Sarah Alter1, Peter R. Rhode1, Emily K. Jeng1, and Hing C. Wong1*

1Altor BioScience, Miramar, Florida

This mini review provides an overview and rationale for creating IL-15-based fusion protein complexes to be used as targeted immunotherapeutic agents. IL-15 stimulates proliferation and activation of CD8+ T and natural killer cells which result in augmentation of their anti-tumor activities. We have created ALT-803, an IL-15 superagonist complex which exhibits longer serum half-life, longer retention in lymphoid tissues, and better immunostimulatory and anti-tumor activities compared to native IL-15. When used alone or in combination with other immunotherapeutic molecules in various mouse tumor models, ALT-803 effectively reduces tumor burden and prolongs survival by stimulating the innate and adaptive arms of the immune system. To evaluate whether ALT-803 could be used as a protein scaffold to create IL-15-based tumor cell-specific molecules, we genetically fused it with a single chain anti-CD20 antibody derived from the variable regions of rituximab. This novel fusion protein exhibits enhanced anti-tumor activity compared to rituximab while maintaining IL-15 immunostimulating properties. Thus, ALT-803 may be exploited as a versatile scaffold to produce multivalent targeted fusion proteins to improve the anti-tumor efficacy of other therapeutic agents in the clinic.

DOI: 10.29245/2578-3009/2018/1.1111 View / Download Pdf

Laura Pulze1, Miriam Capri2, Annalisa Grimaldi1, Stefano Salvioli2, Gianluca Tettamanti1, Magda de Eguileor1*

1University of Insubria, Department of Biotechnology and Life Sciences, 21100 Varese, Italy

2University of Bologna, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), 40126 Bologna, Italy

DOI: 10.29245/2578-3009/2018/1.1110 View / Download Pdf

W. Jean Dodds1*

1Hemopet, 938 Stanford Street, Santa Monica, California 90403, USA

DOI: 10.29245/2578-3009/2018/1.1114 View / Download Pdf

Tuan Vo-Dinh*1, Yang Liu1, Bridget M Crawford1, Hsin-Neng Wang1, Hsiangkuo Yuan1, Janna K Register1, Christopher G Khoury1

1Fitzpatrick Institute for Photonics, Department of Biomedical Engineering, Department of Chemistry, Duke University, Durham, NC 27708-0281, USA

Cancer has been a significant threat to human health with more than eight million deaths each year in the world. There is an urgent need to develop novel methods to improve cancer management. Biocompatible gold nanostars (GNS) with tip-enhanced electromagnetic and optical properties have been developed and applied for multifunctional cancer diagnostics and therapy (theranostics). The GNS platform can be used for multiple sensing, imaging and treatment modalities, such as surface-enhanced Raman scattering, two-photon photoluminescence, magnetic resonance imaging and computed tomography as well as photothermal therapy and immunotherapy. GNS-mediated photothermal therapy combined with checkpoint immunotherapy has been found to reverse tumor-mediated immunosuppression, leading to the treatment of not only primary tumors but also cancer metastasis as well as inducing effective long-lasting immunity, i.e. an anticancer ‘vaccine’ effect.

DOI: 10.29245/2578-3009/2018/1.1104 View / Download Pdf

Kao-Pin Hwang1*, Ting-Yu Yen1

1Division of Infectious Diseases, Children’s Hospital, China Medical University, school of Medicine, Taichung, Taiwan

DOI: 10.29245/2578-3009/2018/1.1102 View / Download Pdf

Bettina Sehnert1*, Harald Burkhardt2, Stefan Dübel3, Reinhard E. Voll1

1Department of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg, Freiburg, Germany, Faculty of Medicine, University of Freiburg, Germany
2Division of Rheumatology, Department of Internal Medicine II and Fraunhofer IME-Project-Group Translational Medicine and Pharmacology, Goethe University Frankfurt am Main, Frankfurt am Main, Germany
3Institute of Biochemistry, Biotechnology and Bioinformatics,Technische Universität Braunschweig, Braunschweig, Germany

The activation of intracellular signaling pathways such as the classical nuclear factor kappaB (NF-kappaB) pathway is related to the pathogenesis of several inflammatory autoimmune diseases including rheumatoid arthritis (RA). To clarify the role of disease-relevant cell-types and signaling molecules in vitro or in vivo, it is necessary to target them selectively without disturbing the homeostasis of the immune system. We developed sneaking ligand fusion proteins (SLFPs) for cell-type specific modulation of signaling pathways. We designed the first SLFPs to inhibit the activation of NF-kappaB, a key regulator of inflammation, solely in the activated endothelium. Our “sneaking ligand” NF-kappaB inhibitor (named SLC1) inhibits NF-kappaB activation specifically in E-selectin expressing cells in vitro and in mouse models of arthritis indicating the importance of NF-kappaB in the activated endothelium. Clinical signs of arthritis were ameliorated by SLC1 treatment. We conclude that the SLFP architecture consisting of easily exchangeable domains represents an attractive approach to utilize other disease-relevant biological targets both on the cell surface and intracellularly. By relying on two independent disease specific targets, SLFPs may increase the therapeutic efficacy and reduce adverse effects.

DOI: 10.29245/2578-3009/2018/1.1107 View / Download Pdf

Asylkhan Rakhymzhan1*, Randall L. Lindquist1*, Anja E. Hauser1,2#, Raluca Niesner1#

1German Rheumatism Research Center, A Leibniz Institute, Berlin
2Immundynamics, Charité – University of Medicine, Berlin

In the last two decades intravital multi-photon imaging has become a central tool to investigate cellular and molecular dynamics of immune reactions in vivo. Currently, challenges in exploiting the full power of this technology include limitations on the number of simultaneously detectable parameters as well as in expanding the acquisition in time and space. Here we discuss technological advancements developed in order to overcome these challenges and focus on the example of germinal center reactions as multi-parametric immunological processes evolving over a time course of days and weeks.

DOI: 10.29245/2578-3009/2018/1.1105 View / Download Pdf

Millet Treinin*

Department of Medical Neurobiology, Hadassah Medical School – Hebrew University, Jerusalem, Israel

The nicotinic acetylcholine receptor (nAChR) gene family encodes for subunits of acetylcholine gated ion channels. These receptors are expressed widely and have many functions including anti-inflammatory effects mediated by the α7 nAChR, as part of the cholinergic anti-inflammatory pathway, in immune cells, microglia and astrocytes. Maturation of α7 nAChRs into functional ligand-gated ion channels in the plasma membrane is a complex process likely to require the RIC-3 protein. This endoplasmic reticulum resident chaperone affects maturation of multiple nAChRs, but its interaction with these receptors and its effects on their maturation differ for different nAChRs. Moreover, these interactions and effects are regulated by multiple mechanisms. Genetic analysis has implicated RIC-3 in the neuroinflammatory disease Multiple Sclerosis (MS), and in the neurodegenerative Parkinson's disease (PD). Neuroinflammation contributes to the progression of neurodegenerative diseases including PD. This information combines to suggest that RIC-3 may contribute to progression of both MS and PD via its effects on the α7 nAChR and the cholinergic anti-inflammatory pathway. Furthermore, we suggest that mechanisms regulating RIC-3 expression and activity may have a role in controlling inflammation.

DOI: 10.29245/2578-3009/2018/1.1106 View / Download Pdf

Julie D. Saba*

University of California San Francisco Benioff Children’s Hospital Oakland, Children’s Hospital Oakland Research Institute, Oakland, USA

After undergoing positive and negative selection in the thymus, surviving mature T cells egress from the thymic parenchyma and enter the bloodstream to participate in adaptive immunity. Thymic egress requires signals mediated by sphingosine-1-phosphate (S1P), a bioactive lipid that serves as the ligand for a family of G protein-coupled receptors (S1P1-5) expressed on many cell types, including T cells. In the final stage of their development, T cells upregulate S1P1 expression on the cell surface, which enables them to recognize and respond to a chemotactic S1P gradient that lures them into the bloodstream. The gradient is generated by an S1P source close to the site of egress combined with an S1P sink generated by the actions of S1P catabolic enzymes including S1P lyase (SPL), the only enzyme that irreversibly degrades S1P. The requisite contribution of SPL to thymic egress is demonstrated by the profound lymphopenia observed in SPL knockout (KO) mice and wild type mice treated with SPL inhibitors. SPL is robustly expressed in thymic epithelial cells (TECs), which make up the stromal reticular network of the thymus. However, TEC SPL was recently found to be dispensable for thymic egress. In contrast, deletion of SPL in dendritic cells (DCs) — which represent only a small percent of thymic stroma — disrupts the S1P gradient and blocks thymic egress. These recent observations identify DCs as homeostatic regulators of thymic export through the actions of SPL, thereby adding one more piece to the complex puzzle of how S1P signaling contributes to the regulation of T cell trafficking.

DOI: 10.29245/2578-3009/2018/1.1103 View / Download Pdf

Quanquan Ding, Min Liu, Xiao-Lian Zhang*

State Key Laboratory of Virology and Medical Research Institute, Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, Wuhan University College of Basic Medical Sciences, Wuhan 430071, P. R. China.

DOI: 10.29245/2578-3009/2018/1.1101 View / Download Pdf