The availability of human peripheral blood mononuclear cells (PBMC) from healthy individuals and from patients with various diseases allows for many studies on normal and abnormal functions of human immune cells. Because human and murine immune biology differs in many ways, it is important that various methodologies for studying human immunology are established. The two reports highlighted below demonstrate the usage of human PBMCs for mechanistic and pre-clinical human immune cell studies.
A recent report in The Journal of Immunology by Edwards et. al, demonstrated the usage of healthy human PBMC to elucidate the mechanisms involved in modulation of TH2 T cell responses by Toll-Like Receptor-7 (TLR7) agonists. Because TLR7 stimulation perturbs TH2 responses, the potential use of rapidly metabolized 8-oxoadenine TLR7 antedrugs for treatment of allergic diseases was explored in this study in collaboration between AstraZeneca and Dainippon Sumitomo. The TLR7 agonistic antedrug AZ12441970 was found to inhibit TH2 responses via at least two different mechanisms: TLR7-induced production of type I interferons (IFN) and induction of Notch-ligand expression on TLR7-responsive antigen presenting cells. These led to inhibition of IL-5 production by T cells via the IFN and Notch signaling pathways, respectively. TLR7-induction of IFNα was found to be intact in PBMCs from asthmatic patients when compared with healthy volunteers, and thus the authors proposed that this therapeutic strategy may be effective in allergic disease patients.
This study provides a demonstration of the usage of human PBMCs for elucidating signaling and immune-cell crosstalk mechanisms as well as determining the potential for the effectiveness of candidate drugs in patients with different disease states.
TLR7 Stimulation of APCs Results in Inhibition of IL-5 through Type I IFN and Notch Signaling Pathways in Human Peripheral Blood Mononuclear Cells. Edwards S, Jones C, Leishman AJ, Young BW, Matsui H, Tomizawa H, Murray CM, Biffen M. J Immunol. 2013 Mar 15;190(6):2585-92. doi: 10.4049/jimmunol.1200780.
The role of the cytokine IL-17 in cancer immunity continues to be controversial. IL-17 and the IL-17-producing TH17 T cell subsets have been shown to have both pro-tumor as well as anti-tumor immune modulating functions in different cancer contexts. Monocytes isolated from human PBMC can be differentiated into various myeloid cell types including dendritic cells (DC), providing a tool for studies on these human immune cell types. In a recent Plos One article, Olsson Åkefeldt et. al, explore the role of IL-17 in survival of human monocyte-derived DCs in vitro, and the relevance of this during chemotherapy.
IL-17 was found to significantly prolong DC survival in vitro, however the cells took on expression of macrophage markers (CD14/CD68) and exhibited a pre-M2 macrophage phenotype. The prolonged survival was associated with upregulated expression of pro-survival gene BCL-2A1. Interestingly, IL-17 plus IFNγ treatment in vitro rendered these M2 macrophage-like DCs resistant to cell death induced by 11 of 17 tested chemotherapeutic agents. Thus, to determine if IL-17 treatment would benefit patients by allowing DC survival during therapy, future studies should address whether this chemoresistance of IL-17 treated DCs occurs in patients undergoing chemotherapy, and to determine how IL-17 affects the anti- versus pro-tumor function of these DCs in various types of cancer.
Chemoresistance of Human Monocyte-Derived Dendritic Cells Is Regulated by IL-17A. Olsson Åkefeldt S, Maisse C, Belot A, Mazzorana M, Salvatore G, Bissay N, Jurdic P, Aricò M, Rabourdin-Combe C, Henter JI, Delprat C. PLoS One. 2013;8(2):e56865. doi: 10.1371/journal.pone.0056865. Epub 2013 Feb 18.
Studies like these are examples of the utility of using human PBMCs to elucidate mechanisms of human immune cell biology under normal and diseased conditions.
