Lamina propria phagocytes are key mediators of inflammatory bowel disease (IBD). We aimed to understand the transcriptomic and functional differences in these cells based on location, disease type, ...inflammation state, and medication use in patients with IBD.
Phagocytic immune cells in the lamina propria, as defined by the marker CD11b, were isolated from 54 unique patients (n = 111 gut mucosal biopsies). We performed flow cytometry for cell phenotyping (n = 30) and RNA sequencing with differential gene expression analysis (n = 58). We further cultured these cells in vitro and exposed them to janus kinase inhibitors to measure cytokine output (n = 27). Finally, we matched patient genomic data to our RNA sequencing data to perform candidate gene expression quantitative trait locus analysis (n = 34).
We found distinct differences in gene expression between CD11b+ cells from the colon vs ileum, as well as in different inflammatory states and, to a lesser degree, IBD types (Crohn’s disease or ulcerative colitis). These genes mapped to targetable immune pathways and metabolic and cancer pathways. We further explored the janus kinase-signal transducer and activator of transcription pathway, which was upregulated across many comparisons including in biopsies from anti–tumor necrosis factor refractory patients. We found that isolated CD11b+ cells treated with janus kinase inhibitors had decreased secretion of cytokines tumor necrosis factorα and interleukin-8 (P ≤ .05). We also found 3 genetic variants acting as expression quantitative trait loci (P ≤ .1) within our CD11b+ data set.
Lamina propria phagocytes from IBD mucosa provide pathogenetic clues on the nature of treatment refractoriness and inform new targets for therapy.
Prevention or treatment of relapsed lymphoid malignancies after hematopoietic stem cell transplantation (HSCT) requires novel strategies. We hypothesized that antitumor-cell responses could be ...enhanced by the addition of lenalidomide to the cytotoxic T-lymphocyte-associated protein 4 inhibitor ipilimumab.
We conducted a phase II investigator-initiated trial to assess the safety and activity of ipilimumab and lenalidomide in patients with lymphoid malignancies that relapsed after allogeneic HSCT and in high-risk patients after autologous HSCT. Patients received 10 mg of oral lenalidomide daily for 21 days followed by intravenous ipilimumab at 3 mg/kg bodyweight. The regimen was repeated 4 weeks later for a total of four treatments.
We enrolled 17 patients (10 allogeneic and seven autologous transplant recipients). Immune-mediated toxicity was limited to one patient with asymptomatic hypothyroidism and one with dermatitis in the allogeneic and autologous groups, respectively. One allogeneic transplant recipient had a flare of prior GVHD while taking lenalidomide that precluded further treatment. All others finished treatment without GVHD. Four of 10 patients in the allogeneic group had complete responses (three of which were durable at 19+, 21+, and 32+ months), and three had partial responses. The disease in six of seven patients in the autologous group remains in remission. The groups had similar immune responses, including a two- to threefold increase in inducible ICOS
CD4
FoxP3
T-cell number.
Our early-phase data suggested that ipilimumab plus lenalidomide is well tolerated after HSCT. Adverse events did not differ significantly between the allogeneic and autologous groups.
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