Research Spotlight

Salabert, N., B. Todorova, F. Martinon, R. Boisgard, G. Zurawski, S. Zurawski, N. Dereuddre-Bosquet, A. Cosma, T. Kortulewski, J. Banchereau, Y. Levy, R. Le Grand and C. Chapon (2016). “Intradermal injection of an anti-langerin-hivgag fusion vaccine targets epidermal langerhans cells in nonhuman primates and can be tracked in vivo.” European Journal of Immunology 46(3): 689-700.

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The development of new immunization strategies requires a better understanding of early molecular and cellular events occurring at the site of injection. The skin is particularly rich in immune cells and represents an attractive site for vaccine administration. Here, we specifically targeted vaccine antigens to epidermal Langerhans cells (LCs) using a fusion protein composed of HIV antigens and a monoclonal antibody targeting Langerin. We developed a fluorescence imaging approach to visualize, in vivo, the vaccine-targeted cells. Studies were performed in nonhuman primates (NHPs) because of their relevance as a model to assess human vaccines. We directly demonstrated that in NHPs, intradermally injected anti-Langerin-HIVGag specifically targets epidermal LCs and induces rapid changes in the LC network, including LC activation and migration out of the epidermis. Vaccine targeting of LCs significantly improved anti-HIV immune response without requirement of an adjuvant. Although the co-injection of the TLR-7/8 synthetic ligand, R-848 (resiquimod), with the vaccine, did not enhance significantly the antibody response, it stimulated recruitment of HLA-DR+ inflammatory cells to the site of immunization. This study allowed us to characterize the dynamics of early local events following the injection of a vaccine-targeted epidermal LCs and R-848.

Hundemer, G. L., A. Z. Fenves, K. M. Phillips and M. Emmett (2016). “Sodium Thiosulfate and the Anion Gap in Patients Treated by Hemodialysis.” Am J Kidney Dis. Mar 15. [Epub ahead of print]

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Calciphylaxis is a syndrome of microvascular calcification and thrombosis leading to painful purpuric skin lesions that progress to necrotic ulcers. Calciphylaxis occurs primarily in patients with ESRD, for which its prevalence has been estimated at 1% annually, and carries a high mortality rate. Increasingly, sodium thiosulfate (STS) is used off-label for treating calciphylaxis. The STS mechanism of action in this condition is unknown. One postulated mechanism is by binding to calcium phosphate salts to form soluble calcium thiosulfate, though additional antioxidant, vasodilatory, and direct inhibitory actions on vascular calcification have been proposed. Dosing of STS, which contains 12.7 mEq/g of sodium and thiosulfate, is empirical and typically 12.5 or 25 g is given during the final 30 to 60 minutes of a hemodialysis (HD) session. A retrospective study showed that 73% of patients treated for calciphylaxis with STS had clinical improvement, with 26% having complete resolution of skin lesions . . . Using an electronic database, we identified all patients with a diagnosis of calciphylaxis who were treated with STS at Massachusetts General Hospital and Brigham and Women’s Hospital between January 2005 and December 2014. . . We found that HD patients treated with STS for calciphylaxis develop an elevated anion gap that is variable and often severe. In addition, we found a dose-response effect of STS on anion gap elevation. Future studies should address the exact mechanism of how STS improves calciphylaxis, which anion accumulates with STS treatment, why such high variability in anion gap effect exists, and clinical effects of the anion gap elevation. (Excerpts from text; no abstract.)

Wu, T., C. Xie, J. Han, Y. Ye, S. Singh, J. Zhou, Y. Li, H. Ding, Q. Z. Li, X. Zhou, C. Putterman, R. Saxena and C. Mohan (2016). “Insulin-Like Growth Factor Binding Protein-4 as a Marker of Chronic Lupus Nephritis.” PLoS One 11(3): e0151491.

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Kidney biopsy remains the mainstay of Lupus Nephritis (LN) diagnosis and prognostication. The objective of this study is to identify non-invasive biomarkers that closely parallel renal pathology in LN. Previous reports have demonstrated that serum Insulin-like growth factor binding protein 4 (IGFBP-4) was increased in diabetic nephropathy in both animal models and patients. We proceeded to assess if IGFBP4 could be associated with LN. We performed ELISA using the serum of 86 patients with LN. Normal healthy adults (N = 23) and patients with other glomerular diseases (N = 20) served as controls. Compared to the healthy controls or other glomerular disease controls, serum IGFBP-4 levels were significantly higher in the patients with LN. Serum IGFBP-4 did not correlate well with systemic lupus erythematosus disease activity index (SLEDAI), renal SLEDAI or proteinuria, but it did correlate with estimated glomerular filtration rate (R = 0.609, P < 0.0001). Interestingly, in 18 patients with proliferative LN whose blood samples were obtained at the time of renal biopsy, serum IGFBP-4 levels correlated strongly with the chronicity index of renal pathology (R = 0.713, P < 0.001). IGFBP-4 emerges a potential marker of lupus nephritis, reflective of renal pathology chronicity changes.

Tecson, K. M., M. A. Silver, S. D. Brune, C. Cauthen, M. D. Kwan, J. M. Schussler, A. Vasudevan, J. A. Watts and P. A. McCullough (2016). “Impact of Enhanced External Counterpulsation on Heart Failure Rehospitalization in Patients With Ischemic Cardiomyopathy.” Am J Cardiol 117(6): 901-905.

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Heart failure (HF) affects millions of Americans and causes financial burdens because of the need for rehospitalization. For this reason, health care systems and patients alike are seeking methods to decrease readmissions. We assessed the potential for reducing readmissions of patients with postacute care HF through an educational program combined with enhanced external counterpulsation (EECP). We examined 99 patients with HF who were referred to EECP centers and received heart failure education and EECP treatment within 90 days of hospital discharge from March 2013 to January 2015. We compared observed and predicted 90-day readmission rates and examined results of 6-minute walk tests, Duke Activity Status Index, New York Heart Association classification, and Canadian Cardiovascular Society classification before and after EECP. Patients were treated with EECP at a median augmentation pressure of 280 mm Hg (quartile 1 = 240, quartile 3 = 280), achieved as early as the first treatment. Augmentation ratios varied from 0.4 to 1.9, with a median of 1.0 (quartile 1 = 0.8, quartile 3 = 1.2). Only 6 patients (6.1%) had unplanned readmissions compared to the predicted 34%, p <0.0001. The average increase in distance walked was 52 m (18.4%), and the median increase in Duke Activity Status Index was 9.95 points (100%), p values <0.0001. New York Heart Association and Canadian Cardiovascular Society classes improved in 61% and 60% of the patients, respectively. In conclusion, patients with HF who received education and EECP within 90 days of discharge had significantly lower readmission rates than predicted, and improved functional status, walk distance, and symptoms.

Sorajja, P., M. Mack, S. Vemulapalli, D. R. Holmes, Jr., A. Stebbins, S. Kar, D. S. Lim, V. Thourani, P. McCarthy, S. Kapadia, P. Grayburn, W. A. Pedersen and G. Ailawadi (2016). “Initial Experience With Commercial Transcatheter Mitral Valve Repair in the United States.” J Am Coll Cardiol 67(10): 1129-1140.

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BACKGROUND: Transcatheter mitral valve (MV) repair with the MitraClip received approval in 2013 for the treatment of prohibitive-risk patients with primary mitral regurgitation (MR). OBJECTIVES: The aim of this study was to report the initial U.S. commercial experience with transcatheter MV repair. METHODS: Data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry on patients commercially treated with this percutaneous mitral valve repair device were analyzed. RESULTS: Of 564 patients (56% men, median age 83 years), severe symptoms were present in 473 (86.0%). The median Society of Thoracic Surgeons Predicted Risk of Mortality scores for MV repair and replacement were 7.9% (interquartile range: 4.7% to 12.2%) and 10.0% (interquartile range: 6.3% to 14.5%), respectively. Frailty was noted in 323 patients (57.3%). Transcatheter MV repair was performed for degenerative disease, present in 90.8% of patients. Overall, MR was reduced to grade