Alan Lazarus, PhD

• Mechanism of action of intravenous immunoglobulin (IVIG) in treating autoimmune diseases
• Mechanisms of action of anti-D in preventing hemolytic disease of the fetus and newborn

• Platelet research

IVIG in Autoimmune Disease: There are cases in which the body's immune system is faulty, causing one's own immune system to attack the body. These cases are called 'autoimmune diseases' and we are investigating a particular autoimmune disease termed idiopathic thrombocytopenic purpura, or ITP (1). Patients with this disease have antibodies against their own platelets. These antibodies bind to platelets and mark them for removal by the spleen. A loss of platelets can lead to uncontrolled bleeding and in rare cases death. 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. One of these products is called IVIG. IVIG is provided by the Canadian Blood Services to hospitals to treat ITP (as well as many other diseases, as determined by your physician). IVIG is very expensive, it is available in limited supply, and we do not know it works (1). Dr. Lazarus's team has shed light on how IVIG improves the thrombocytopenia (low platelet numbers in the blood) which occurs in ITP (2,3), as well as derived several new potential IVIG substitutes (4). They have discovered that IVIG causes of the priming of a type of white blood cell called a dendritic cell which ameliorates the autoimmunity (5). His team has also demonstrated that a novel drug, which would be much less costly to produce than IVIG, could be employed to treat ITP as well as some other autoimmune diseases (6).

How Does Anti-D Work? One of the most effective immunological interventions that we have to prevent a disease, is the prevention of hemolytic disease of the fetus and newborn (HDFN) using a product called anti-D. Anti-D is a plasma-derived (antibody) product which is provided by the Canadian blood services to hospitals and doctors to prevent HDFN. Although anti-D is roughly 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 (using a model) 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 (7-9). Anti-D is also used to treat the autoimmune disease ITP. Again, we do not know how anti-D works in treating ITP but several theories have been proposed. One of these theories was that anti-D worked by the same mechanism as IVIG in ITP. Dr. Lazarus's group has demonstrated (using the model) that anti-D works by a distinct and different mechanism than IVIG in ameliorating ITP (10). Under standing how anti-D works is the first step in designing a synthetic replacement for this blood-derived product.

Platelet Research: Dr. Lazarus' team has also worked on platelet transmembrane signalling with relevance to a blood product called HYATE:C (a type of Factor VIII preparation used in some patients with haemophilia); for a review of some of this work, see reference (11).

Selected Publications:

Crow AR, Lazarus AH. The Mechanism of action of IVIg and anti-D in ITP. Transfusion Med Rev. 22:103-116, 2008.

Crow AR, Song S, Freedman J, Semple J, Lazarus AH. A role for IL-1 receptor antagonist or other key regulatory cytokines in the acute therapeutic effects of IVIg in murine ITP? Blood 109:155-158, 2007. This manuscript has been highlighted by the journal in the form of a commentary (see Inside Blood:109:4, 2007)

Siragam V, Brinc D, Crow AR, Freedman J, Lazarus AH. Can antibodies with specificity for soluble antigens mimic the therapeutic effects of intravenous IgG in the treatment of autoimmune disease? J Clin Invest 115:155-160, 2005. This manuscript has been highlighted by the journal in the form of a commentary (see commentary:115:25, 2005)

Song S, Freedman J, Crow AR, Lazarus AH. Monoclonal intravenous immunoglobulins can substitute for IVIG in the treatment of a murine model of immune thrombocytopenia. Blood 101:3708-3713, 2003. This manuscript has been highlighted by the journal in the form of a commentary (see Inside Blood:101:3344, 2003)

Siragam V, Crow AR, Brinc D, Song S, Freedman J, Lazarus AH. Intravenous immunoglobulin ameliorates ITP via activating Fc? receptors on dendritic cells. Nature Medicine 12:688-692, 2006.

Podolanczuk A, Lazarus AH, Crow AR, Grossbard E, Bussel JB. Of Mice and Men: an Open Label Pilot Study for Treatment of Immune Thrombocytopenic Purpura (ITP) by an Inhibitor of Syk. Blood 113:3154-3160, 2009. This manuscript has been highlighted by the journal in the form of a commentary (see Inside Blood:113:3133, 2009)

Brinc D, Le-Tien H, Crow AR, Freedman J, Lazarus AH. IgG-mediated immunosuppression is not dependent on erythrocyte clearance or immunological evasion: implications for the mechanism of action of anti-D in HDN? Br J Haem 139: 275-279, 2007.

Brinc, D, Le-Tien H, Crow AR, Siragam V, Freedman J, Lazarus AH. IgG-mediated regulation of the murine immune response to transfused red blood cells occurs in the absence of active immune suppression: implications for the mechanism of action of anti-D in the prevention of haemolytic disease of the foetus and newborn? Immunol 124: 141-146, 2008.

Brinc D, Le-Tien H, Crow AR, Siragam V, Freedman J, Lazarus AH. Transfusion of IgG-opsonized foreign red blood cells mediates reduction of antigen-specific B cell priming in a murine model. J Immunol 181:948-953, 2008.

Song S, Crow AR, Siragam V, Freedman J, Lazarus AH. Monoclonal antibodies that mimic the action of anti-D in the amelioration of murine ITP function by a mechanism distinct from that of IVIG. Blood 105:1546-1548, 2005.

Lazarus AH, Song S, Crow AR. Understanding platelet function through signal transduction. Transfusion Med Rev. 17:45-56, 2003