Immune biomarkers in relation to exposure to particulate matter: a cross-sectional survey in 17 cities of Central Europe.

Human population data on air pollution and its effects on the immune system are scarce. A survey was conducted within the framework of the Central European Study of Air Quality and Respiratory Health (CESAR) to measure a panel of immune biomarkers in children of Bulgaria, Czech Republic, Hungary, Poland, Romania, and Slovakia. Seventeen cities were chosen to represent a wide range of exposure to outdoor air pollution. In each, ambient particulate matter of less than 10 microns diameter and less than 2.5 microns diameter (PM10 and PM2.5) were measured with a Harvard impactor. Blood was collected from 366 school children aged 9 to 11 yr between 11 April and 10 May 1996. The percentage of B, total T, CD4+, CD8+, and natural killer (NK) lymphocytes was determined by flow cytometry (Becton Dickinson); total immunoglobulins of class G, M, A and E (IgG, IgM, IgA, and IgE) were measured in serum using nephelometry (Behring). Associations between PM and each log-transformed biomarker concentration were studied by linear regression, in a two-stage model. The yearly average concentrations varied from 41 to 96 micrograms/m3 for PM10 across the 17 study areas, from 29 to 67 micrograms/m3 for PM2.5, and from 12 to 38 micrograms/m3 for PM10-2.5 (coarse). Number of B, CD4+, CD8+, and NK lymphocytes increased with increasing concentration of PM, having adjusted for age, gender, parental smoking, laboratory of analysis, and recent respiratory illness. Differences in lymphocyte number were larger and statistically significant for exposure to PM2.5. Similar results were found when we examined the association between PM and lymphocyte number separately for each laboratory. Total IgG was increased with increasing concentration of PM, significantly in the case of PM2.5. When we repeated the analyses with two other statistical approaches the results did not differ from those reported here. The effect of coarse PM on lymphocyte numbers appears small in comparison to PM2.5. One possible interpretation of our findings is that long-term exposure to airborne particulates leads to inflammation of the airways and activation of the cellular and humoral immune system

Arginase 1 2 inhibitor OATD 02 from discovery to first in man setup in cancer immunotherapy

Pharmacologic inhibition of the controlling immunity pathway enzymes arginases 1 and 2 ARG1 and ARG2 is a promising strategy for cancer immunotherapy. Here, we report the discovery and development of OATD 02, an orally bioavailable, potent arginases inhibitor. The unique pharmacologic properties of OATD 02 are evidenced by targeting intracellular ARG1 and ARG2, as well as long drug target residence time, moderate to high volume of distribution, and low clearance, which may jointly provide a weapon against arginase related tumor immunosuppression and ARG2 dependent tumor cell growth. OATD 02 monotherapy had an antitumor effect in multiple tumor models and enhanced an efficacy of the other immunomodulators. Completed nonclinical studies and human pharmacokinetic predictions indicate a feasible therapeutic window and allow for proposing a dose range for the first in human clinical study in patients with cance