and J E Talmadge. M P Castelli, P L Black, M Schneider, R Pennington, F Abe http://www.jimmunol.org/content/140/11/3830. 1988; 140:3830-3837; ;. J Immunol.
0022-1767/88/14011-3830$02,00/0
THEJOURNAL OF IMMUNOLOGY
Vol. 140.3830-3837. No. 11. June 1 . 1988 Prtnted Ln U.S.A.
Copyright 01 1988 by The American Assoclatlonof Irnrnunologlsts
PROTECTIVE, RESTORATIVE, AND THERAPEUTIC PROPERTIES OF RECOMBINANTHUMAN I L L IN RODENT MODELS' MARIA PAOLA CASTELLI, PAULL. BLACK, MARK SCHNEIDER, ROBIN PENNINGTON, FUMINORI ABE, AND JAMESE. TALMADGE2 From the Preclinical Screening Laboratory, Program Resources, Inc.. National Cancer Institute-Frederick Cancer Research FacllLty. Frederick. MD 21 701
Human rIL-la and -18 are shown to increase sig- chemotherapeutic agents or radiotherapy is limited by nificantly the CFU-culture activity in the spleen as myelosuppression, subsequentneutropenia,andother well as at other sites after i.v. or i.p. administration. toxic effects of these agents. However, immunotherapy IL-1 can also significantly increase survival and can with cytokines or with agents which induce cytokines "rescue" a number of animals if administered either may help to minimize the myelosuppressive effects of before or after lethaldoses of cyclophosphamideor DNA-damagingagents. Thus,it may be possible to accel?-irradiation. The protective and reconstitutiveac- erate stem-cell cycling and repopulation of the bone martivities of the rIL-1areshown to correlatewith row or to protect bone marrow cells from the DNA-damincreased CFU-culture frequency and total number, aging agents.Possible mechanisms of bone marrow proas well as increased cellularity in the bone marrow and peripheral blood, suggesting that this is one of tection include placing bone marrow cells in a protected their mechanismsof action. The sequence and tim- portion of the cell cycle, inducingscavenging, or uping of administration of human rIL-1 is critical for regulating repair mechanisms. In addition, the accelerthe protectionor rescue of animals receiving DNA- ated cycling or entry of increased numbers of stem cells damaging agents: maximal activity is achieved into the cell cycle can facilitate myeloid reconstitution when IL-1 is given 20 h before insult or 48 h after and limit the toxicity (neutropenia) of DNA-damaging alkylating agent administration. Minimal therapeu- agents. In the studiesdescribed herein, we examined the ability tic activity is observed with IL-1 as a single agent for the treatment of metastatic disease compared of rH IL-1 to protect and reconstitute bone marrow from the lethal effects of the alkylating agentCTX3 and lethal withotherbiologicresponsemodifiersincluding irradiation. rH IL-1 ' s protective and reconstitutive propIFN-7. erties presumably arise, at least in part, from its ability to induce CFU-C activity.
IL-1 is an important mediator of systemichost responses to tissue injury or infection (1). This cytokine MATERIALS AND METHODS induces manyof the classical systemicaspects of inflamAnimals. Specific pathogen-free female C57BL/6 mice (H-Zb)and mation, including fever, neutrophilia, lymphocyte acti- C57BL/6 X DBA/P (B6D2) F1 mice (H-2b X H-2d), 4 or 6 wk of age, vation, and hepatic synthesis of acute phase reaction were obtalned from the Animal Production Area of the National proteins (1, 2). Recent studies (3-5)have found that in Cancer Instltute-Frederick Cancer Research Facility. Agents. Thefollowing agents were used in thisstudy: rM CSF-gm addition toits inflammatory and immunoregulatory abil- (Immunex. Seattle. WA: 1 to 2 X 10' U/mg, sp. act.]; rH I L - l a and ities, IL-1 also protectsmice in a dose-dependent manner l p (Immunex: 1.4 x 10' U/mg, sp. act.]: and rM IFN--, (Genentech. from the lethal effects of ionizing radiation. Potential South San Francisco,CA: 2.3 X lo7 U/mg, sp. act.). The sp. act. of mechanisms of activity include the induction of acute these various materials variedslightlyfrom lot to lot and were standardized in each experiment based on a n aliquot of a n In-house phase reaction proteins (1, 2), which have scavenging standard. Poly (1,C)-LCwas a generous gift of Dr. Hilton Levy (Nacapabilities, and enhanced production of lymphokines tional Institute of Allergy and Infections Disease, National Cancer such as CSF (6).Although the efficacy of chemotherapy Institute-Frederick Cancer Research Facility, Frederick. MD). CTX obtained from Aldrich Chemical Co. (Milwaukee, WI). Allagents against advanced tumor burdens depends on the dose was and media were determined to be endotoxin-free with the Lfmulus intensity of thedrugs utilized (7, 8). treatment with lysate test (
