In vivo interleukin-2 activated sheep lung lymph lymphocytes increase ovine vascular endothelial permeability by non-lytic mechanisms.
Therapeutic doses of recombinant interleukin-2 (rIL-2) often result in systemic toxicity consistent with increased vascular permeability. rIL-2 activated lymphocytes (IALs) may produce endothelial dysfunction and have cytolytic potential. However, much of the data on IAL cytotoxicity comes from the use of in vitro activated IALs. Alternatively, rIL-2 may enhance permeability directly or via release of various cytokines by host effector cells. The cytotoxicity of in vivo activated lung lymph lymphocytes has been studied in an ovine model of rIL-2 toxicity. The in vivo IALs had no significant endothelial cytolysis at effector to target ratios of 100:1. However, the in vivo IALs increased endothelial monolayer permeability to albumin, dependent on the concentration of IALs. rIL-2 induced no endothelial cytolysis or permeability alterations at doses of 10(5) and 2 x 10(5) U/ml, respectively. These findings suggest that the acute endothelial dysfunction characteristic of the vascular leak syndrome is not due to rIL-2 directly, but is mediated by in vivo IALs via non-cytolytic mechanisms and/or the release of secondary cytokines in response to rIL-2.
Bechard
D E
DE
Department of Pulmonary Medicine, Richmond, VA 23298.
Fairman
R P
RP
Hinshaw
D B
DB
Fowler
A A
AA
Glauser
F L
FL
D000418:Albumins / Q000493:pharmacokinetics; D000818:Animals; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D002860:Chromium Radioisotopes; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology*; D007457:Iodine Radioisotopes; D008168:Lung / Q000166:cytology*; D008196:Lymph / Q000166:cytology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012756:Sheep
D000418:Albumins; D002860:Chromium Radioisotopes; D007376:Interleukin-2; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins