Diet effects on colonic health influence the efficacy of Bin1 mAb immunotherapy for ulcerative colitis.

Ulcerative colitis (UC) is an idiopathic disease of the large intestine linked to high fat-high protein diets, a dysbiotic microbiome, and a metabolome linked to diet and/or aberrant circadian rhythms associated with poor sleeping patterns. Understanding diet-affected factors that negatively influence colonic health may offer new insights into how to prevent UC and enhance the efficacy of UC immunotherapy. In this preclinical study, we found that standard or high fiber diets in mice positively influenced their colonic health, whereas a high fat-high protein diet negatively influenced colonic health, consistent with clinical findings. Animals fed a high fat/high protein diet experienced obesity and a reduced colon length, illustrating a phenotype we suggest calling peinosis [hunger-like-condition; Greek, peina: hunger; osis: condition], as marked by a lack of nutrient energy remaining in fecal pellets. Notably, a high fat/high protein diet also led to signs of muscle weakness that could not be explained fully by weight gain. In contrast, mice on a high fiber diet ranked highest compared to other diets in terms of colon length and lack of muscle weakness. That said, mice on a high fiber diet were more prone to UC and toxic responses to immunotherapy, consistent with clinical observations. Recent studies have suggested that a standard diet may be needed to support the efficacy of immunotherapeutic drugs used to prevent and treat UC. Here we observed that protection against UC by Bin1 mAb, a passive UC immunotherapy that acts by coordinately enforcing intestinal barrier function, protecting enteric neurons, and normalizing the microbiome, was associated with increased colonic levels of healthful short-chain fatty acids (SCFA), particularly butyric acid and propionic acid, which help enforce intestinal barrier function. This work offers a preclinical platform to investigate how diet affects UC immunotherapy and the potential of dietary SCFA supplements to enhance it. Further, it suggests that the beneficial effects of passive immunotherapy by Bin1 mAb in UC treatment may be mediated to some extent by promoting increased levels of healthful SCFA.

Chimeric TIM-4 receptor-modified T cells targeting phosphatidylserine mediates both cytotoxic anti-tumor responses and phagocytic uptake of tumor-associated antigen for T cell cross-presentation.

To leverage complementary mechanisms for cancer cell removal, we developed a novel cell engineering and therapeutic strategy co-opting phagocytic clearance and antigen presentation activity into T cells. We engineered a chimeric engulfment receptor (CER)-1236, which combines the extracellular domain of TIM-4, a phagocytic receptor recognizing the "eat me" signal phosphatidylserine, with intracellular signaling domains (TLR2/TIR, CD28, and CD3ζ) to enhance both TIM-4-mediated phagocytosis and T cell cytotoxic function. CER-1236 T cells demonstrate target-dependent phagocytic function and induce transcriptional signatures of key regulators responsible for phagocytic recognition and uptake, along with cytotoxic mediators. Pre-clinical models of mantle cell lymphoma (MCL) and EGFR mutation-positive non-small cell lung cancer (NSCLC) demonstrate collaborative innate-adaptive anti-tumor immune responses both in vitro and in vivo. Treatment with BTK (MCL) and EGFR (NSCLC) inhibitors increased target ligand, conditionally driving CER-1236 function to augment anti-tumor responses. We also show that activated CER-1236 T cells exhibit superior cross-presentation ability compared with conventional T cells, triggering E7-specific TCR T responses in an HLA class I- and TLR-2-dependent manner, thereby overcoming the limited antigen presentation capacity of conventional T cells. Therefore, CER-1236 T cells have the potential to achieve tumor control by eliciting both direct cytotoxic effects and indirect-mediated cross-priming.

Retinoic acid improves baseline barrier function and attenuates TNF-α-induced barrier leak in human bronchial epithelial cell culture model, 16HBE 14o.

Retinoic acid (RA) has been shown to improve epithelial and endothelial barrier function and development and even suppress damage inflicted by inflammation on these barriers through regulating immune cell activity. This paper thus sought to determine whether RA could improve baseline barrier function and attenuate TNF-α-induced barrier leak in the human bronchial epithelial cell culture model, 16HBE14o- (16HBE). We show for the first time that RA increases baseline barrier function of these cell layers indicated by an 89% increase in transepithelial electrical resistance (TER) and 22% decrease in 14C-mannitol flux. A simultaneous, RA-induced 70% increase in claudin-4 attests to RA affecting the tight junctional (TJ) complex itself. RA was also effective in alleviating TNF-α-induced 16HBE barrier leak, attenuating 60% of the TNF-α-induced leak to 14C-mannitol and 80% of the leak to 14C-inulin. Interleukin-6-induced barrier leak was also reduced by RA. Treatment of 16HBE cell layers with TNF-α resulted in dramatic decrease in immunostaining for occludin and claudin-4, as well as a downward "band-shift" in occludin Western immunoblots. The presence of RA partially reversed TNF-α's effects on these select TJ proteins. Lastly, RA completely abrogated the TNF-α-induced increase in ERK-1,2 phosphorylation without significantly decreasing the TNF-driven increase in total ERK-1,2. This study suggests RA could be effective as a prophylactic agent in minimizing airway barrier leak and as a therapeutic in preventing leak triggered by inflammatory cascades. Given the growing literature suggesting a "cytokine storm" may be related to COVID-19 morbidity, RA may be a useful adjuvant for use with anti-viral therapies.

Prevalence and Characterization of Yoga Mentions in the Electronic Health Record.

BACKGROUND: There is a growing patient population using yoga as a therapeutic intervention, but little is known about how yoga interfaces with health care in clinical settings. PURPOSE: To characterize how yoga is documented at a large academic medical center and to systematically identify clinician-derived therapeutic use cases of yoga. METHODS: We designed a retrospective observational study using a yoga cohort (n = 30,976) and a demographically matched control cohort (n = 92,919) from the electronic health records at Penn Medicine between 2006 and 2016. We modeled the distribution of yoga notes among patients, clinicians, and clinical service departments, built a multinomial Naïve Bayes classifier to separate the notes by context-dependent use of the word yoga, and modeled associations between clinician recommendations to use yoga and 754 diagnostic codes with Fisher's exact test, setting an false discovery rate (FDR)-adjusted P-value ≤ .05 (ie, q-value) as the significance threshold. RESULTS: Yoga mentions in the electronic health record have increased 10.4-fold during the 10-year study period, with 2.6% of patients having at least 1 mention of yoga in their notes. In total, 30,976 patients, 2398 clinicians, and 41 clinical service departments were affiliated with yoga notes. The majority of yoga notes are in primary care. Nine diagnoses met the significance criteria for having an association with clinician recommendations to use yoga including Parkinson's disease (Odds ratio [OR], 6.3 [3.7 to 11.4]; q-value < 0.001), anxiety (OR, 5.8 [3.8 to 9.0]; q-value < 0.001), and backache (OR, 3.8 [2.4 to 6.3]; q-value = 0.001). CONCLUSIONS: There is a widespread and growing trend to include yoga as part of the clinical record. In practice, clinicians are recommending yoga as a nonpharmacological intervention for a subset of common chronic diseases.

Activation of the RIG-I pathway during influenza vaccination enhances the germinal center reaction, promotes T follicular helper cell induction, and provides a dose-sparing effect and protective immunity.

UNLABELLED: Pattern recognition receptors (PRR) sense certain molecular patterns uniquely expressed by pathogens. Retinoic-acid-inducible gene I (RIG-I) is a cytosolic PRR that senses viral nucleic acids and induces innate immune activation and secretion of type I interferons (IFNs). Here, using influenza vaccine antigens, we investigated the consequences of activating the RIG-I pathway for antigen-specific adaptive immune responses. We found that mice immunized with influenza vaccine antigens coadministered with 5'ppp-double-stranded RNA (dsRNA), a RIG-I ligand, developed robust levels of hemagglutination-inhibiting antibodies, enhanced germinal center reaction, and T follicular helper cell responses. In addition, RIG-I activation enhanced antibody affinity maturation and plasma cell responses in the draining lymph nodes, spleen, and bone marrow and conferred protective immunity against virus challenge. Importantly, activation of the RIG-I pathway was able to reduce the antigen requirement by 10- to 100-fold in inducing optimal influenza-specific cellular and humoral responses, including protective immunity. The effects induced by 5'ppp-dsRNA were significantly dependent on type I IFN and IPS-1 (an adapter protein downstream of the RIG-I pathway) signaling but were independent of the MyD88- and TLR3-mediated pathways. Our results show that activation of the RIG-I-like receptor pathway programs the innate immunity to achieve qualitatively and quantitatively enhanced protective cellular adaptive immune responses even at low antigen doses, and this indicates the potential utility of RIG-I ligands as molecular adjuvants for viral vaccines. IMPORTANCE: The recently discovered RNA helicase family of RIG-I-like receptors (RLRs) is a critical component of host defense mechanisms responsible for detecting viruses and triggering innate antiviral cytokines that help control viral replication and dissemination. In this study, we show that the RLR pathway can be effectively exploited to enhance adaptive immunity and protective immune memory against viral infection. Our results show that activation of the RIG-I pathway along with influenza vaccination programs the innate immunity to induce qualitatively and quantitatively superior protective adaptive immunity against pandemic influenza viruses. More importantly, RIG-I activation at the time of vaccination allows induction of robust adaptive responses even at low vaccine antigen doses. These results highlight the potential utility of exploiting the RIG-I pathway to enhance viral-vaccine-specific immunity and have broader implications for designing better vaccines in general.