IL2/IL2mAb促使CD8细胞增殖

IC

New treatments based on T-cell stimulation possible
http://www.drugresearcher.com/news/ng.asp?n=66067-autoimmune-immunology-cytokine
02/03/2006 - Scientists have found that certain T-cell stimulation could help improve treatment of autoimmune disease and cancer, which could be significant for developing new drug treatments to help patients with autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, or juvenile diabetes.

An autoimmune disorder occurs when the immune system attacks the body's own tissues. To properly function, the immune system must identify foreign substances such as bacteria, viruses, parasites, slivers, and it must be able to distinguish normal body tissue from these foreign substances.
If it fails to distinguish the difference, it attempts to destroy the tissue it wrongly identifies as foreign. For example, in autoimmune haemolytic anaemia, the body destroys its own red blood cells.

Scientists from the Scripps Research Department of Immunology, found that monoclonal antibody injections caused a massive selective increase in the immune system's two main types of T cells.

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 tumour 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 tumour 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. We concluded that, despite its reported neutralising 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,”Boyman said.

"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 tumour 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.

以下是Science的文章摘要
http://www.sciencemag.org/cgi/content/abstract/1122927v1
Reports
Submitted on November 22, 2005
Accepted on January 27, 2006

Selective Stimulation of T Cell Subsets with Antibody-Cytokine Immune Complexes
Onur Boyman 1, Marek Kovar 1, Mark Rubinstein 1, Charles D. Surh 1, Jonathan Sprent 2*
1 Department of Immunology, IMM4, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
2 Department of Immunology, IMM4, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA; Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia.

Interleukin-2 (IL-2), a growth factor for T lymphocytes, can also sometimes be inhibitory. Thus, proliferation of CD8+ T cells in vivo is increased after injection of monoclonal antibody specific for IL-2 (IL-2 mAb), perhaps reflecting removal of IL-2 dependent CD4+ T regulatory cells (T regs). Instead, we show here that IL-2 mAb augments proliferation of CD8+ cells simply by increasing the biological activity of pre-existing IL-2 through formation of immune complexes. When coupled with recombinant IL-2, some IL-2/IL-2 mAb complexes cause massive (>100-fold) expansion of CD8+ cells in vivo while others selectively stimulate CD4+ T regs. Thus, different cytokine/antibody complexes can be used to selectively boost or inhibit the immune response.