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Combined Interleukin 1ß/Interleukin 2 Treatment in Mice: Synergistic Myelostimulatory Activity and Protection against Cyclophosphamide-induced Myelosuppression¹

Departments of Virology [E. P., L. G., G. G., F. B.] and Hematology and Oncology [E. T., U. T., E. P., M. G., C. P.], Istituto Superiore di Sanità, 0061 Rome, Italy

We have studied the effects of single and combined treatment with interleukin 1ß (IL-1ß) and interleukin 2 (IL-2) on spleen and bone marrow hematopolesis in normal mice.

Injection of IL-1ß alone was followed by a significant increase in the number of granulocytes in spleen and progenitors (burst-forming units-erythroid and colony-forming units-granulomonocytic) in both spleen and bone marrow, as compared to control mice. In contrast, IL-2 alone induced only a slight increase in the number of marrow colony-forming units-granulomonocytic and had no significant effect on spleen progenitors. Repeated injections of both IL-1ß and IL-2 resulted in a synergistic increase in spleen weight and splenocyte number, as compared to mice treated with the single cytokine regimen; in particular, the combined treatment induced a marked rise in the number of neutrophilic granulocytes and erythroblasts, whereas splenic lymphocytes were not affected. This regimen also caused a synergistic increase in the number of spleen and marrow progenitor cells: a time-course analysis showed an elevation in numbers of both burst-forming units-erythroid and colony-forming units-granulomonocytic, first in marrow (day 10) and subsequently in spleen (day 18). Combined IL-1ß/IL-2 treatment dampened the decrease and accelerated the recovery of myeloid cells after cyclophosphamide injection, whereas the single cytokine regimen was not effective. Similarly, the rebound of WBC (especially neutrophilic granulocytes) after cyclophosphamide treatment was markedly enhanced by the combined treatment, whereas the single cytokine regimen was ineffective.

These results, indicating a myelostimulatory effect by the combined cytokine regimen, together with our previous observations showing a synergistic antitumor activity by IL-1/IL-2 treatment in experimental mouse tumors (V. Ciolli et al., J. Exp. Med., 173: 313–322, 1991), may provide the basis for the development of new combination therapies with cytokines and antiblastic agents in the treatment of cancer patients.

¹ Supported in part by grants from the Programma Terapia dei Tumori, Istituto Superiore di Sanità, Rome, and the Associazione Italiana Ricerca sul Cancro.

² To whom requests for reprints should be addressed, at Department of Virology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

Received 7/23/92. Accepted 11/12/92.

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