Differences in Peripheral and Tissue Immune Cell Populations Following Haematopoietic Stem Cell Transplantation in Crohn’s Disease Patients

Abstract

Background and Aims Recent studies have shown the efficacy of autologous haematopoietic stem cell transplantation [HSCT] in severely refractory Crohn’s disease [CD] patients. HSCT is thought to eliminate auto-reactive cells; however, no specific studies of immune reconstitution in CD patients are available. Methods We followed a group of CD patients [ n = 18] receiving autologous HSCT, with 50% of them achieving endoscopic drug-free remission. To elucidate the mechanisms driving efficacy, we monitored changes after HSCT in blood and intestine immune-cell composition. CD patients [ n = 22] receiving anti-tumour necrosis factor [TNF]-α were included for comparison. Results Severe immune ablation followed by HSCT induced dramatic changes in both peripheral blood T and B cells in all patients regardless of the efficacy of the treatment. Endoscopic remission at week 52 following HSCT was associated with significant intestinal transcriptional changes. A comparison of the remission signature with that of anti-TNFα identified both common and unique genes in the HSCT-induced response. Based on deconvolution analysis of intestinal biopsy transcriptome data, we show that response to HSCT, but not to anti-TNFα, is associated with an expansion of naïve B-cells, as seen in blood, and a decrease in the memory resting T-cell content. As expected, endoscopic remission, in response to both HSCT and anti-TNFα, led to a significant reduction in intestinal neutrophil and M1 macrophage content. Conclusions Peripheral blood immune remodelling after HSCT does not predict efficacy. In contrast, a profound intestinal T-cell depletion that is maintained long after transplant is associated with mucosal healing following HSCT, but not anti-TNFα.

Medical, ethical, and legal aspects of hematopoietic stem cell transplantation for Crohn’s disease in Brazil

“…Post-HSCT, compared with pre-HSCT, a robust increase in the percentage of CD4+CD25brightcells was observed: Pre-HSCT (2.6% ± 2.01%, n = 13); 6 months post-HSCT 2.91% ± 1.74% ( P < 0.05, n = 9); 1 year post-HSCT (3.55% ± 1.63%, n = 13, P < 0.05); 2 years post-HSCT (3.36% ± 1.63%, n = 10, P < 0.05); 3 years post-HSCT (3.99% ± 0.78%, n = 4, P = not significant)[ 20 ]. In another human study, when HSCT was compared to anti-tumor necrosis factor (TNF) treatment, the peripheral blood post-HSCT, unlike anti-TNF therapy, demonstrated expansion of naïve B cells and a decrease in memory T cells[ 21 ]. HSCT, but not anti-TNF therapy, induced a significant decrease in intestinal luminal T cell content[ 21 ].…”

“…In another human study, when HSCT was compared to anti-tumor necrosis factor (TNF) treatment, the peripheral blood post-HSCT, unlike anti-TNF therapy, demonstrated expansion of naïve B cells and a decrease in memory T cells[ 21 ]. HSCT, but not anti-TNF therapy, induced a significant decrease in intestinal luminal T cell content[ 21 ].…”

Inferring intestinal mucosal immune cell associated microbiome species and microbiota-derived metabolites in inflammatory bowel disease

“…To investigate changes of intestine mucosal immune cells in IBD patients relative to non-IBD controls, we estimated immune cell composition and abundance from bulk RNA-seq of intestinal biopsies in IBD patients using a few cellular composition deconvolution methods, including quanTIseq 52 , ABIS 53 , and xCell 54 . We first collected four independent datasets 19,[55][56][57] where none of the species were found to be differentially abundant or correlated with cytokine signatures. B cells (for both ABIS and quanTIseq deconvolutions) and Bacteroides ovatus, which has been used for successful monotherapy in murine colitis models 59,60 and Anaaerostipes hadrus, respectively, two butyrate producing bacteria; butyrate has protective effects in IBD [62][63][64] .…”

“…We utilized quanTIseq 52 We first selected four test data sets that include both RNA-seq data and immune cell quantity data determined by flow cytometry 19,[55][56][57] . The performance of each method was assessed by comparison of their predicted results with experimental flow cytometry measurements.…”

“…Previous studies have focused on the roles of CD4+ helper T cell subsets and demonstrated key functions of proinflammatory Th1, Th2, and Th17 cells and anti-inflammatory regulatory T cells [14][15][16] in IBD. In recent years many studies have been extended to examine changes in T cell subsets [17][18][19] , plasma cells 17,20,21 , tissue macrophages, and dendritic cells 22 to investigate pathogenesis of IBD in humans, along with the utilization of single cell RNA-seq technology to characterize changes in human intestinal cell compositions in IBD 20,23 . Evidence showed that the human intestine is massively infiltrated with plasmablasts in both CD and UC 17,20,21 , but both CD8+ memory T cells (Trm) and gut-homing CD8+ T cells in the epithelium and lamina propria colonic tissue are reduced in CD and UC relative to controls 17 .…”