Effect of intranasal exposure to cigarette smoke on the Immune System as a model for COPD

We have carried out extensive research examining the role of the immune system in Chronic Obstructive Pulmonary Disease (COPD). COPD remains a growing but neglected global epidemic. Our research utilised human samples and was key in identifying the important role for cytotoxic cells, NK cells, NKT cells and B cells in disease. We are currently using this knowledge to identify novel compounds that may be used for treatment of COPD (MRC P2D funding). Presently there are limited murine models that accurately reflect COPD phenotype and none are available in the Midlands. As such the aim of this PhD project will be to develop an intranasal cigarette smoke model to enable comprehensive study of the immune system, specifically with the goal of examining cells and mediators of the immune system known to be related to disease.

CD8+ T-lymphocytes, natural killer T-like (NKT) cells and natural killer (NK) cells are the three main classes of human killer cells that are implicated in the pathogenesis of COPD. We have shown that these cells are reduced in both number and cytotoxic function in the peripheral blood of COPD patients (Urbanowicz et al, 2009), but conversely are up-regulated in number and cytotoxic function in the lungs of COPD patients (Urbanowicz et al, 2010). In addition, activation of these cells can initiate immune responses by virtue of their production of inflammatory cytokines and chemokines that cause lung tissue damage, mucus hypersecretion and emphysema. We have shown systemic activation appears to be related to current smoking whereas lung activation is related to the presence or absence of COPD, irrespective of current smoking status (Wang et al, 2012). These findings suggest that modulating killer cell function and/or activation may be a new target for the treatment of COPD.

In addition, we have shown that multiple cytokines are co-elevated in COPD (Selvarajah et al, 2016), specifically we showed numerous circulating cytokines were raised such that their combined, but not individual, elevation was significantly associated with severity of disease, and these may be further indicators of, and contributors to, the systemic inflammatory manifestations of COPD.

Furthermore, we have shown multiple autoantibodies (AAbs) are elevated in COPD (Shindi et al, 2017). Interestingly, there were significant differences in the autoantigenic specificities of IgM AAbs compared to IgG AAbs in the COPD sera: for example, AAbs to histone and scl-70 were mainly IgG, whereas AAbs to CENP-B and La/ssB were mainly IgM; by contrast, IgM and IgGAAbs to collagen-V were equally prevalent.

Thus, a combination of IgM and IgG AAbs specific for multiple autoantigens are detected in all cases of COPD at a level at which all non-COPD controls are negative for AAbs. This highlights the importance of different classes of AAbs to a range of autoantigens in COPD.

This project will develop a murine model to examine the role of cells, cytokines and autoantibodies known to be important in the biological mechanisms leading to COPD.