Programmed death-1 controls T cell survival by regulating oxidative metabolism.

The coinhibitory receptor programmed death-1 (PD-1) maintains immune homeostasis by negatively regulating T cell function and survival. Blockade of PD-1 increases the severity of graft-versus-host disease (GVHD), but the interplay between PD-1 inhibition and T cell metabolism is not well studied. We found that both murine and human alloreactive T cells concomitantly upregulated PD-1 expression and increased levels of reactive oxygen species (ROS) following allogeneic bone marrow transplantation. This PD-1(Hi)ROS(Hi) phenotype was specific to alloreactive T cells and was not observed in syngeneic T cells during homeostatic proliferation. Blockade of PD-1 signaling decreased both mitochondrial H2O2 and total cellular ROS levels, and PD-1-driven increases in ROS were dependent upon the oxidation of fatty acids, because treatment with etomoxir nullified changes in ROS levels following PD-1 blockade. Downstream of PD-1, elevated ROS levels impaired T cell survival in a process reversed by antioxidants. Furthermore, PD-1-driven changes in ROS were fundamental to establishing a cell's susceptibility to subsequent metabolic inhibition, because blockade of PD-1 decreased the efficacy of later F1F0-ATP synthase modulation. These data indicate that PD-1 facilitates apoptosis in alloreactive T cells by increasing ROS in a process dependent upon the oxidation of fat. In addition, blockade of PD-1 undermines the potential for subsequent metabolic inhibition, an important consideration given the increasing use of anti-PD-1 therapies in the clinic.

Effector T cells require fatty acid metabolism during murine graft-versus-host disease.

Activated T cells require increased energy to proliferate and mediate effector functions, but the metabolic changes that occur in T cells following stimulation in vivo are poorly understood, particularly in the context of inflammation. We have previously shown that T cells activated during graft-versus-host disease (GVHD) primarily rely on oxidative phosphorylation to synthesize adenosine 5'-triphosphate. Here, we demonstrate that alloreactive effector T cells (Teff) use fatty acids (FAs) as a fuel source to support their in vivo activation. Alloreactive T cells increased FA transport, elevated levels of FA oxidation enzymes, up-regulated transcriptional coactivators to drive oxidative metabolism, and increased their rates of FA oxidation. Importantly, increases in FA transport and up-regulation of FA oxidation machinery occurred specifically in T cells during GVHD and were not seen in Teff following acute activation. Pharmacological blockade of FA oxidation decreased the survival of alloreactive T cells but did not influence the survival of T cells during normal immune reconstitution. These studies suggest that pathways controlling FA metabolism might serve as therapeutic targets to treat GVHD and other T-cell-mediated immune diseases.

Fear of Deportation and Associations with Mental Health Among Michigan Residents of Middle Eastern & North African Descent.

Anti-immigrant rhetoric and immigration policy enforcement in the United States over the last 2 decades has increased attention to fear of deportation as a determinant of poor health. We describe its association with mental health outcomes among Middle East and North African (MENA) residents of Michigan. Using a convenience sample of MENA residents in Michigan (n = 397), we conducted bivariate and multiple variable regression to describe the prevalence of deportation worry and examine the relationship between deportation worry and depressive symptoms (PHQ-4 scores). We found that 33% of our sample worried a loved one will be deported. Deportation worry was associated with worse mental health (p < 0.01). Immigration policies are health policies and deportation worry impacts mental and behavioral health.

The Association of Unfairness with Mental and Physical Health in a Multiethnic Sample of Adults: Cross-sectional Study.

BACKGROUND: Two psychosocial constructs that have shown consistent associations with negative health outcomes are discrimination and perceived unfairness. OBJECTIVE: The current analyses report the effects of discrimination and unfairness on medical, psychological, and behavioral outcomes from a recent cross-sectional survey conducted in a multiethnic sample of adults in Michigan. METHODS: A cross-section survey was collected using multiple approaches: community settings, telephone-listed sample, and online panel. Unfairness was assessed with a single-item previously used in the Whitehall study, and everyday discrimination was assessed with the Williams 9-item scale. Outcomes included mental health symptoms, past-month cigarette use, past-month alcohol use, past-month marijuana use, lifetime pain medication use, and self-reported medical history. RESULTS: A total of 2238 usable surveys were collected. In bivariate analyses, higher unfairness values were significantly associated with lower educational attainment, lower age, lower household income, and being unmarried. The highest unfairness values were observed for African American and multiracial respondents followed by Middle Eastern or North African participants. Unfairness was significantly related to worse mental health functioning, net adjustment for sociodemographic variables, and everyday discrimination. Unfairness was also related to self-reported history of depression and high blood pressure although, after including everyday discrimination in the model, only the association with depression remained significant. Unfairness was significantly related to 30-day marijuana use, 30-day cigarette use, and lifetime opiate use. CONCLUSIONS: Our findings of a generally harmful effect of perceived unfairness on health are consistent with prior studies. Perceived unfairness may be one of the psychological pathways through which discrimination negatively impacts health. Future studies examining the relationships we observed using longitudinal data and including more objective measures of behavior and health status are needed to confirm and extend our findings.

Development of an Ethnic Identity Measure for Americans of Middle Eastern and North African Descent: Initial Psychometric Properties, Sociodemographic, and Health Correlates.

BACKGROUND: Southeast Michigan is home to the second largest Middle Eastern and North African (MENA) US population. There is increasing interest in understanding correlates of psychosocial outcomes and health behaviors in this growing population. One potentially important health correlate is ethnic identity (EI). This paper reports the development, validity, and initial correlates of a new measure of MENA identity named the MENA-IM. METHODS: We used convenience sampling at locations frequented by individuals of MENA descent in southeast Michigan. We also measured EI centrality, religiosity, cultural mistrust, substance use, and health status to assess convergent and divergent validity. Exloratory and Confirmatory Factor Analysis identified three subscales, which were valid for both Arab and Chaldean respondents and were named (1) MENA cultural affiliation, (2) MENA media use, and (3) multicultural affiliation. We also created and tested a 20-item, single-factor version. RESULTS: We obtained data from 378 adults, 73% of whom identified as Arab and 27% as Chaldean. MENA-IM scores were higher among older, lower-educated, lower-income, non-US born, and Arabic-speaking respondents. Arab respondents reported significantly higher scores than Chaldeans. MENA-IM scores were positively associated with EI centrality and religiosity. Higher MENA-IM scores were found among those not reporting use of marijuana, alcohol, and opiates. Higher MENA-IM scores were also found among those without a self-reported history of heart disease and among those with better mental health status. DISCUSSION: The MENA-IM has strong psychometric properties and demonstrated initial evidence of convergent and discriminant validity. In general, values on the measure were associated with better psychosocial and health status. How the measure performs with MENA populations outside of Michigan and how it may relate to other health outcomes merit investigation.

Study protocol: A Randomized Controlled Trial of a Comprehensive Breast Cancer Treatment Patient Decision Tool (iCanDecide).

BACKGROUND: Patients newly diagnosed with breast cancer face a series of complex decisions regarding locoregional and systemic treatment. There is a need to improve the quality of locoregional and systemic decisions for breast cancer patients, and to help patients understand the role of evaluative tests in this decision process. We are now conducting a randomized controlled trial (RCT) of an online decision tool-called iCanDecide, which we expect will help patients with these difficult decisions. Furthermore, the results of this RCT will be highly relevant to future breast cancer patients making these decisions and to their clinicians. METHODS: This is a two-arm randomized controlled trial with the target of 222 participants per arm. Participants are recruited from 25 surgical practices (total 40 surgeons) and 2 medical oncology practices (total 2 oncologists) in Michigan, Georgia, Tennessee, and California. Participants are newly-diagnosed female breast cancer patients between 21 and 84 years, with stage I-II invasive breast cancer or ductal carcinoma in situ (DCIS) and who are eligible for and considering either mastectomy or lumpectomy with radiation, and who may be eligible for adjuvant systemic treatment.The RCT tests an interactive, tailored website, called iCanDecide (intervention arm), compared to a static version of the website (control arm). The static control arm is designed to include the same basic content as the intervention version, but without tailoring and interactive features. The primary outcome includes the rate of making a high-quality decision. The hypothesis is that patients randomized to the interactive version of iCanDecide will have higher rates of high quality decisions (informed and values-concordant), and will appraise their decision-making process more positively, for both surgical and systemic treatment. DISCUSSION: The goal of this study is to evaluate the impact of the iCanDecide interactive website on decision-making for locoregional and systemic breast cancer treatments. The results of this study will be important for future breast cancer patients and their clinicians as we determine how to better individualize decision making across this complex treatment landscape.

Mutants of listeriolysin O for enhanced liposomal delivery of macromolecules.

Delivery of macromolecules into the cytosolic space of eukaryotic cells is a pressing challenge in biopharmaceutics. Macromolecules are often encapsulated into liposomes for protection and improved distribution, but the their size often induces endocytosis of the vehicle at the target site, leading to degradation of the cargo. Listeriolysin O is a key virulence factor of Listeria monocytogenes that forms pores in the endosomal membrane, ultimately allowing the bacterium to escape into the cytosol. This function of LLO has been used to improve cytosolic delivery of liposomally encapsulated macromolecules in a number of instances, but its innate toxicity and immunogenicity have prevented it from achieving widespread acceptance. Through site-directed mutagenesis, this study establishes a mutant of LLO (C484S) with enhanced activity, allowing for a reduction in the amount of LLO used for future applications in liposomal drug delivery.