Previous Talents Program Awardees

2008

Dr Jacob Pendergrast, Canada

Dr Pendergrast is a Transfusion Medicine Specialist at Toronto General Hospital, in addition to holding a lectureship at the University of Toronto.

Research proposal: ‘Clinical Significance of ABO Antibodies In Commercial Intravenous Gammaglobulin Products’ (2 years).

All intravenous immunoglobulin (IGIV) products contain the donor-derived isoagglutinins anti-A and anti-B. In half of all infusion recipients these isoagglutinins can induce a positive direct-antiglobulin test (DAT). Due to this minor ABO incompatibility there are increasing reports of IGIV-mediated hemolysis. The true incidence remains unknown.

The aim of this study is to determine the incidence of clinically significant IGIV-mediated hemolysis. This will be achieved using a uniform patient population receiving a standard dose of IGIV and assessing the evidence of accelerated red blood cell destruction. The primary outcome is hemolysis; the secondary outcomes are a positive DAT plus eluate and symptomatic hemolytic anemia. It is anticipated that 5% of patients will have hemolysis following the infusion of IGIV. In investigations to be performed in subsequent studies, patients will be assessed for risk-factors for IVIG-mediated hemolysis, including Secretor status and isotypes of ABH antigens.

The study is a satellite study to the Talents-funded trial by Dr Bril and may assist in identifying high-risk patient subgroups in which high-dose IGIV infusions should be used with particular caution.

Dr Barbara Wasowska, USA

Dr Wasowska is Assistant Professor at the Johns Hopkins University School of Medicine, Baltimore, MD.

Research proposal: ‘Strategies to modulate complement activation by modifying IGIV’ (2 years).

Clinically, antibody-mediated transplant rejection has become critical because this form of rejection is usually unresponsive to conventional anti-rejection therapy. Alloantibodies contribute to rejection through the complement system.  Irreversible graft rejection correlates with high levels of alloantibodies specific to HLA and the deposition of C4d in the graft. Inhibition of complement activation is one of the proposed mechanisms by which IGIV prevents antibody-mediated transplant rejection.  IGIV can also reverse this type of rejection and prevent reemergence of specific alloantibodies after transplantation.

Dr Wasowska has previously generated a clinically relevant model to investigate how IGIV prevents the activation of complement and the subsequent deposition of C4d.  In preliminary studies she documented that IGIV inhibits MBL-dependent complement activation.

The hypothesis of this study is that the interaction of MBL with different IVIG glycoforms modulates the effectiveness of IGIV to inhibit complement activation. This will be tested using human microvascular endothelial cells derived from brain and kidney donors sensitized with anti-HLA antibodies in the presence of different IGIV-glycoforms. These studies may lead to the production of more effective preparations of IGIV that could be used to prevent transplant rejection in highly sensitized patients.

Dr Mark Ballow, USA

Dr Ballow is Professor of Pediatrics at University at Buffalo Pediatric Associates Inc, NY. He is also Chief of the Division of Allergy and Immunology.

Research proposal: ‘Effects of IGIV on dendritic cell maturation and function; comparison of gamunex with other commercial IGIVs’ (1 year).

Dendritic cells (DCs) are important antigen-presenting cells and play a critical role in the immunological events at the interface between the innate and the adaptive immune response. Limited data suggest that different preparations of IGIV may affect the maturation process of DCs.

Preliminary data indicate that Gamunex® significantly upregulates the expression of two DC cell surface antigens involved in maturation and co-stimulation; this contradicts another study that used Carimmune NF®. In this study, DCs will be isolated from peripheral blood of healthy donors and monocytes (CD14+), cultured and matured into DCs, and various IGIV preparations will be added at specific time points. DC maturation will then be assessed. The primary objective is to determine whether peripheral blood derived DC-induced maturation modulated by IGIV is influenced by the type of IGIV product used. In addition, it is hoped that the mechanism(s) responsible for these differences are elucidated. These studies using DC maturation may offer an insight into the biological differences between IGIV preparations.

Dr Franz Blaes, Germany

Dr Blaes is the Head of Clinical Neurophysiology Department and Group Leader of the Autoantibody Research Group at the Neurological Department, Justus-Liebig-University in Giessen. He is also on the advisory board of the German Society for Muscle Diseases.

Research proposal: ‘Double-blind, placebo-controlled cross-over study to investigate the effect of intravenous immunoglobulins on complex regional pain syndrome (CRPS, M. Sudeck)’ (2 years).

Complex regional pain syndrome (CRPS) is a severe chronic pain syndrome associated with serious trophic disturbances that frequently occur after limb trauma. Two forms, CRPS1 and CRPS2, can be distinguished, one without and one with associated nerve injury, respectively. Evidence to date suggests there is an autoimmune component to the disorder, with neurogenic inflammation and autoantibodies found against peripheral nervous system structures in CRPS patients. This is supported by case reports that document the positive effects of IGIV in CRPS patients.

The aim of this double-blind, placebo controlled, randomized, cross-over study is to investigate the efficacy and safety of IGIV in CRPS. The primary end point of the study is a 40% reduction in the McGill pain questionnaire or a decrease of the trophic disturbances. Secondary endpoints include: reduction in pain disability score, decrease in associated pain medication and decrease in antineuronal autoantibodies. If this trial confirms that IGIV is effective and safe in the treatment of CRPS, it could lead to further clinical trials and stimulate further research into other chronic pain disorders.

Dr Hamid Rabb, USA

Dr Rabb is a Professor of Medicine and Physician Director in kidney and pancreas transplantation at Johns Hopkins University, Baltimore, MD.

Research proposal: ‘IGIV to protect kidney from ischemia reperfusion injury’ (2 years).

Kidney ischemia reperfusion injury (IRI) is the leading cause of acute renal failure in native kidneys and worsens the outcomes for kidney transplantation. A broad-based immunomodulatory agent such as IGIV could dampen the immune response and may have a positive impact on kidney IRI.

The primary objective of this study is to confirm if IGIV is a protective agent for kidney IRI. The study will test this hypothesis in vivo using a mouse model. Dr Rabb hypothesizes that as IGIV is a relatively safe agent with the potential to downregulate detrimental immune responses, pre-treatment with IGIV could protect the kidney from IRI. In addition, this study may confirm if post-reperfusion treatment could also be protective and evaluate the mechanisms by which IGIV protects the kidney from IRI. The outcomes of this study may set the stage for future human studies and clinical trials for kidney IRI.