Baylor Research Institute

Cheng, L., Z. Zhang, G. Li, F. Li, L. Wang, L. Zhang, S. M. Zurawski, G. Zurawski, Y. Levy and L. Su (2017). “Human innate responses and adjuvant activity of tlr ligands in vivo in mice reconstituted with a human immune system.” Vaccine: 2017 Sep [Epub ahead of print].

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TLR ligands (TLR-Ls) represent a class of novel vaccine adjuvants. However, their immunologic effects in humans remain poorly defined in vivo. Using a humanized mouse model with a functional human immune system, we investigated how different TLR-Ls stimulated human innate immune response in vivo and their applications as vaccine adjuvants for enhancing human cellular immune response. We found that splenocytes from humanized mice showed identical responses to various TLR-Ls as human PBMCs in vitro. To our surprise, various TLR-Ls stimulated human cytokines and chemokines differently in vivo compared to that in vitro. For example, CpG-A was most efficient to induce IFN-alpha production in vitro. In contrast, CpG-B, R848 and Poly I:C stimulated much more IFN-alpha than CpG-A in vivo. Importantly, the human innate immune response to specific TLR-Ls in humanized mice was different from that reported in C57BL/6 mice, but similar to that reported in nonhuman primates. Furthermore, we found that different TLR-Ls distinctively activated and mobilized human plasmacytoid dendritic cells (pDCs), myeloid DCs (mDCs) and monocytes in different organs. Finally, we showed that, as adjuvants, CpG-B, R848 and Poly I:C can all enhance antigen specific CD4+ T cell response, while only R848 and Poly I:C induced CD8+ cytotoxic T cells response to a CD40-targeting HIV vaccine in humanized mice, correlated with their ability to activate human mDCs but not pDCs. We conclude that humanized mice serve as a highly relevant model to evaluate and rank the human immunologic effects of novel adjuvants in vivo prior to testing in humans.

Azzalini, L., L. Candilio, P. A. McCullough and A. Colombo (2017). “Current risk of contrast-induced acute kidney injury after coronary angiography and intervention: A reappraisal of the literature.” Can J Cardiol 33(10): 1225-1228.

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Contrast-induced acute kidney injury (CI-AKI) is the acute impairment of renal function further to the intravascular administration of iodinated contrast media, and occurs most frequently after coronary angiography, percutaneous coronary intervention, and contrast-enhanced computed tomography. CI-AKI has been associated with the development of acute renal failure, worsening of chronic kidney disease, requirement for dialysis, prolonged hospital stay, and higher mortality rates and health care costs. Recently, a number of studies suggested that contrast media exposure might not be the causative agent in the occurrence of acute kidney injury, particularly in stable patients who receive small to moderate amounts of contrast media. However, those who undergo coronary angiography and intervention are indeed subject to an increased hazard of CI-AKI, in view of a more significant contrast media exposure as well as the presence of concomitant risk factors. Solid randomized clinical trials are therefore required to identify preventative strategies to reduce the risk of CI-AKI and its complications in these patients.

Surenaud, M., C. Lacabaratz, G. Zurawski, Y. Levy and J. D. Lelievre (2017). “Development of an epitope-based hiv-1 vaccine strategy from hiv-1 lipopeptide to dendritic-based vaccines.” Expert Rev Vaccines 16(10): 955-972.

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INTRODUCTION: Development of a safe, effective and globally affordable Human Immunodeficiency Virus strain 1 (HIV-1) vaccine offers the best hope for future control of the HIV-1 pandemic. However, with the exception of the recent RV144 trial, which elicited a modest level of protection against infection, no vaccine candidate has shown efficacy in preventing HIV-1 infection or in controlling virus replication in humans. There is also a great need for a successful immunotherapeutic vaccine since combination antiretroviral therapy (cART) does not eliminate the reservoir of HIV-infected cells. But to date, no vaccine candidate has proven to significantly alter the natural history of an individual with HIV-1 infection. Areas covered: For over 25 years, the ANRS (France Recherche Nord&Sud Sida-HIV hepatites) has been committed to an original program combining basic science and clinical research developing an epitope-based vaccine strategy to induce a multiepitopic cellular response against HIV-1. This review describes the evolution of concepts, based on strategies using HIV-1 lipopeptides towards the use of dendritic cell (DC) manipulation. Expert commentary: Understanding the crucial role of DCs in immune responses allowed moving from the non-specific administration of HIV-1 sequences with lipopeptides to DC-based vaccines. These DC-targeting strategies should improve HIV-1 vaccine efficacy.

Chang, C. A., M. C. Lawrence and B. Naziruddin (2017). “Current issues in allogeneic islet transplantation.” Curr Opin Organ Transplant 22(5): 437-443.

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PURPOSE OF REVIEW: Transplantation of allogenic pancreatic islets is a minimally invasive treatment option to control severe hypoglycemia and dependence on exogenous insulin among type 1 diabetes (T1D) patients. This overview summarizes the current issues and progress in islet transplantation outcomes and research. RECENT FINDINGS: Several clinical trials from North America and other countries have documented the safety and efficacy of clinical islet transplantation for T1D patients with impaired hypoglycemia awareness. A recently completed phase 3 clinical trial allows centres in the United States to apply for a Food and Drug Administration Biologics License for the procedure. Introduction of anti-inflammatory drugs along with T-cell depleting induction therapy has significantly improved long-term function of transplanted islets. Research into islet biomarkers, immunosuppression, extrahepatic transplant sites and potential alternative beta cell sources is driving further progress. SUMMARY: Allogeneic islet transplantation has vastly improved over the past two decades. Success in restoration of glycemic control and hypoglycemic awareness after islet transplantation has been further highlighted by clinical trials. However, lack of effective strategies to maintain long-term islet function and insufficient sources of donor tissue still impose limitations to the widespread use of islet transplantation. In the United States, wide adoption of this technology still awaits regulatory approval and, importantly, a financial mechanism to support the use of this technology.

Mack, M. J., M. A. Acker, A. C. Gelijns, J. R. Overbey, M. K. Parides, J. N. Browndyke, M. A. Groh, A. J. Moskowitz, N. O. Jeffries, G. Ailawadi, V. H. Thourani, E. G. Moquete, A. Iribarne, P. Voisine, L. P. Perrault, M. E. Bowdish, M. Bilello, C. Davatzikos, R. F. Mangusan, R. A. Winkle, P. K. Smith, R. E. Michler, M. A. Miller, K. L. O’Sullivan, W. C. Taddei-Peters, E. A. Rose, R. D. Weisel, K. L. Furie, E. Bagiella, C. S. Moy, P. T. O’Gara and S. R. Messe (2017). “Effect of cerebral embolic protection devices on cns infarction in surgical aortic valve replacement: A randomized clinical trial.” Jama 318(6): 536-547.

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Importance: Stroke is a major complication of surgical aortic valve replacement (SAVR). Objective: To determine the efficacy and adverse effects of cerebral embolic protection devices in reducing ischemic central nervous system (CNS) injury during SAVR. Design, Setting, and Participants: A randomized clinical trial of patients with calcific aortic stenosis undergoing SAVR at 18 North American centers between March 2015 and July 2016. The end of follow-up was December 2016. Interventions: Use of 1 of 2 cerebral embolic protection devices (n = 118 for suction-based extraction and n = 133 for intra-aortic filtration device) vs a standard aortic cannula (control; n = 132) at the time of SAVR. Main Outcomes and Measures: The primary end point was freedom from clinical or radiographic CNS infarction at 7 days (+/- 3 days) after the procedure. Secondary end points included a composite of mortality, clinical ischemic stroke, and acute kidney injury within 30 days after surgery; delirium; mortality; serious adverse events; and neurocognition. Results: Among 383 randomized patients (mean age, 73.9 years; 38.4% women; 368 [96.1%] completed the trial), the rate of freedom from CNS infarction at 7 days was 32.0% with suction-based extraction vs 33.3% with control (between-group difference, -1.3%; 95% CI, -13.8% to 11.2%) and 25.6% with intra-aortic filtration vs 32.4% with control (between-group difference, -6.9%; 95% CI, -17.9% to 4.2%). The 30-day composite end point was not significantly different between suction-based extraction and control (21.4% vs 24.2%, respectively; between-group difference, -2.8% [95% CI, -13.5% to 7.9%]) nor between intra-aortic filtration and control (33.3% vs 23.7%; between-group difference, 9.7% [95% CI, -1.2% to 20.5%]). There were no significant differences in mortality (3.4% for suction-based extraction vs 1.7% for control; and 2.3% for intra-aortic filtration vs 1.5% for control) or clinical stroke (5.1% for suction-based extraction vs 5.8% for control; and 8.3% for intra-aortic filtration vs 6.1% for control). Delirium at postoperative day 7 was 6.3% for suction-based extraction vs 15.3% for control (between-group difference, -9.1%; 95% CI, -17.1% to -1.0%) and 8.1% for intra-aortic filtration vs 15.6% for control (between-group difference, -7.4%; 95% CI, -15.5% to 0.6%). Mortality and overall serious adverse events at 90 days were not significantly different across groups. Patients in the intra-aortic filtration group vs patients in the control group experienced significantly more acute kidney injury events (14 vs 4, respectively; P = .02) and cardiac arrhythmias (57 vs 30; P = .004). Conclusions and Relevance: Among patients undergoing SAVR, cerebral embolic protection devices compared with a standard aortic cannula did not significantly reduce the risk of CNS infarction at 7 days. Potential benefits for reduction in delirium, cognition, and symptomatic stroke merit larger trials with longer follow-up.