Biology subjects

Furtado, G. C.

Publications and source records attributed to Furtado, G. C..

3 recordsLinked to original sources

bioRxiv2018

Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1 infected individuals

Herein, we present the first human study of anti-4{beta}7 therapy in a cohort of HIV-1 infected subjects with mild inflammatory bowel disease. 4{beta}7+ gut homing CD4+ T cells are early viral targets and contribute to HIV-1 pathogenesis, likely by seeding the gastrointestinal (GI) tract with HIV. Although, simianized anti-4{beta}7 monoclonal antibodies (Mab) have shown promise in preventing or attenuating the disease course of SIV in Non-Human Primate studies, the mechanisms of drug action remain elusive and the impact on HIV-1 persistence remains unanswered. By sampling the immune inductive and effector sites of the GI tract, we have discovered that anti-4{beta}7 therapy led to a significant and unexpected attenuation of lymphoid aggregates, most notably in the terminal ileum. Given that lymphoid aggregates serve as important sanctuary sites for establishing and maintaining viral reservoirs, their attrition by anti-4{beta}7 therapy has important implications for HIV-1 therapeutics and eradication efforts, and defines a rational basis for the continued evaluation of anti-4{beta}7 therapy in HIV-1 infection.\n\nOne Sentence SummaryAnti-4{beta}7 integrin therapy results in attrition of lymphoid aggregates within the gastrointestinal tract of HIV-1 infected individuals

immunology↗

bioRxiv2018

Interleukin 22 mediates interleukin 23-induced pathology in newborn mice by disrupting the function of intestinal and pancreatic cells

Mice expressing IL-23 constitutively in the intestine or skin fail to grow and die prematurely. These phenotypes are associated with marked changes in the levels of circulating cytokines and with changes in the transcriptome of the pancreas and intestine. Marked changes are observed in the expression of molecules involved in digestion and absorption of carbohydrates, proteins, and lipids, resulting in a malabsorptive condition. Genetic ablation of IL-22, or one of the subunits of the IL-22R in mice expressing IL-23, restores normal growth and increases the life span of the animals. Mechanistically, IL-22 acts directly at the level of pancreatic acinar cells to decrease expression of the pancreas associated transcription factor 1a (Ptfla), an important transcription factor controlling expression of genes encoding pancreatic enzymes, and acinar cell identity. The results indicate that dysregulated expression of IL-23 and IL-22 has severe consequences in newborns and reveal an unsuspected role for IL-22 in controlling pancreatic enzyme secretion and food absorption.

immunology↗

bioRxiv2018

Diet Modifies Colonic Microbiota and CD4+ T cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23

A wealth of experimental data points to immunological and environmental factors in the pathogenesis of inflammatory bowel disease (IBD). Here we study the role of IL-23, the microbiome, and the diet in the development of colitis. To promote IL-23 expression in vivo, we generated a mouse model in which IL-23 was conditionally expressed by CX3CR1+ myeloid cells, upon cyclic administration of tamoxifen in a specific diet (diet 2019). IL-23 expression induced an intestinal inflammatory disease that resembled ulcerative colitis in humans with cycles of acute disease and remission. The relapses were caused by the diet switch from the conventional diet used in our facility (diet 5053) to the diet 2019, and were not dependent on tamoxifen after the first cycle. The switch in the diet modified the microbiota, but did not alter the levels of IL-23. Colitis induction depended on the microbiota and required CD4 T lymphocytes. Colitis-inducing CD4+ T cells were found in the mesenteric lymph node and large intestine during remission and were able to trigger disease when transferred to lymphopenic mice, but only upon diet modification. The CD4 TCR repertoire in the diseased recipient Rag-/- mice had reduced diversity associated with the expansion of dominant T cell clones. These findings reveal a critical role for IL-23 in generation of a CD4+ T cell population in mice that is sensitive to a modification of intestinal bacterial flora subsequent to a dietary manipulation. Dietary changes occurring in the context of altered IL-23 expression may contribute to the onset and progression of IBD.

immunology↗