Baylor Research Institute

Alaoui, L., G. Palomino, S. Zurawski, G. Zurawski, S. Coindre, N. Dereuddre-Bosquet, C. Lecuroux, C. Goujard, B. Vaslin, C. Bourgeois, P. Roques, R. Le Grand, O. Lambotte and B. Favier (2018). “Early SIV and HIV infection promotes the LILRB2/MHC-I inhibitory axis in cDCs.” Cell Mol Life Sci 75(10): 1871-1887.

Full text of this article.

Classical dendritic cells (cDCs) play a pivotal role in the early events that tip the immune response toward persistence or viral control. In vitro studies indicate that HIV infection induces the dysregulation of cDCs through binding of the LILRB2 inhibitory receptor to its MHC-I ligands and the strength of this interaction was proposed to drive disease progression. However, the dynamics of the LILRB2/MHC-I inhibitory axis in cDCs during early immune responses against HIV are yet unknown. Here, we show that early HIV-1 infection induces a strong and simultaneous increase of LILRB2 and MHC-I expression on the surface of blood cDCs. We further characterized the early dynamics of LILRB2 and MHC-I expression by showing that SIVmac251 infection of macaques promotes coordinated up-regulation of LILRB2 and MHC-I on cDCs and monocytes/macrophages, from blood and lymph nodes. Orientation towards the LILRB2/MHC-I inhibitory axis starts from the first days of infection and is transiently induced in the entire cDC population in acute phase. Analysis of the factors involved indicates that HIV-1 replication, TLR7/8 triggering, and treatment by IL-10 or type I IFNs increase LILRB2 expression. Finally, enhancement of the LILRB2/MHC-I inhibitory axis is specific to HIV-1 and SIVmac251 infections, as expression of LILRB2 on cDCs decreased in naturally controlled chikungunya virus infection of macaques. Altogether, our data reveal a unique up-regulation of LILRB2 and its MHC-I ligands on cDCs in the early phase of SIV/HIV infection, which may account for immune dysregulation at a critical stage of the anti-viral response.

Majtan, T., E. M. Bublil, I. Park, E. Arning, T. Bottiglieri, F. Glavin and J. P. Kraus (2018). “Pharmacokinetics and pharmacodynamics of PEGylated truncated human cystathionine beta-synthase for treatment of homocystinuria.” Life Sci 200: 15-25.

Full text of this article.

AIMS: PEGylated human truncated cystathionine beta-synthase, lacking the C-terminal regulatory domain (PEG-CBS), is a promising preclinical candidate for enzyme replacement therapy in homocystinuria (HCU). It was designed to function as a metabolic sink to decrease the severely elevated plasma and tissue homocysteine concentrations. In this communication, we evaluated pharmacokinetics (PK), pharmacodynamics (PD) and sub-chronic toxicity of PEG-CBS in homocystinuric mice, wild type rats and monkeys to estimate the minimum human efficacious dose for clinical trials. MAIN METHODS: Animal models received single or multiple doses of PEG-CBS. Activity of PEG-CBS and sulfur amino acid metabolites were determined in plasma and used to determine PK and PD. KEY FINDINGS: The plasma half-lives of PEG-CBS after a single subcutaneous (SC) injection were approximately 20, 44 and 73h in mouse, rat and monkey, respectively. The SC administration of PEG-CBS resulted in a significant improvement or full correction of metabolic imbalance in both blood and tissues of homocystinuric mice. The PD of PEG-CBS in mouse was dose-dependent, but less than dose-proportional, with the maximal efficacy achieved at 8mg/kg. PEG-CBS was well-tolerated in mice and monkeys, but resulted in dose-dependent minimal-to-moderate inflammation at the injection sites and vacuolated macrophages in rats. Allometric scaling of animal data was linear and the estimated human efficacious dose was determined as 0.66mg/kg administered once a week. SIGNIFICANCE: These results provide critical preclinical data for the design of first-in-human PEG-CBS clinical trial.

Betts, A. C., K. Froehlich-Grobe, S. Driver, D. Carlton and M. K. Kramer (2018). “Reducing barriers to healthy weight: Planned and responsive adaptations to a lifestyle intervention to serve people with impaired mobility.” Disabil Health J 11(2): 315-323.

Full text of this article.

BACKGROUND: People with impaired mobility (IM) disabilities have a higher prevalence of obesity and obesity-related chronic conditions; however, lifestyle interventions that address the unique needs of people with IM are lacking. OBJECTIVE: This paper describes an adapted evidence-based lifestyle intervention developed through community-based participatory research (CBPR). METHODS: Individuals with IM, health professionals, disability group representatives, and researchers formed an advisory board to guide the process of thoroughly adapting the Diabetes Prevention Program Group Lifestyle Balance (DPP GLB) intervention after a successful pilot in people with IM. The process involved two phases: 1) planned adaptations to DPP GLB content and delivery, and 2) responsive adaptations to address issues that emerged during intervention delivery. RESULTS: Planned adaptations included combining in-person sessions with conference calls, providing arm-based activity trackers, and adding content on adaptive cooking, adaptive physical activity, injury prevention, unique health considerations, self-advocacy, and caregiver support. During the intervention, participants encountered numerous barriers, including health and mental health issues, transportation, caregivers, employment, adjusting to disability, and functional limitations. We addressed barriers with responsive adaptations, such as supporting electronic self-monitoring, offering make up sessions, and adding content and activities on goal setting, problem solving, planning, peer support, reflection, and motivation. CONCLUSIONS: Given the lack of evidence on lifestyle change in people with disabilities, it is critical to involve the community in intervention planning and respond to real-time barriers as participants engage in change. A randomized controlled trial (RCT) is underway to examine the usability, feasibility, and preliminary effectiveness of the adapted intervention.

Saravanan, P. B., M. A. Kanak, C. A. Chang, C. Darden, G. Yoshimatsu, M. C. Lawrence and B. Naziruddin (2018). “Islet damage during isolation as assessed by miRNAs and the correlation of miRNA levels with posttransplantation outcome in islet autotransplantation.” Am J Transplant 18(4): 982-989.

Full text of this article.

High-quality pancreatic islets are essential for better posttransplantation endocrine function in total pancreatectomy with islet autotransplantation (TPIAT), yet stress during the isolation process affects quality and yield. We analyzed islet-enriched microRNAs (miRNAs) -375 and -200c released during isolation to assess damage and correlated the data with posttransplantation endocrine function. The absolute concentration of miR-375, miR-200c, and C-peptide was measured in various islet isolation steps, including digestion, dilution, recombination, purification, and bagging, in 12 cases of TPIAT. Posttransplantation glycemic control was monitored through C-peptide, hemoglobin A1c , insulin requirement, and SUITO index. The amount of miR-375 released was significantly higher during enzymatic digestion followed by the islet bagging (P < .001). Mir-200c mirrored these changes, albeit at lower concentrations. In contrast, the C-peptide amount was significantly higher in the purification and bagging steps (P < .001). Lower amounts of miR-375 were associated with a lower 6-month insulin requirement (P = .01) and lower hemoglobin A1c (P = .04). Measurement of the absolute quantity of miRNA-375 and -200c released during islet isolation is a useful tool to assess islet damage. The quantity of released miRNA is indicative of posttransplantation endocrine function in TPIAT patients.

Ross, R. D., R. C. Shah, S. Leurgans, T. Bottligieri, R. S. Wilson and D. R. Sumner (2018). “Circulating Dkk1 and TRAIL are Associated with Cognitive Decline in Community-Dwelling, Older Adults with Cognitive Concerns.” J Gerontol A Biol Sci Med Sci. Feb 8. [Epub ahead of print].

Full text of this article.

Background: Osteoporosis and Alzheimer’s disease (AD) are common diseases of aging that would seem to be unrelated, but may be linked through the influence of bone-derived signals on brain function. The current study aimed to investigate the relationship between circulating levels of bone-related biomarkers and cognition. Methods: The population included 103 community-dwelling older individuals with memory concerns but without cognitive impairment. A global cognition summary measure was collected at baseline and 6, 12, and 18-months post-enrollment by converting raw scores from 19 cognitive function tests to z-scores and averaging. Baseline plasma concentrations of bone-related biomarkers, including undercarboxylated, carboxylated, and total osteocalcin, parathyroid hormone (PTH), C-terminal telopeptide of collagen 1 (CTX-1), procollagen type 1 amino-terminal propeptide (PINP), osteoprotegrin (OPG), osteopontin (OPN), Dickkopf WNT signaling pathway inhibitor 1 (Dkk1), sclerostin, and amyloid beta peptides (Abeta40 and Abeta42) were measured. Results: Using sex, age, and education-adjusted mixed-effects models, we found that baseline levels of TRAIL (p<0.001), Dkk1 (p=0.014), and CTX-1 (p=0.046) were related to the annual rate of change of global cognition over the 18-month follow-up. In cognitive domain-specific analysis, baseline TRAIL was found to be positively related to the annual rate of change in episodic (p<0.001) and working memory (p=0.016) and baseline Dkk1 was positively related to semantic memory (p=0.027) and negatively related to working memory (p=0.016). Conclusions: These results further confirm the link between bone and brain health and suggest that circulating levels of bone-related biomarkers may have diagnostic potential to predict worsening cognition.