Lymphoproliferative disease in the rectum 4 years after local mesenchymal stromal cell therapy for refractory perianal Crohn's fistulas:a case report

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Fecal Microbiota Transplantation for Immune Checkpoint Inhibitor-Induced Colitis Is Safe and Contributes to Recovery: Two Case Reports

Immune checkpoint inhibitors (ICIs) have improved the prognosis in multiple cancer types. However, ICIs can induce immune-related adverse events such as immune-mediated enterocolitis (IMC). The gut microbiota may be implicated in IMC development. Therefore, we investigated fecal microbiota transplantation (FMT) as a treatment option for 2 patients with metastatic cancer suffering from refractory IMC. The patients were treated with, respectively, 1 and 3 FMTs after vancomycin pre-treatment. We monitored defecation frequency, fecal calprotectin, and microbiota composition. After FMT, both patients improved in defecation frequency, were discharged from the hospital, and received lower dosage of immunosuppressive therapy. Patient 1 developed an invasive pulmonary aspergillosis deemed to be related to prolonged steroid exposure. Patient 2 suffered from a Campylobacter jejuni infection after the first FMT and was treated with meropenem, resulting in a low-diversity microbiota profile and increased calprotectin levels and defecation frequency. After a second and third FMT, bacterial diversity increased and defecation frequency and calprotectin levels decreased. Pre-FMT, both patients showed low bacterial richness, but varying bacterial diversity. After FMT, diversity and richness were similar to healthy donor levels. In conclusion, FMT resulted in improvement of IMC symptoms and corresponding microbial changes in 2 cancer patients with refractory IMC. While more research is warranted, microbiome-modulation could be a promising new therapeutic option for IMC

Crohn’s Disease-Associated and Cryptoglandular Fistulas: Differences and Similarities

Perianal fistulas are defined as pathological connections between the anorectal canal and the perianal skin. Most perianal fistulas are cryptoglandular fistulas, which are thought to originate from infected anal glands. The remainder of the fistulas mainly arises as complications of Crohn’s disease (CD), trauma, or as a result of malignancies. Fistulas in CD are considered as a consequence of a chronic and transmural inflammatory process in the distal bowel and can, in some cases, even precede the diagnosis of CD. Although both cryptoglandular and CD-associated fistulas might look similar macroscopically, they differ considerably in their complexity, treatment options, and healing rate. Therefore, it is of crucial importance to differentiate between these two types of fistulas. In this review, the differences between CD-associated and cryptoglandular perianal fistulas in epidemiology, pathogenesis, and clinical management are discussed. Finally, a flow chart is provided for physicians to guide them when dealing with patients displaying their first episode of perianal fistulas

Local but not systemic administration of mesenchymal stromal cells ameliorates fibrogenesis in regenerating livers

Chronic liver injury leads to the accumulation of myofibroblasts resulting in increased collagen deposition and hepatic fibrogenesis. Treatments specifically targeting fibrogenesis are not yet available. Mesenchymal stromal cells (MSCs) are fibroblast-like stromal (stem) cells, which stimulate tissue regeneration and modulate immune responses. In the present study we assessed whether liver fibrosis and cirrhosis can be reversed by treatment with MSCs or fibroblasts concomitant to partial hepatectomy (pHx)-induced liver regeneration. After carbon tetrachloride-induced fibrosis and cirrhosis, mice underwent a pHx and received either systemically or locally MSCs in one of the two remaining fibrotic/cirrhotic liver lobes. Eight days after treatment, liver fibrogenesis was evaluated by Sirius-red staining for collagen deposition. A significant reduction of collagen content in the locally treated lobes of the regenerated fibrotic and cirrhotic livers was observed in mice that received high dose MSCs. In the non-MSC-treated counterpart liver lobes no changes in collagen deposition were observed. Local fibroblast administration or intravenous administration of MSCs did not ameliorate fibrosis. To conclude, local administration of MSCs after pHx, in contrast to fibroblasts, results in a dose-dependent on-site reduction of collagen deposition in mouse models for liver fibrosis and cirrhosis.status: publishe

Targeting Endoglin-Expressing Regulatory T Cells in the Tumor Microenvironment Enhances the Effect of PD1 Checkpoint Inhibitor Immunotherapy

Purpose: Endoglin is a coreceptor for TGFb ligands that is highly expressed on proliferating endothelial cells and other cells in the tumor microenvironment. Clinical studies have noted increased programmed cell death (PD)-1 expression on cytotoxic T cells in the peripheral blood of patients with cancer treated with TRC105, an endoglin-targeting antibody. In this study, we investigated the combination of endoglin antibodies (TRC105 and M1043) with an anti-PD1 antibody. Experimental Design: The combination anti-endoglin/anti-PD1 antibodies was tested in four preclinical mouse models representing different stages of cancer development. To investigate the underlying mechanism, Fc-receptor–knockout mice were used complemented with depletion of multiple immune subsets in mice. Tumor growth and the composition of immune infiltrate were analyzed by flow cytometry. Finally, human colorectal cancer specimens were analyzed for presence of endoglin-expressing regulatory T cells (Treg). Results: In all models, the combination of endoglin antibody and PD1 inhibition produced durable tumor responses, leading to complete regressions in 30% to 40% of the mice. These effects were dependent on the presence of Fcg receptors, indicating the involvement of antibody-dependent cytotoxic responses and the presence of CD8þ cytotoxic T cells and CD4þ Th cells. Interestingly, treatment with the endoglin antibody, TRC105, significantly decreased the number of intratumoral Tregs. Endoglin-expressing Tregs were also detected in human colorectal cancer specimens. Conclusions: Taken together, these data provide a rationale for combining TRC105 and anti-PD1 therapy and provide additional evidence of endoglin's immunomodulatory role

Contribution of CD3+CD8- and CD3+CD8+ T Cells to TNF-α Overexpression in Crohn Disease–Associated Perianal Fistulas and Induction of Epithelial-Mesenchymal Transition in HT-29 Cells

Background Fistulas represent a frequent and severe complication in patients with Crohn disease (CD). Tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta, and interleukin (IL)-13 are known to trigger epithelial-mesenchymal transition (EMT), promoting fistula formation. Here, we investigated the role of T-lymphocytes (T cells) in fistula pathogenesis. Methods CD3+CD8-, CD3+CD8+, or CD45+CD3- cells from healthy volunteers, patients with CD, and patients with CD with perianal fistula were co-cultured with HT-29 cells. The EMT, cytokine production, and mRNA expression were analyzed. Perianal CD fistula specimens were immunohistochemically stained for cytokines and their receptors. The effect of cytokines on EMT induction was investigated using an EMT spheroid model. Results Patients with CD with fistula revealed more CD3+CD8- and less CD3+CD8+ T cells in blood than healthy control patients and patients with CD without fistula. In perianal fistula specimens, CD4+ cells—and to a lesser extent CD8+ cells—were highly present around fistula tracts. When co-cultured with HT-29 cells, both cell subsets promoted EMT-related gene expression and TNF-α production in a time-dependent manner. The CD3+CD8- T cells from patients with CD with fistula also produced higher amounts of IL-13 than cells from healthy control patients or patients with CD without a fistula. We found that IL-22 and IL-22Rα1 were highly expressed in perianal CD fistula specimens and that IL-22 cotreatment potentiated TNF-α-induced EMT in HT-29 spheroids. Conclusions Our data indicate that both CD3+CD8- and CD3+CD8+ T cells play an important role in the pathogenesis of perianal CD fistulas by the secretion of TNF-α. Our data support clinical evidence indicating that anti-TNF-α therapy is effective in fistula treatment and identify IL-13 and IL-22 as possible novel therapeutic targets for fistula therapy

Intraluminal Injection of Mesenchymal Stromal Cells in Spheroids Attenuates Experimental Colitis

Intraluminally injected MSC spheroids at least partially attenuate experimental colitis, with fewer phagocytes and proinflammmatory cytokines, when a high dose of MSCs in spheroids was administered.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Long-term Evaluation of Allogeneic Bone Marrow-derived Mesenchymal Stromal Cell Therapy for Crohn's Disease Perianal Fistulas

BACKGROUND AND AIMS: The long-term safety and efficacy of allogeneic bone marrow-derived mesenchymal stromal cell [bmMSC] therapy in perianal Crohn's disease [CD] fistulas is unknown. We aimed to provide a 4-year clinical evaluation of allogeneic bmMSC treatment of perianal CD fistulas. METHODS: A double-blind dose-finding study for local bmMSC therapy in 21 patients with refractory perianal fistulising Crohn's disease was performed at the Leiden University Medical Center in 2012-2014. All patients treated with bmMSCs [1 x 107 bmMSCs cohort 1, n = 5; 3 × 107 bmMSCs cohort 2, n = 5; 9 × 107 bmMSCs cohort 3, n = 5] were invited for a 4-year evaluation. Clinical events were registered, fistula closure was evaluated, and anti-human leukocyte antigen [HLA] antibodies were assessed. Patients were also asked to undergo a pelvic magnetic resonance imaging [MRI] and rectoscopy. RESULTS: Thirteen out of 15 patients [87%] treated with bmMSCs were available for long-term follow-up. Two non-MSC related malignancies were observed. No serious adverse events thought to be related to bmMSC therapy were found. In cohort 2 [n = 4], all fistulas were closed 4 years after bmMSC therapy. In cohort 1 [n = 4] 63%, and in cohort 3 [n = 5] 43%, of the fistulas were closed, respectively. In none of the patients anti-HLA antibodies could be detected 24 weeks and 4 years after therapy. Pelvic MRI showed significantly smaller fistula tracts after 4 years. CONCLUSIONS: Allogeneic bmMSC therapy for CD-associated perianal fistulas is also in the long-term a safe therapy. In bmMSC-treated patients, fistulas with closure at Week 24 were still closed after 4 years