Understanding Diseases to Optimize Transfusion Practice
Dr. Lazarus’ laboratory is investigating a particular autoimmune disease termed immune thrombocytopenia (ITP) in which patients have antibodies against their own platelets. This autoimmune disease results in a loss of platelets which in turn can lead to uncontrolled bleeding and in rare cases death. Dr. Lazarus’ expertise also extends to hemolytic disease of the fetus and newborn (HDFN) in which antibodies produced by a mother can target the red blood cells of her fetus or newborn. Understanding ITP and HDNF, and how current treatments for these immune diseases work, could help provide better treatments for patients.
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.
Yu X, Menard M, Prechl J, Bhakta V, Sheffield WP, Lazarus AH. Monovalent Fc receptor blockade by an anti-Fcγ receptor-albumin fusion protein ameliorates murine ITP with abrogated toxicity. Blood; doi: blood-2015-08-664656. [Epub ahead of print]
Campbell IK, Miescher S, Branch DR, Mott PJ, Lazarus AH, Han D, Maraskovsky E, Zuercher AW, Neschadim A, Leontyev D, McKenzie BS, Käsermann F: Therapeutic Effect of IVIG on Inflammatory Arthritis in Mice Is Dependent on the Fc Portion and Independent of Sialylation or Basophils. The J Immunol 2014; 192:5031-5038.
Chen X, Ghaffar H, Jen CC, Lazarus AH: Antibody specific for the glycophorin A complex mediates intravenous immune globulin–resistant anemia in a murine model. Transfusion 2014; 54:655-664.
Crow AR, Yu H, Han D, Lazarus AH: Amelioration of Murine Passive Immune Thrombocytopenia by IVIg and a Therapeutic Monoclonal CD44 Antibody Does Not Require the Myd88 Signaling Pathway. PLoS One 2013; 8:e71882.
Lazarus AH: Monoclonal versus polyclonal anti-D in the treatment of ITP. Expert Opin Biol Th 2013; 13:1353-1356.
Semple JW, Kim M, Hou J, McVey M, Lee YJ, Tabuchi A, Kuebler WM, Chai Z-W, Lazarus AH: Intravenous immunoglobulin prevents murine antibody-mediated acute lung injury at the level of neutrophil reactive oxygen species (ROS) production. PLoS One 2012; 7:e31357.
Crow AR, Suppa SJ, Chen X, Mott PJ, Lazarus AH. The neonatal Fc receptor (FcRn) is not required for IVIg or anti-CD44 monoclonal antibody–mediated amelioration of murine immune thrombocytopenia. Blood 2011; 118:6403-6406.