Comprendre les maladies en vue de tirer le meilleur parti de la pratique transfusionnelle
Le laboratoire d’Alan Lazarus étudie un trouble auto-immun appelé « purpura thrombocytopénique idiopathique ». Les patients qui en souffrent produisent des anticorps dirigés contre les plaquettes de leur organisme. Cette maladie provoque une baisse du nombre de plaquettes qui peut causer des hémorragies et, dans de rares cas, la mort. M. Lazarus a également fait valoir son expertise en matière de prévention de la maladie hémolytique du fœtus et du nouveau-né; une maladie provoquant la production, par la mère, d’anticorps nuisibles aux globules rouges du fœtus ou du nouveau-né.
Why is this important?
Comprendre le purpura thrombocytopénique idiopathique et la maladie hémolytique du fœtus et du nouveau-né, ainsi que les mécanismes d’action de leurs traitements, pourrait permettre de mettre au point de nouveaux traitements.
At present there is no cure for ITP, but several products or treatments offer patients a chance for a better life in spite of the disease. Dr. Lazarus’ work focuses on two of these products: intravenous immunoglobulin (IVIg) and anti-D. IVIg is provided by Canadian Blood Services to hospitals to treat ITP (as well as many other diseases, as determined by physicians). IVIg is available in limited supply, is very expensive, and we do not know how it works. Dr. Lazarus's team is internationally recognized for its work on the molecular mechanisms of IVIg. Their work has provided insight on how IVIg treatment counteracts the thrombocytopenia (low platelet numbers in the blood) which occurs in ITP. For example, they used a mouse model of ITP to show that IVIg treatment works through the action of a cell called a dendritic cell – the cell that orchestrates the immune system. In collaboration with Dr. John Semple’s group, they showed that the activity of IVIg also involved cells called T regulatory cells — cells important in autoimmunity that are activated downstream of dendritic cells. They have also demonstrated that monoclonal antibodies against CD44 can mimic the effects of IVIg, at least in mouse models. Such an IVIg substitute could constitute a novel treatment for ITP and other autoimmune diseases which could be more readily manufactured than IVIg. In collaboration with Dr. Bill Sheffield and postdoctoral fellow Dr. Ben Yu, they have recently found an effective way to block the receptors which cause the thrombocytopenia (FcγRIII) in a manner that does not trigger adverse events in a mouse model of ITP.
Anti-D, a plasma-derived (antibody) product provided by Canadian Blood Services, is also used to treat ITP. Again, we do not know how anti-D works in treating ITP but Dr. Lazarus's group has demonstrated (using animal models) that anti-D works by a distinct mechanism slightly different than IVIg in ameliorating ITP. The prevention of hemolytic disease of the fetus and newborn (HDFN) using anti-D is known to be one of the most effective immunological interventions to prevent a disease. Although anti-D can be 99% effective in preventing HDFN, oddly, we do not really know how it works. Dr. Lazarus's team is attempting to determine how anti-D prevents HDFN. Thus far his group has demonstrated that an antibody very similar to anti-D works by inhibiting the immune response by shutting down a subset of white blood cells called B lymphocytes.