Constitutive expression of IL-2Rbeta chain and its effects on IL-2-induced vascular leak syndrome.
IL-2-induced vascular leak syndrome (VLS) is an important mechanism explaining the toxic effects of this cytokine and limiting its therapeutic use. We previously characterized a mouse model of IL-2-induced pulmonary VLS used to demonstrate that NK lymphocytes are involved in early/acute phase VLS (after one IL-2 injection). We also showed that NK cells and polymorphonuclear neutrophils (PMN) are involved in the late/chronic phase of the syndrome (after four daily IL-2 injections). In this study we use our mouse model to evaluate the role played by the IL-2 receptor (IL-2R) in VLS induction. Mouse and human IL-2R are different since the mouse IL-2Rbeta chain does not recognize IL-2. Here, we compare the acute and late VLS responses in human IL-2Rbeta transgenic and C57BL/6 wild type mice. Parameters linked to early phase VLS (bronchoconstriction and PMN mobilization) are enhanced in human IL-2Rbeta transgenic mice. By contrast, parameters used to measure late events (protein leakage and edema) are similar in human IL-2Rbeta transgenic mice and C57BL/6 wild type animals. However, after four IL-2 injections, the cellular content of the bronchoalveolar lavage fluids was different between the two types of animals. This study also characterizes a humanized animal model that could be further used to study human IL-2 activity and side effects in vivo.
Assier
Eric
E
Unité de Pharmacologie Cellulaire, Institut Pasteur, Paris, France.
Jullien
Valérie
V
Lefort
Jean
J
Moreau
Jean-Louis
JL
Vargaftig
B Boris
BB
Lapa e Silva
Jose R
JR
Thèze
Jacques
J
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D019559:Capillary Leak Syndrome / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology* / Q000633:toxicity; D053646:Interleukin-2 Receptor beta Subunit; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D010993:Plethysmography, Whole Body; D011506:Proteins / Q000032:analysis / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000235:genetics*
C508020:IL2RB protein, human; C508022:Il2rb protein, mouse; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; D011506:Proteins; D015375:Receptors, Interleukin-2; D016210:Methacholine Chloride; D009195:Peroxidase