To understand the mechanism of synergistic anti-tumor effects, we have examined lymphoid cell proliferation in-vivo in various organs of mice in response to IL-2 and IFN-alpha administration. We have utilized a technique for labeling newly synthesized DNA in-vivo with 125-IUdR to examine proliferation of endogenous cells. After 4 days of IL-2 administration, a significant uptake of 125-IUdR was observed in the lungs, liver, kidneys an spleen. IFN-alpha alone mediated very little incorporation of radiolabel bu when administered in combination with IL-2, a reduction of IL-2 induced proliferation was seen on day 4. Similar inhibition of IL-2 induced proliferation was observed in the lungs, kidneys and spleen. In contrast, on days 7 or 8, higher uptake of radiolabel was obtained in IFN-alpha plus IL-2 treated lungs, liver and kidneys compared to organs of mice treated with IL-2 alone or IFN-alpha alone. The effects of IFN-alpha on IL-2 induce proliferation was dose dependent. Continued proliferation of cells was observed in most organs when IL-2 plus IFN-alpha was injected for 9 consecutive days. Pretreatment irradiation of mice at 500 rad largely eliminated the proliferative response to IL-2 as well as to IFN-alpha plus IL-2 at both days 3 and 7. Histological studies of lungs receiving cytokine therapy for days 3 and 7 corroborated the results of the l25-IUdR incorporation assay. These studies indicate that in-vivo IFN-alpha interact with IL-2 in a complex manner and prolonged treatment with IFN-alpha and IL-2 increases tissue infiltration of lymphoid cells that may play a role in antitumor effector functions. The initial manuscript is in press in the Cancer Research.
