Acute graft-versus-host disease (aGVHD) is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT) and patients with steroid-refractory aGVHD have a dismal prognosis. We have previously shown that the enteroendocrine hormone glucagon-like peptide-2 (GLP-2) has tissue regenerative activity in the lower GI in mice and patients with steroid-refractory aGVHD. Here we explored the tissue protective effect of the enteroendocrine hormone gastrin for aGVHD of the stomach. We observed that aGVHD caused a loss of gastrin-producing G-cells and parietal cells (PCs) and an increase of pH in the stomach, while allogeneic T cells infiltrated the stomach wall. Pentagastrin treatment of aGVHD mice rescued the loss of PCs, normalized the pH in the stomach, increased stomach stem cell marker expression and abundance of LGR5+ cells, and changes in the stomach microbiome. Gastrin also increased the viability of stomach and small intestine organoids in vitro. Gast-/- mice experienced more severe aGVHD in the intestine and liver compared to WT mice, which was rescued by pentagastrin-treatment. In patients developing aGVHD, low gastrin levels in stomach biopsies were connected to reduced survival. Moreover, gastrin expression in the stomach correlated with aGVHD severity and tissue damage scores in independent patient cohorts. This study delineates the protective role of gastrin in aGVHD of the stomach in mice and patients and provides a rationale for therapeutic use of pentagastrin in a clinical trial for patients with aGVHD.
Abstract: The treatment landscape of B-cell non-Hodgkin lymphomas is rapidly evolving. However, few advances have occurred in marginal zone lymphoma (MZL), with a single US Food and Drug Administration-approved agent impacting the treatment landscape. Multiple factors are associated with this slower pace of progress, with a lower MZL incidence representing a significant factor. Pivotal randomized indolent lymphoma clinical trials analyzed MZL subsets without the appropriate power to capture differences between treatment arms. Furthermore, the current Lugano classification may not fully capture the presentation or treatment responses of some subtypes, preventing access to clinical trials and limiting an efficacy assessment across the disease spectrum. Thus, current MZL treatment is largely informed by single-arm studies with relatively empiric treatment sequencing among available agents. Although frontline strategies in early and advanced-stage MZL can achieve prolonged disease control, few options exist in the relapsed/refractory setting capable of achieving similar results. Emerging data demonstrate the encouraging efficacy of CD3×CD20 bispecific antibodies and antibody-drug conjugates in achieving deep responses, as well as the potential of circulating tumor DNA in risk stratification and molecular response monitoring. Compounding all these considerations, it is essential to recognize MZL as a heterogeneous group of diseases characterized by unique biology, clinical presentation, treatment response, toxicity, and survival. Nonetheless, a common characteristic across MZL subtypes is their general indolent disease course, emphasizing the need to incorporate patient-centered assessment in clinical trials to better inform the decision-making process.
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