The findings could also be significant for developing new ways to help patients with autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, or juvenile diabetes.
The study, which was published in the February 16 issue of the online journal Science Express, showed that these injections caused a massive selective increase in the immune system's two main types of T cells.
"Our study shows that different cytokine-antibody complexes such as IL-2/IL-2 mAb could be clinically useful to selectively boost or inhibit the immune response in vivo," said Onur Boyman, a member of the Scripps Research Department of Immunology and lead author of the study.
The type of monoclonal antibody that was injected was specific to interleukin-2 (IL-2), a naturally occurring protein and a known immunotherapy for metastatic melanoma and renal cancer. The researchers showed that the anti-IL-2 monoclonal antibody (IL-2 mAb) expands the proliferation of specific T cells in vivo by increasing the biological activity of naturally occurring IL-2 through the formation of immune complexes. When combined with recombinant IL-2, some IL-2/IL-2 mAb complexes cause more than a 100-fold proliferation in CD8+ T cells, which can target virally infected cells or tumor cells.
Interleukin-2 increases the number of a subset of CD8+ T cells (referred to as antigen-experienced or memory T cells) in circulation and is often used for tumor immunotherapy and vaccination. However, IL-2 also stimulates CD4+ T regulatory cells, which can suppress those same memory T cells. Therefore, the prevailing view was that administration of IL-2 mAb removes the IL-2-dependent CD4+ T regulatory cells, which in turn leads to an expansion of CD8+ T cells.
"In the study, however, we noticed that the enhancing effect of IL-2 mAb correlated with naturally occurring levels of IL-2," Boyman said. "We concluded that, despite its reported neutralizing effect, IL-2 mAb actually expanded the proliferation of CD8+ T cells simply by increasing the biological activity of pre-existing IL-2 through the formation of antibody-cytokine immune complexes in vivo. We next combined recombinant IL-2 with IL-2 mAb, which led to an even more dramatic expansion. This expansion effect also extended to other types of antibody-cytokine complexes, such as IL-4/IL-4 mAb and IL-7/IL-7 mAb."
Despite these findings, Boyman noted, no one yet knows why these antibody-cytokine complexes are such potent immune response boosters in vivo.
"A few studies have suggested that injecting a cytokine together with the right antibody increases the half-life of the cytokine in vivo, accompanied by a very mild immune activation," he said. "But our study suggests a different mechanism and that joining a cytokine to its specific antibody opens the way for selective and vigorous stimulation of T cell subsets. With some types of antibodies, injecting IL-2/IL-2 mAb complexes might be clinically useful for tumor immunotherapy and for expanding T cell numbers after bone marrow transplantation. On the other hand, expansion of CD4+ T regulatory cells by IL-2 combined with another type of IL-2 mAb might provide a basis for treating autoimmune disease."
Other authors of the study include Marek Kovar, Mark Rubinstein, and Charles D. Surh of the Scripps Research Department of Immunology and Jonathan Sprent of the Scripps Research Department of Immunology and the Garvan Institute of Medical Research, Darlinghurst, Australia.
The study was supported by the National Institutes of Health, the Swiss National Science Foundation and the Novartis Foundation.
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