IL2-caspase3 chimeric protein controls lymphocyte reactivity by targeted apoptosis, leading to amelioration of experimental autoimmune encephalomyelitis.
IL2-caspase3 chimeric protein was designed to target and kill cells expressing the high affinity IL-2 receptor. Its effects on lymphocyte reactivity and on experimental autoimmune encephalomyelitis (EAE), a T-cell mediated disease, were tested in this study. Our data show that IL2-caspase3 promoted cell specific apoptosis both in vitro and in vivo. Cell lines preferentially expressing the IL-2R alpha chain and encephalitogenic lymphocytes derived from EAE-induced mice were highly sensitive to the chimeras' activity. This was demonstrated by increased DNA fragmentation and annexin labeling together with reduced specific T-cell proliferation in response to IL2-casepase3 treatment. Furthermore, IL2-caspase3 treatment of EAE-induced mice caused a significant delay in disease onset together with a reduction in disease burden. The efficacy of IL2-caspase3 treatment was dependent on the time at which treatment begun, with the chimera ameliorating EAE only when administered at maximal activation of peripheral lymphocytes. According to our findings we suggest that the chimeric protein IL2-caspase3 may provide a novel approach for the treatment of a variety of autoimmune disorders, such as multiple sclerosis, as well as for other pathological conditions that involve uncontrolled expansion of activated T cells.
Irony-Tur-Sinai
Michal
M
Laboratory of Neuroimmunology, Department of Neurology, the Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Lichtenstein
Michal
M
Brenner
Talma
T
Lorberboum-Galski
Haya
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D053148:Caspase 3 / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D018450:Disease Progression; D016503:Drug Delivery Systems; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D007376:Interleukin-2 / Q000235:genetics; D051379:Mice; D015202:Protein Engineering; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D053148:Caspase 3