SECOND INTERNATIONAL WORKSHOP ON CYTOKINES / 131

349

IN VIVO DOWN REGULATION OF THE RESPONSE TO IL-1 WITH ANTI-IL-1 RECEPTOR ANTIBODY 35F5. R. Neta and R. Chizzonite. Armed Forces Radiobiology Research Institute, Bethesda, MD 20814, and Hoffmann-LaRoche, Nutley, NJ 07110.

Administration of recombinant human IL-I to mice results in multiple biological effects. We have shown previously that IL-I is radioprotective and induces an increase in circulating acute phase protein, fibrinogen. In this work the effect of administration of an anti-l L-l receptor antibody on these two in viva effects of IL-1 has been examined. Monoclonal 35F5 antibody has been shown to block IL-1 binding to thymocytes, the DIO cell line, and keratinocytes, but not B-cells, macrophage cell lines, or bone marrow granu- locytes. Administration of 120 fig of this antibody to mice 4-6 hrs before IL-1 lad to the following results. (1) 16 of 18 of CD2Fl micegiven 200 ng IL-I and an LDIm,30 dose of radiation (9.5 Gy) were protected from death. However, 17 of 18 micegiven 35F5 antibody, died within 9.16 days, and 18 of 18 control, saline treated, mice died within the same period. (2) In contrast to the above inhibition of radioprotection, 35F5 antibody exer- tad a much smaller effect on the fibrinogen levels induced by IL-l. Whereas 500 ng IL-I resulted in an increase in fibrinogen to 288 f 30% and 100 ng to 185 f 14% of control, antibody administration resulted in 177 f 74% and 182 * 17%. respectively. These results suggest the presence of cells with high- and low- sensitivity to IL-l. Inhibition of radioprotection suggests that cells with low sensitivity may be more critical for radioprotection, whereas cells with both high- and low-sensitivity contribute to induction of circulating fibrinogen.

350

Relationship of local cytokine production to the severity of proliferative immune complex nephritis. Bernice Noble, Ray Price and Keyong Ren, Microbiology Dept., State University of New York at Buffalo, Buffalo, New York 14214

Chronic serum sickness of rats, a model of proliferative immune complex glomerulonephritis, progresses in 3 discrete stages, Mild, Moderate and Severe. The characteristics of kidney function and the macrophage content of glomeruli are distinctive in each stage. Proteinuria develops in the Moderate stage, but cachexia, uremia and tissue necrosis are only seen in the Severe stage. TNF and IL-1 production were measured in each stage. Glomerular production of IL-1 was first detected at the start of the Moderate stage, and increasedwith increasing proteinuria, until the Severe stage. In contrast, TNF production was closely linked to the onset of the Severe stage, and increased until death from renal failure. It seems likely that local glomerular production of TNF contributes significantly to the pathophysiology and histopathology of Severe chronic serum sickness. Regulation in viva of cytokine synthesis appears to be an important factor in the progression of proliferative immune complex glomerulonephritis. In this animal model, measurements of urinary cytokine excretion provided a reliable means to monitor disease progression.

351 HUMAN IL-l THE RABBIT.

INHIBITOR (IL-li) BLOCKS THE EFFECTS OF IL-lp IN Kiell Ohlsson. Peter Biork. Maenus Bergenfeldt.

Stephen P. Eisenbew John Childs. Charles H. Hannun. and Robert C. Thomoson. University of Lund Medical School, Sweden, and Synergen, Inc., Boulder Colorado USA.

IL-lfi administered to rabbits causes hypotension and leukopenia (Okusawa, et al., J. Clin. Invest. 1988), and the synthesis of the acute phase proteins CRP and fibrinogen. We have tested recombinant human IL-li (Eisenberg, et al., this volume) for its ability to modify these responses. The response to 15 fig/kg IL-lp delivered iv is blocked by 1 mg/kg IL-li delivered at the same time andby the same route. The magnitude of the inhibition is dose related. lmg/kg IL- lihas no effect on the animals in the absence of IL-l. When IL-li is delivered before IL-1 it renders the rabbits unresponsive to IL-1 for several hours.

352

IL6: A PYROGKNIC CYTOKINK THAT IS NOT SOMSOGENIC M. R. Gnu. F. Obal. Jr.. and J. H. Krueuer. Univ. of TN, Memphis, TR 38163

Injury or infection leads to several reactions collectively termed the acute phase response. This response includes systemic and central symptoms and is mediated by cytokines. Central effects induced by ILl, TNF, and IFN include fever and excess non-rapid-eye-movement sleep (NRKRS). To determine whether IL6 also possesses pyrogenic and somnogenic actions, we injected 20, 40, 80, and 200 ng human recombinant IL6 (expressed in E. a; Genetics Institute) intracerebroventricularly (ICV) into male rabbits and recorded sleep-wake activity and brain temperature (m) for 6-h. Vehicle was injected as a control into the same animals. ICV injection of IL6 resulted in a dose-related febrile response. After ICV injection of the 20, 40, and 80 ng doses, NRKKS duration was slightly reduced compared to controls. The 200 ng dose resulted in durations of NRKRS virtually identical to control values. IL6 therefore, is the first cytokine reported to induce fever without promoting NRKKS. supported by: WIH NS 25378. NIH ws 27250, ONR ~00014.85.<-07i3, USAHRDC DPIIID- 17-86-C-6194. and a univ. of TN seuroscience center of sxcelLence rettoushiw

353

ROLE OF PROSTAGLANDINS IN THE BEHAVIORAL CHANGES INDUCED BY MURINE IL-la IN THE RAT. I. Otterness, H. Golden, P. Sevmour, 1. Eskra and G Daumv. Pfizer Central Research. Groton. CT06340.

The continuous infusion of.murine rIL-la produces weight loss, appetite suppression, reduction in horizontal locomotor activity (crossovers) and vertical locomotor activity (rears) and an increase in drinking behavior in the rat. The role of prortaglandins in the elicitation of these effects was studied. Infusion of rIL-la produced an increase In serum PGEz which peaked at 24-48 hours and declined thereafter. The increase in serum PGEz could be completely inhibited by piroxicam. However, inhibition of circulating PGEz did not block the reductions in appetite, crossovers and rears induced by rIL-la, but it restored normal drinking behavior. Continuous infusion of PGEz at 24 pg/day produced a constant serum PGEz concentration. Under these conditions, exposure to PGEz was slightly greater than that resulting from rIL-loadministration. At the point of maximum weight loss induced by rIL-lo (72 hours), PGEz produced only a quarter of the weight loss. Compared to rII-la, PGEl produced significantly smaller reductions in appetite, crossovers and rears, and had no effect on drinking.

From these results we conclude that the rIL-a-induced increase in drinking behavior was fully dependent on products of the cyclooxygenase pathway, but it was not reproduced by infusion of PGE2. Although PGs can contribute to the anorexia, reduction in mobility, and weight loss observed after continuous infusion of rIL-la, there must be a more significant prortaglandin- independent component to account for these effects.

354

BIOLOGICAL BFFJXI OF GAMM IRlW!FK ROU 111 EAT FxP88IKKKTAL scu1sTosoBlLks1s. V. Pancr6, C. Auriault, H. Schellekens* and A. Capron C.I.B.P., Institut Pasteur, Lille (France) and *TN0 Primate Center, Rijswijk (The Netherlands).

We demonstrate the production of gannna interferon (IFN- Xjdurine the course of exoerimental infection of rat bv iihiatoioma mansoni (S. mansoni). This production is con: comitant with those of IzE and oerfectlv correlates with the expression of platelet cytotoxic properties in vitro. Indeed IgE, but also IFN-g, present in the sera of infected rats induce together platelets from normal rats into cyto- toxic effecters for the parasitic larvae. This second mechanism of platelet activation depending on lymphokine is also effective in viva since the passive transfer of Il0l-msl platelets treated by recombinant IFN-X (rIFN-r) confered a high degree of protection toward a challenge in- fection. Finally, the administration of rIFN-X to rats indu- ces a protective immunity tc S. mansoni.