Paris, 4 February 2010 -- A UMR INSERM 643 group at the University of Nantes (jointly led by Bernard Vanhove PhD and IUN Director Professor Gilles Blancho) has announced the publication of an article on a new promising approach for transplanted patients in the February 3, 2010, edition of the prestigious scientific journal Science Translational Medicine. In an article entitled “Inducing CTLA- 4–Dependent Immune Regulation by Selective CD28 Blockade Promotes Regulatory T Cells in Organ Transplantation” (Poirier et al., Science Translational Medicine, 2010), Professors Soulillou and Blancho, Dr Vanhove, their colleagues at UMR INSERM 643 and their collaborators at TcL Pharma (Nantes, France) and the University of the Maryland (Baltimore, USA) tested an alternative immunosuppression strategy for controlling host-versus-graft immune responses while maintaining the immune system’s ability to defend the body against infections and tumors. Inducing immune tolerance and reducing toxicity in transplantation.
Rapid growth in the use of organ transplantation was facilitated by the discovery (in the early 1980s) of cyclosporin’s powerful immunosuppressant properties. However, cyclosporin and the other calcineurin inhibitors discovered since then display not only conventional drug toxicity but also immune toxicity related to the non-specific nature of the resulting immunosuppression.
T lymphocytes play a major role in host-versus-graft immune responses. These cells are activated after specific antigen recognition by the T cell receptor and engagement of the costimulatory molecules CD80/CD86 through the CD28 receptor. T cells are capable of subsequently synthesizing another receptor, CTLA-4, which also binds CD80/86, blocks cell activation and induces the differentiation of regulatory T cells. The latter are important for (i) inhibiting the excessive immune responses which can generate autoimmune diseases and (ii) inducing a background of tolerance for transplanted tissues and organs.
Although several small molecule inhibitors of CD80/86 have already been tested with a view to replacing the calcineurin inhibitors, they affect the CD28-dependent T cell activation pathways by blockading the CTLA-4 regulation pathways. With the objective of selectively inhibiting the activation pathways while maintaining the regulatory pathways, the IUN researchers tested monovalent anti-CD28 monoclonal antibody fragments in preclinical models of renal and cardiac transplantation in the baboon and the macaque. The anti-CD28 antibody fragments induced the regulatory T cells which specifically control immune responses against transplanted organs; this led to inhibition of acute and chronic rejection reactions and a synergistic effect was seen with low doses of calcineurin inhibitors. The present results suggest that it may be possible to reduce the dose of calcineurin inhibitor (and thus the associated toxicity) in clinical transplantation by using CD28 costimulation blockade to induce specific immune regulation of the transplant.
Nantes University Medical Center and transplantation
The IUN (based at Nantes University Medical Center) is now Europe’s leading kidney transplant center, France’s leading center for combined kidney-pancreas transplants and one of the European leaders for pancreas transplants.
Organ transplantation - a major public health issue In 2009, the donation of organs, blood, platelets and bone marrow was designated as a “Major National Cause” by the French government, in order to raise public awareness of organ shortages - a true challenge in public health.
In 2008, there were 43,400 transplant recipients in France. 4,620 patients had received a transplant in that year alone, including 2,937 kidney transplants (i.e. 64% of the total). Today, over 13,6001 patients are on the waiting list for a transplant (versus 13,112 in 2007) and the average waiting time is 3 years! More generally, there are two other major problems in organ transplantation: the risk of transplant rejection and complications related to taking immunosuppressants including infections, cancers and cardiovasculars issues.
Researchers at the IUN are focusing on these two problems (notably by collaborating with biotech companies).
