Different behaviour of radioiodinated human recombinant interleukin-1 and its receptor antagonist in an animal model of infection.
Recently, we demonstrated that radiolabelled interleukin-1alpha (IL-1) specifically accumulates in focal infection in mice through interaction with its receptor. Unfortunately, systemic side-effects of IL-1 limit its clinical application. We investigated whether this problem could be circumvented by using the interleukin-1 receptor antagonist (IL-1ra), an equally sized protein that binds to the same receptors as IL-1 without induction of biological effects. Biodistribution of 125I-IL-1 and 125I-IL-1ra was determined in Swiss mice with Staphylococcus aureus-induced abscesses in the left calf muscle at 4, 12, 24 and 48 h after injection of either 0.4 MBq 125I-IL-1 or 0.4 MBq 125I-IL-1ra. In vitro, the proteins displayed similar binding characteristics. High-performance liquid chromatographic analysis revealed a tendency for IL-1ra to associate with serum proteins. Both proteins rapidly cleared from most organs. However, the abscess uptake of 125I-IL-1ra was significantly lower than that of 125I-IL-1 at all time points (48 h p.i.: 0.06+/-0. 01%ID/g vs 0.60+/-0.04%ID/g; P<0.02). The abscess-to-contralateral muscle ratios did not exceed 15.5+/-2.9 for 125I-IL-1ra, while the ratios for 125I-IL-1 reached 46.9+/-5.7 at 48 h p.i. Despite similar in vitro receptor binding, the abscess uptake of IL-1ra was much lower than that of IL-1. The interaction of IL-1ra with serum proteins in vivo may reduce its availability for receptor binding in the infection. Although on theoretical grounds IL-1ra is very interesting, these characteristics will prevent its development as a clinically useful radiopharmaceutical to image infection.
van der Laken
C J
CJ
Department of Nuclear Medicine, University Hospital Nijmegen, Nijmegen, The Netherlands.
Boerman
O C
OC
Oyen
W J
WJ
van de Ven
M T
MT
Claessens
R A
RA
van der Meer
J W
JW
Corstens
F H
FH
D000038:Abscess / Q000000981:diagnostic imaging*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006614:Hindlimb; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes; D051379:Mice; D008815:Mice, Inbred Strains; D011877:Radionuclide Imaging; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D012795:Sialoglycoproteins / Q000493:pharmacokinetics; D013203:Staphylococcal Infections / Q000000981:diagnostic imaging*; D013997:Time Factors; D014018:Tissue Distribution
C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D007457:Iodine Radioisotopes; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins