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

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.

Figure 1. Time course of fasting C-peptide (A), Cmax (B), AUCC (C), GADA (D) and HbA1c (E) in IF group and ID group respectively.

Black circles, insulin free. Black squares, insulin dependent. X axis represents the time course relative to HSCT. A p<0.05, pre-treatment vs all follow-up time in IF group; IF vs ID group at 1 month and 12 months post-treatment. B p<0.05, pre-treatment vs all follow-up times in IF group; IF vs ID group at one month and six months post-treatment. C p<0.05, pre-treatment vs all follow-up times in IF group; IF vs ID group at 12 months post-treatment. D p = 0.036, IF vs ID group at six months post-treatment.

Figure 2. 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.

Figure 3. Sector plots of differential network analysis in IF group (A) and ID group (B).

The difference in connectivity (DiffK) is plotted on the X axis, and p values are plotted on the Y axis. Horizontal lines indicate a difference in connectivity of −0.2 and 0.2, whereas vertical lines depict a p value 0.05. Number indicates sector 1–6 and plots represent genes. The genes ploted in the sector 1 and 3 are considered as difference in connectivity.