Chimeric cytotoxin IL2-PE40 delays and mitigates adjuvant-induced arthritis in rats.
Adjuvant arthritis in rats is a T-cell dependent "autoimmune" disease with close similarities to several forms of human arthritis. Injection of mycobacterial adjuvant leads to T-cell activation and proliferation, processes in which the de novo expression of the interleukin 2 (IL-2) receptor plays a pivotal role. The subsequent massive mononuclear cell infiltration of the joints ultimately results in complete joint destruction. Because activation of the helper/inducer subset of T lymphocytes is critical to the establishment of disease, we reasoned that IL2-PE40, a cytotoxic IL-2-Pseudomonas exotoxin fusion protein that targets the membrane-penetration and ADP-ribosylation domains of the toxin to cells bearing the IL-2 receptor, would be an effective and specific therapy. Adjuvant-injected rats were randomized to treatment with IL2-PE40, phosphate-buffered saline, or either of two control proteins related to IL2-PE40 but lacking either the receptor-binding moiety or an enzymatically active toxin domain and previously demonstrated to lack cytotoxicity in vitro. Intraperitoneal IL2-PE40 given before the establishment of overt clinical disease proved an effective and specific modifier of adjuvant arthritis by clinical, histological, and radiographic criteria. Our data suggest that IL2-PE40 may be effective in those diseases in which activated T-cells play an important role.
Case
J P
JP
Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Disease, Bethesda, MD 20892.
Lorberboum-Galski
H
H
Lafyatis
R
R
FitzGerald
D
D
Wilder
R L
RL
Pastan
I
I
D036002:ADP Ribose Transferases; D000818:Animals; D001168:Arthritis / Q000517:prevention & control*; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control*; D001175:Arthrography; D001427:Bacterial Toxins; D002678:Chimera; D003603:Cytotoxins / Q000627:therapeutic use*; D005098:Exotoxins / Q000627:therapeutic use*; D005260:Female; D007167:Immunotherapy; D000922:Immunotoxins; D007376:Interleukin-2 / Q000627:therapeutic use*; D007596:Joints / Q000473:pathology; D011550:Pseudomonas aeruginosa; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use*; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D003603:Cytotoxins; D005098:Exotoxins; D000922:Immunotoxins; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C057961:IL-2-PE40 chimeric protein, recombinant