RECOMBINANT HUMAN INTERLEUKIN-1 RECEPTOR ANTAGONIST PROTECTS EARLY MYELOID PROGENITORS IN A MURINE MODEL OF CYCLOPHOSPHAMIDE-INDUCED MYELOTOXICITY

Expression of hematoregulatory cytokines such as interleukin-1 (IL-1) in response to cytotoxic chemotherapy hastens hematopoietic recovery, but may also potentiate myelotoxicity if myeloid progenitors enter cel l cycle before drug clearance, In the present study, the ability of re combinant human IL-1 receptor antagonist (IL-1ra) to protect hematopoi etic progenitors was studied in a murine model of cyclophosphamide (CP A)-induced myelotoxicity, CF-1 female mice received 200 mg/kg CPA and either 10 mg/kg IL-1ra or an equal volume of 0.05% human serum albumin (HSA) intraperitoneally (i.p.), followed 12 hours later by IL-1ra or HSA, CPA and IL-1ra increased absolute neutrophil counts (ANCs) at day s 2 (P = .001) and 14 (P = .0025) after CPA. In IL-1ra-treated mice, c olony-forming units granulocyte-macrophage (CFU-GM)/tibia were increas ed twofold and threefold at days 2 (P = .0047) and 7 (P = .023), respe ctively, whereas high proliferative potential colony-forming cells (HP P-CFC)/tibia were decreased twofold to threefold at 8 hours (P = .039) and 24 hours (P = .0033), but were approximately threefold higher tha n HSA-treated mice at day 7 after CPA, Coadministration of CPA and IL- 1 enhanced myelotoxicity compared with mice injected with CPA and IL-1 ra or HSA, In vivo, IL-1ra protected HPP-CFC, but not CFU-GM, from hyd roxyurea suicide after a single dose of CPA, suggesting that IL-1ra in hibited cycling of HPP-CFC. In vitro, IL-1ra did not alter proliferati on of CFU-GM, but inhibited IL-1-enhanced proliferation of HPP-CFC. Th ese data suggest that IL-1ra acts as an indirect negative regulator of hematopoiesis and protects HPP-CFC from CPA, possibly by inhibiting I L-1-enhanced proliferation of early myeloid progenitors. (C) 1995 by T he American Society of Hematology.