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In Vivo Effects of Recombinant Human Interleukin 2 on Antitumor and Antiviral Natural Immunity in Induced or Natural Murine Immunodeficiency States

Department of Immunology Research [L. D. B., C. P. B., N. K. L., P. R., P. M.], Department of Infectious Disease Research [J. T., D. D.], Department of Biochemistry Research [J. M., L. B.], and Department of Molecular Biology Research [J. S., R. G.], Lilly Research Laboratories, Indianapolis, Indiana 46285

We have examined the ability of in vivo treatment of mice with recombinant interleukin 2 (rIL-2) to affect natural immunity measured against tumor (YAC-1) or virally infected (herpes simplex type 1) target cells. rIL-2 treatment leads to significant increases in natural killer/lymphocyte-activated killer (NK/LAK) function and spleen cells recovered. This effect is dose dependent and strain related. The latter parameter correlated with the pretreatment NK activity level of the strain. The rIL-2 induced NK/LAK augmentation is also kinetically restricted as treatment must have occurred within 48–72 h of assay to be effective. The rIL-2 therapy effectively enhances both antitumor and antiviral NK/LAK activity and results in a noticeable increase in asialo-G_M1-positive cells in the spleens of treated mice as well as a significant increase in IL-2 receptor expression as monitored by either cytometry or radioligand binding. In vivo treatment of mice with an antibody directed to the ASG_M1 determinant effectively reduces the rIL-2 augmentation of both antitumor and antiviral activity even though this treatment does not affect the pretreatment level of antiviral activity. Various natural and induced immunodeficiency states (immunotherapy, irradiation, immunosuppressive drugs, cytoreductive drugs) have been examined for the ability of in vivo treatment with rIL-2 to enhance NK/LAK activity. In vivo rIL-2 administration is differentially effective in enhancing NK/LAK activity in these situations. Notably, in these induced immunodeficiency states, although NK/LAK activity is commonly enhanced, the number of spleen cells recovered often is only marginally affected. Thus, as expected, a limiting aspect in this use of a natural immunomodulator is the number of potentially responsive cells present in the immunodeficiency condition. In addition, correlations between rIL-2 effect, several of the immunodeficiency states, and vascular leak syndrome are briefly discussed.

¹ To whom requests for reprints should be addressed, at Department of Immunology Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.

Received 12/ 8/87. Revised 6/22/88. Accepted 8/ 1/88.