Endothelial activation during interleukin 2 immunotherapy. A possible mechanism for the vascular leak syndrome.
A major sequela of immunotherapy with interleukin 2 (IL-2) is development of a vascular leak syndrome. The pathogenesis of this toxic effect is not known. We have examined pre- and post-treatment skin biopsies from 14 patients undergoing systemic administration of IL-2 for evidence of endothelial cell activation. Specifically, we have used the immunoperoxidase technique to detect the expression of three different activation antigens: endothelial-leukocyte adhesion molecule 1, detected with monoclonal antibody H4/18; intercellular adhesion molecule 1, detected with antibody RR1/1; and histocompatibility leukocyte antigen-DQ, detected with antibody Leu 10. Each of these antigens may be induced on cultured endothelial cells by various cytokines (although not by IL-2) and is expressed during endothelial cell activation in vivo at sites of delayed hypersensitivity and other immune responses. Pretreatment biopsies from each patient showed no endothelial expression of endothelial-leukocyte adhesion molecule 1 and only weak to moderate expression of intercellular adhesion molecule 1 and histocompatibility leukocyte antigen-DQ (except for one specimen unreactive with Leu 10). After 5 days of treatment, every patient showed marked endothelial expression of all three antigens (except for the same patient who remained unreactive with Leu 10). Endothelial-leukocyte adhesion molecule-1 expression was confined to postcapillary venular endothelium whereas intercellular adhesion molecule-1 and Leu 10 also were expressed on stromal cells and mononuclear cells. Thus, we conclude that i.v. administration of IL-2 leads to endothelial cell activation. Because IL-2 fails to induce the same antigens on cultured endothelial cells, we infer that IL-2 acts in vivo by inducing the production of other cytokines (e.g., interleukin 1, tumor necrosis factor, lymphotoxin, and interferon-gamma). Finally, since endothelial cell activation at sites of cell-mediated immune responses is well known to result in vascular leakiness to macromolecules, we propose that the vascular leak syndrome accompanying IL-2 therapy may arise from widespread inappropriate endothelial cell activation.
Cotran
R S
RS
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115.
Pober
J S
JS
Gimbrone
M A
MA
Springer
T A
TA
Wiebke
E A
EA
Gaspari
A A
AA
Rosenberg
S A
SA
Lotze
M T
MT
D000954:Antigens, Surface / Q000032:analysis; D001688:Biological Products / Q000096:biosynthesis; D015815:Cell Adhesion Molecules; D002478:Cells, Cultured; D016207:Cytokines; D004487:Edema / Q000139:chemically induced* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology*; D005786:Gene Expression Regulation; D006683:HLA-DQ Antigens / Q000032:analysis; D006801:Humans; D007376:Interleukin-2 / Q000009:adverse effects* / Q000627:therapeutic use; D009369:Neoplasms / Q000628:therapy; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012867:Skin / Q000098:blood supply / Q000473:pathology; D013577:Syndrome
D000954:Antigens, Surface; D001688:Biological Products; D015815:Cell Adhesion Molecules; D016207:Cytokines; D006683:HLA-DQ Antigens; D007376:Interleukin-2; D011994:Recombinant Proteins