The derivation of co-expression networks based on coefficient correlations of all differently modified genes identified a total of 77 and 52 ‘hub’ genes in the IF and ID groups respectively (Figure 3). The top 20 ‘hub’ genes for each group are summarized in Table S3.

Bottom Line: We found six patients obtained insulin free (IF group) and three remained insulin dependent (ID group); C-peptide production was significantly higher in IF group compared to ID group.The acute responses in lymphocytes at six-month follow-up include declined CD3(+)CD4(+), CD3(+)CD8(+) T cell population and recovered B cell, NK cell population in both groups but with no significant differences between the two groups; most immune-related genes and pathways were up-regulated in peripheral blood mononuclear cell (PBMC) of both groups while none of transcription factors for immune regulatory component were significantly changed; the IF group demonstrated more AHST-modified genetic events than the ID group and distinct pattern of top pathways, co-expression network as well as 'hub' genes (eg, TCF7 and GZMA) were associated with each group.AHST could improve the islet function in newly diagnosed T1D patients and elimination of the islet specific autoreactive T cells might be one of the mechanisms involved; T1D patients responded differently to AHST possibly due to the distinct transcriptional events occurring in PBMC.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Key Laboratory for Endocrine Tumors, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, School of Medicine, Shanghai Jiaotong University, Ruijin Hospital, Shanghai, People's Republic of China.

ABSTRACT

Objective: Autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) was the first therapeutic approach that can improve β cell function in type 1 diabetic (T1D) patients. This study was designed to investigate the potential mechanisms involved.

Design and methods: We applied AHST to nine T1D patients diagnosed within six months and analyzed the acute responses in peripheral blood for lymphocyte subpopulation as well as for genomic expression profiling at the six-month follow-up.

Results: We found six patients obtained insulin free (IF group) and three remained insulin dependent (ID group); C-peptide production was significantly higher in IF group compared to ID group. The acute responses in lymphocytes at six-month follow-up include declined CD3(+)CD4(+), CD3(+)CD8(+) T cell population and recovered B cell, NK cell population in both groups but with no significant differences between the two groups; most immune-related genes and pathways were up-regulated in peripheral blood mononuclear cell (PBMC) of both groups while none of transcription factors for immune regulatory component were significantly changed; the IF group demonstrated more AHST-modified genetic events than the ID group and distinct pattern of top pathways, co-expression network as well as 'hub' genes (eg, TCF7 and GZMA) were associated with each group.

Conclusions: AHST could improve the islet function in newly diagnosed T1D patients and elimination of the islet specific autoreactive T cells might be one of the mechanisms involved; T1D patients responded differently to AHST possibly due to the distinct transcriptional events occurring in PBMC.

Trial registration: ClinicalTrials.gov NCT00807651.

Show MeSH