Previous Talents Program Awardee Profiles

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.

Prof Melvin Berger, USA

Dr Berger is Professor of Pediatrics and Pathology at the Children’s Research Foundation of Cleveland. He is also Director of the Jeffrey Modell Foundation Center for Primary Immunodeficiencies at Rainbow, Babies and Children’s Hospital, Cleveland, OH.

Research proposal: ‘Subcutaneous vs. Intravenous Immune Globulin Treatment in Animal Models of Neuromuscular Disease’ (2 years).

It is not known if the high peaks achieved by large IV doses are necessary in autoimmune diseases or if near-constant elevated serum IgG levels obtained by frequent subcutaneous injections (which generally result in fewer systemic adverse events) would work equally well.

This study is investigating whether immunoglobulin given by frequent subcutaneous injections (SCIG) is as effective as equivalent intravenous doses of immunoglobulin (IGIV) in rat and mouse models of myasthenia gravis and myositis. In both models, and in the corresponding human diseases, the pathogenesis involves complement deposition induced by auto-antibodies. This is likely to be a continuous, ongoing process and thus the total amount of IgG given over time is more likely to be the main determinant of efficacy than the height of the peaks achieved by IV therapy. If the results confirm that SCIG is effective in these models, it is likely that clinical trials in the corresponding human diseases would follow directly, with the aim that, in future, patients can treat themselves at home and achieve a better quality of life.

Dr Andreas Goebel, UK

Dr Goebel is a Consultant Anesthetist and Honorary Research Associate at the UCLH Pain Clinic, London, in addition to holding a position as Honorary Research Associate at the Institute for Molecular Medicine in Oxford.

Research proposal: ‘Intravenous immunoglobulin in the treatment of primary trigeminal neuralgia refractory to carbamazepine’ (2 years).

Trigeminal neuralgia (TN) is a severe chronic facial pain syndrome. A significant proportion of patients do not benefit from pharmacotherapy, such as carbamazepine, or surgery.

The study is examining the use of IGIV for TN in patients that do not respond to standard treatments. The study hypothesis is that treatment with IGIV will relieve pain from TN better than saline control in a prospective, randomized controlled trial. The primary endpoint of the study is the length of time that patients remain in the study (total study length is 3 months). There are clear stopping rules based on patient’s pain score and, in addition, patients are free to leave the trial at any stage. Secondary endpoints of the study are pain, noted on an 11-point numeric rating scale, and patient global impression of change (PGIC) on days 4-7 after treatment. A successful trial outcome will hopefully stimulate clinical research in the efficacy of IGIV in other intractable chronic pain conditions, including neuropathic pain.

Dr Frederick Goldman, USA

Dr Goldman is Associate Professor of Pediatrics at the University Of Iowa College Of Medicine, IA. He is also Director of the Carver Hematopoietic Stem Cell Bank and the Pediatric Immune Disorders Clinics at the University of Iowa, IA.

Research proposal: ‘Immunomodulatory properties of IGIV in developing immune systems post hematopoietic stem cell transplant’ (1 year).

IGIV has been used extensively in hematopoietic stem cell transplant (HSCT) recipients, both as replacement therapy and as an immune modifier. This study is investigating the use of IGIV in patients undergoing HSCT, as these individuals are immunocompromised for a period of several months, and are thus predisposed to a variety of infections and other complications.

In particular, the study is examining the effect of IGIV on T cells. The study hypothesis is that IGIV displays an inhibitory effect on T cells, and that this effect occurs in a dose-dependent manner. Also, the study is investigating whether IGIV is associated with down-regulation of Th2 cytokine responses in IGIV-treated HSCT recipients. Information gained from this study could modify current strategies of dosing and timing of IGIV infusions in the transplant setting and perhaps even extend the use of this drug for a greater length of time following transplant. Furthermore, understanding the mechanism of action of IGIV with regards to how it interacts with the immune system could enhance its use in the setting of other diseases, including autoimmune disorders in general.

Dr Régine Mydlarski, Canada

Dr Mydlarski is Director of Immunodermatology at the Faculty of Medicine,
University of Calgary. She previously served as Director of Immunodermatology at Sunnybrook & Women’s College Health Science Center, Toronto.

Research proposal: ‘A randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of intravenous immunoglobulin in the treatment of pemphigus vulgaris’ (2 years).

Pemphigus vulgaris (PV) is a potentially life-threatening autoimmune blistering disease of the skin and mucous membranes. Oral steroids (such as prednisone) and immunosuppressive drugs are currently considered the treatment of choice. However, these drugs are associated with a number of serious and dangerous side effects.

Dr Mydlarski’s study is comparing the efficacy and safety of IGIV to placebo in PV patients receiving standard therapies. In this study, patients meeting the study entry criteria have received standard therapies, in addition to being randomized to treatment with either IGIV or placebo. The primary outcome measure is the number of days required for both resolution of existing lesions and prevention of new ones. Secondary outcome measures include: the number of relapses, adverse events, quality of life measurements and costs of therapy. This randomized, double-blind, placebo-controlled trial may revolutionize the therapeutic approach to patients with this devastating immunobullous disease.

Dr Vera Bril, Canada

Dr Bril is a Professor of Medicine at the University of Toronto. She is also Division Director of Neurology.

Research proposal: ‘A randomized trial of plasma exchange compared with IGIV in the treatment of myasthenia gravis’ (2 years).

Acquired Mayasthenia Gravis (MG) is an autoimmune disease caused by antibodies against the acetylcholine receptor or muscle specific tyrosine kinase. Although immunotherapies are used widely to treat MG, each therapy has a different side effect profile, cost and availability.

This study is investigating the effectiveness of intravenous immunoglobulin (IGIV) to plasma exchange (PLEX) in a large number of patients with moderate-severe MG in a randomized study. Previously, only two small studies have compared immunomodulation with IGIV and PLEX. The primary endpoint of the study is the change in Quantitative Myasthenia Gravis Score (QMGS) from baseline to day 14 after treatment has ended. Secondary endpoints include the changes in QMGS from days 14-28, changes in subjective patient visual-analogue scale score, changes in acetylcholine receptor antibody titers and requirement for additional therapy. The study hypothesis is that both IGIV and PLEX will have comparable outcomes with different side-effect profiles. This trial could confirm which therapy is better for patients. In addition, information about response times, treatment duration and cost may be obtained.

Dr David Saperstein, USA

Co-Director Banner Good Samaritan Neuropathy Clinic and Clinical Associate Professor of Neurology, University of Arizona College of Medicine, Phoenix, AZ

Research proposal: ‘Database of suspected CIDP patients: identification and treatment responses’ (2 years).

The effectiveness of IGIV as a treatment for chronic inflammatory demyelinating polyneuropathy (CIDP) has previously been demonstrated in several placebo-controlled trials. These trials had rigorous and restrictive criteria which most CIDP patients do not meet. Currently, there are no universally accepted minimum criteria for selecting which polyneuropathy patients to treat for CIDP. Due to costs, therapy cannot be given too liberally.

The project involves the creation of a database containing patients treated for immune-mediated neuropathy but who do not meet formal criteria for CIDP. The project is utilizing data collected from patients treated with IGIV for suspected immune-mediated polyneuropathy from 10 neuromuscular centers throught the United States. Information collected consists of demographics, clinical findings, test results, and response to IGIV. On completion of the database it will be easier to assess factors that correlate with treatment response. Using multivariate regression analysis Dr Saperstein aims to create a predictive model. In the future this will generate the key data needed to plan a prospective, randomized trial.

Dr Mieko Toyoda, USA

Dr Toyoda is a Professor of Pediatrics, School of Medicine, UCLA, CA. She is also Director of Transplant Immunology Laboratory at Cedars-Sinai Medical Centre, CA.

Research proposal: ‘Development of novel assays to monitor human B-cell responses to alloantigens in patients undergoing desensitization with IVIG: relationship to antibody mediated rejection and responses to IVIG therapy’ (2 years).

Approximately 25% of IVIG-treated transplant patients experience antibody mediated allograft rejection. No tests currently exist to assess the efficacy of IVIG desensitization and distinguish patients who will do well from those who experience antibody mediated allograft rejection after transplantation.

This project is establishing tests to address the above issues. Dr Toyoda’s previous work has indicated that polyclonal B-cell activation and response against alloantigens may be the cause of antibody mediated rejection (AMR) in highly sensitized patients. The detection of B-cell activation could predict the risk of rejection. The study hypothesizes that abatement of B-cell activation is essential for successful transplantation in highly sensitized patients. The study is therefore investigating B-cell responses using intracellular cytokine flow cytometry (CFC) from the blood obtained pre- and post-IVIG treatment after kidney transplantation. The primary endpoint is whether alloantigen-specific B-cell responses correlate with transplantation rate, AMR and graft survival. If results confirm the hypothesis, B-cell CFC negative patients will have successful transplantations, and those who are positive are unlikely to receive transplantation and develop AMR if transplanted.