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Individual computational models of single myeloid, lymphoid, epithelial, and cancer cells were created and combined into multi-cell computational models and used to predict the collective chemokine, cytokine, and cellular biomarker profiles often seen in inflamed or cancerous tissues. Predicted chemokine and cytokine output profiles from multi-cell computational models of gingival epithelial keratinocytes (GE KER), dendritic cells (DC), and helper T lymphocytes (HTL) exposed to lipopolysaccharide (LPS) or synthetic triacylated lipopeptide (Pam3CSK4) as well as multi-cell computational models of multiple myeloma (MM) and DC were validated using the observed chemokine and cytokine responses from the same cell type combinations grown in laboratory multi-cell cultures with accuracy. Predicted and observed chemokine and cytokine responses of GE KER + DC + HTL exposed to LPS and Pam3CSK4 matched 75% (15/20, p = 0.02069) and 80% (16/20, P = 0.005909), respectively. Multi-cell computational models became 'personalized' when cell line-specific genomic data were included into simulations, again validated with the same cell lines grown in laboratory multi-cell cultures. Here, predicted and observed chemokine and cytokine responses of MM cells lines MM.1S and U266B1 matched 75% (3/4) and MM.1S and U266B1 inhibition of DC marker expression in co-culture matched 100% (6/6). Multi-cell computational models have the potential to identify approaches altering the predicted disease-associated output profiles, particularly as high throughput screening tools for anti-inflammatory or immuno-oncology treatments of inflamed multi-cellular tissues and the tumor microenvironment.

Long-chain bases are present in the oral cavity. Previously we determined that sphingosine, dihydrosphingosine, and phytosphingosine have potent antimicrobial activity against oral pathogens. Here, we determined the cytotoxicities of long-chain bases for oral cells, an important step in considering their potential as antimicrobial agents for oral infections. This information would clearly help in establishing prophylactic or therapeutic doses. To assess this, human oral gingival epithelial (GE) keratinocytes, oral gingival fibroblasts (GF), and dendritic cells (DC) were exposed to 10.0-640.0 μM long-chain bases and glycerol monolaurate (GML). The effects of long-chain bases on cell metabolism (conversion of resazurin to resorufin), membrane permeability (uptake of propidium iodide or SYTOX-Green), release of cellular contents (LDH), and cell morphology (confocal microscopy) were all determined. GE keratinocytes were more resistant to long-chain bases as compared to GF and DC, which were more susceptible. For DC, 0.2-10.0 μM long-chain bases and GML were not cytotoxic; 40.0-80.0 μM long-chain bases, but not GML, were cytotoxic; and 80.0 μM long-chain bases induced cellular damage and death in less than 20 min. The LD50 of long-chain bases for GE keratinocytes, GF, and DC were considerably higher than their minimal inhibitory concentrations for oral pathogens, a finding important to pursuing their future potential in treating periodontal and oral infections., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)