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IntroductionIt is unknown how intestinal B cell populations and B cell receptor (BCR) repertoires are established and maintained over time in humans. Following intestinal transplantation (ITx), surveillance ileal mucosal biopsies provide a unique opportunity to map the dynamic establishment of recipient gut lymphocyte populations in immunosuppressed conditions.MethodsUsing polychromatic flow cytometry that includes HLA allele group-specific antibodies distinguishing donor from recipient cells along with high throughput BCR sequencing, we tracked the establishment of recipient B cell populations and BCR repertoire in the allograft mucosa of ITx recipients.ResultsWe confirm the early presence of naïve donor B cells in the circulation (donor age range: 1-14 years, median: 3 years) and, for the first time, document the establishment of recipient B cell populations, including B resident memory cells, in the intestinal allograft mucosa (recipient age range at the time of transplant: 1-44 years, median: 3 years). Recipient B cell repopulation of the allograft was most rapid in infant (

Abstract Background Celiac disease (CD) is characterized histologically by inflammation and villous atrophy. Villous atrophy is thought to result from a disruption of epithelial cellular proliferation and death. Epithelial cells in intestinal mucosa normally proliferate in the crypts and migrate towards the lumen, eventually dying. Apoptotic bodies in crypts are usually abnormal and are associated with certain disease states. The presence of crypt apoptosis in celiac disease has not been thoroughly examined by routine histologic assessment of crypt apoptotic body count (ABC). Methods We quantified the ABC in duodenal biopsies from celiac patients before and after initiation of a gluten-free diet (GFD). We examined twenty-three duodenal biopsies from adult patients with celiac disease at diagnosis and following GFD and determined the maximum ABC in 10 consecutive crypts. Fourteen biopsies from heartburn patients served as controls. Results Mean duration between paired biopsies was 2.9 (0.5–8.5) years. Mean maximum ABC in active celiac disease was 5.44 per crypt and decreased to 2.60 with GFD (p =

Immune checkpoint inhibitors have demonstrated significant efficacy in the treatment of a variety of cancers, however their therapeutic potential is limited by abstruse immune related adverse events. Currently, no robust animal model exists of checkpoint inhibitor-induced adverse events. Establishing such a model will improve our mechanistic understanding of this process, which in turn will inform design of improved therapies. We developed a mouse model to determine inflammatory toxicities in response to dual checkpoint blockade in the presence of syngeneic tumors. Mice from susceptible genetic backgrounds received intraperitoneal injections of anti-mouse PD-1 and CTLA-4 antibodies. The mice were monitored for weight loss and histologic evidence of inflammation. Blood was collected for basic metabolic panels and titers of anti-nuclear antibodies. In parallel, mice were also treated with prednisolone, which is commonly used to treat immune related adverse events among cancer patients. Among all the genetic backgrounds, B6/lpr mice treated with anti-CTLA-4 and anti-PD-1 antibodies developed more substantial hepatitis, pancreatitis, colitis, and pneumonitis characterized by organ infiltration of immune cells. Mice that developed tissue infiltration demonstrated high serum levels of glucose and high titers of anti-nuclear antibodies. Finally, while administration of prednisolone prevented the development of the inflammatory adverse events, it also abrogated the protective anti-tumor effect of the checkout inhibitors. Genetic background and treatment modalities jointly modified the inflammatory adverse events in tumor bearing mice, suggesting a complex mechanism for checkpoint inhibitor-related inflammation. Future studies will assess additional genetic susceptibility factors and will examine possible contributions from the administration of other anti-inflammatory drugs.