Tuesday November 06 2007
CEA
What are the mechanisms underpinning tolerance in transplantation?
Blood, (2007) (in press)
CEA
What mechanisms come into play in graft acceptance? Why do grafts sometimes function well, and why, other times, are they rejected? These are questions to which the I²BM’s Blood Immunology Research Department (the SRHI) is searching for answers. The team recently described the mechanisms of action involved in graft tolerance1.
1996: the SRHI team demonstrates that the HLA-G protein plays a role in maternal tolerance of the foetus, thereby explaining why a foetus is not rejected by the mother. They went on to show that HLA-G also plays a tolerance-related role in heart, kidney and liver-kidney transplantation. It was noted that in patients who successfully accepted their grafts, the HLA-G molecule was expressed both in the graft and as a molecule in the peripheral blood (plasma levels).
In their latest article, the SRHI research team confirms that high plasma HLA-G levels are significantly associated with graft acceptance in three groups of transplanted patients (kidney, liver, kidney + liver), going on to demonstrate the dual action of HLA-G.
On one hand, HLA-G is an inhibitor of the T-lymphocytes involved in graft rejection. These cells, which are found in white blood cells, play a part in the body’s immune defence response and fight virus-infected cells. In an organ graft context, without action from HLA-G, these cells would go on to destroy the graft.
On the other hand, HLA-G also induces regulatory CD4 and CD8 T-cells which amplify the mechanisms of tolerance by inhibiting the T-lymphocyte function involved in graft rejection. These regulatory T-cells are characterized by a downregulation of CD4 and CD8 activation molecules. This graft-tolerant environment is further secured by a HLA-G-secreted immunosuppressant cytokine: interleukin-10*.
In addition to this newly-reported mechanism of action of HLA-G, the article also opens perspectives for significant breakthroughs in diagnostics, since the ability to assay plasma HLA-G levels would provide clinicians with a clinical indicator of graft acceptance and viability. The results of this kind of assay could then make it possible to prescribe better-adapted immunosuppressive treatments, with the added advantage of fewer side effects.
* Interleukins: natural proteins produced by the immune system and which act on the immune system itself. They play a messenger role between cells in the immune system.
1 Référence: Naji A, Le Rond S, Durrbach A, Krawice-Radanne I, Creput C, Daouya M, Caumartin J, Lemaoult J, Carosella ED, Rouas-Freiss N. (2007). CD3+CD4low and CD3+CD8low are induced by HLA-G: novel human peripheral blood suppressor T cell subsets involved in transplant acceptance. Blood. (in press)
Contact: Nathalie Rouas-Freiss / Nathalie.Rouas-Freiss@ cea.fr