Chimeric cytotoxin IL2-PE40 delays and mitigates adjuvant-induced arthritis in rats

J. P. Case, H. Lorberboum-Galski, R. Lafyatis, D. FitzGerald, R. L. Wilder, I. Pastan

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Adjuvant arthritis in rats is a T-cell dependent 'autoimmune' disease with close similarities to several forms of human arthritis. Injection of myobacterial 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.

Original languageAmerican English
Pages (from-to)287-291
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume86
Issue number1
DOIs
StatePublished - 1989
Externally publishedYes

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