A Leader in Immunogenetics
McGowan Institute for Regenerative Medicine faculty member Massimo Trucco, MD (pictured), is an international leader in the field of immunogenetics, having dedicated his life’s work to finding a cure for diabetes. Dr. Trucco is the Director of the Division of Immunogenetics at the Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center, the Hillman Professor of Pediatric Immunology at Children’s Hospital, and a Professor of Pediatrics at the University of Pittsburgh School of Medicine. Other academic affiliations of Dr. Trucco include:
• Founder and Director, Pediatric Research Section, University of Pittsburgh Diabetes Institute
• Director, Juvenile Diabetes Foundation Center for Gene Therapy Approaches to Type 1 Diabetes
• Director, Children's Hospital Histocompatibility Center (affiliated with the National Marrow Donor Program)
• Member, Pittsburgh Cancer Institute
Dr. Trucco was born in Savona, Italy. During his medical residency at Regina Marghertia Children's Hospital, University of Torino, School of Medicine, he worked on research in tissue compatibility, an area directly related to bone marrow transplantation. His curiosity has driven him to move to three countries to study at renowned universities and research institutes, and work side-by-side with two Nobel Prize winners.
An established scientist, Dr. Trucco came to Pittsburgh in 1986 to focus his genetic and immunologic research on several significant diseases of childhood, including diabetes. Since then, his discoveries have led to:
• a better process for molecular typing for matching bone marrow donors and recipients;
• the ability to identify those at risk for diabetes;
• an understanding of the link between a virus and Type 1 diabetes;
• a potential cure for the pancreatic damage that causes insulin dependence.
Dr. Trucco and his team are closing in on a cure for Type 1 diabetes. He has made several significant findings including the isolation of a super-antigen that is believed to trigger juvenile diabetes in children. It is widely suspected that this discovery, and others that Dr. Trucco has made, will lead to a cure.
A Career Dedicated to Diabetes Research
Type 1 diabetes is regarded as an autoimmune disease because a person’s immune system’s T-cells attack and destroy the beta cells in the pancreas that produce insulin. Type 1 diabetes also is known as insulin-dependent diabetes mellitus or juvenile-onset diabetes. The National Institutes of Health (NIH) reports that more than 1 million children and teenagers (age 19 and younger) have Type 1 diabetes. According to the NIH, 5 percent to 10 percent of diagnosed diabetes cases in the United States are Type 1 diabetes.
Building on his 1994 discovery that Type 1 diabetes susceptibility may be genetic in nature and triggered by viruses, Dr. Trucco's discoveries have continued to lead to better processes for molecular typing for matching bone marrow donors and recipients, the ability to identify those at risk for diabetes, an understanding of the link between a common virus and Type 1 diabetes, and a potential cure for the pancreatic damage that causes insulin dependence. The research milestones of Dr. Trucco include:
In 1977-78, research into why some organ transplants were successful and why some were not, as well as why all donors and recipients were not compatible, showed that abnormalities in HLA cells (histocompatibility locus antigens) were a genetic predisposition for autoimmune disease.
In 1988-90, landmark studies were published on the genetic susceptibility of certain individuals to Type 1 diabetes. Research also showed that the low incidence of diabetes in China is related to that population’s relative genetic resistance to the disease, while the high incidence of diabetes in Finland is related to that population’s genetic predisposition.
In 1998, the Coxsackievirus B is identified as one of the viruses responsible for triggering Type 1 diabetes, making it possible to potentially develop a vaccine.
In 2006, Dr. Trucco’s lab discovered a process using a patient’s own blood, combined with a safe mixture of molecules. With the use of this combination, it is possible to interrupt T-cell and beta cell interaction, which is known to cause diabetes. The team removed dendritic cells from the patient’s own blood, and the cells were mixed with the proteins CD40, CD80, and CD86, and injected back into the patient where it was found that the CD40, 80, and 86 block the process of the T-cell and beta cell interaction.
Over the years, Dr. Trucco and his team have received continuous grant support from various organizations and agencies. This funding helped facilitate Dr. Trucco’s career and his dedication to diabetes research. The Trucco Lab funding sources, their related projects, and their descriptions include:
Title: Juvenile Diabetes Mellitus: Epidemiology & Etiology
Agency: The National Institute of Diabetes and Digestive and Kidney Diseases
Description: Immunological and environmental causes for IDDM (insulin-dependent diabetes mellitus) are studied in the families included in the IDDM registry of Allegheny County.
Title: Gene Therapy Approaches to Type I Diabetes
Agency: Juvenile Diabetes Research Foundation
Description: Different gene therapy approaches are proposed in this Program Project to take care of many different aspects of diabetic patients: from cell lines artificially programmed to secrete insulin when the glycemia increases, to the immunologic prevention of autoimmunity attacks against transplanted islets of the pancreas.
Title: New Advanced Technology to Improve Prediction and Prevention of Type 1 Diabetes
Agency: U.S. Army Medical Research Acquisition Activity
Description: Genetic determination of susceptibility and resistance to diabetes can be determined in large populations using pyrosequencing technology. The genetic risk will be associated with autoantibody ascertainments able to better able to predict diabetes onset.
Title: TRIGR (Trial to Reduce IDDM in the Genetically at Risk) Study; CHP Portion: Nutritional Primary Prevention of Type 1 Diabetes
Agency: National Institutes of Health
Description: A possible trigger of the autoimmune process that brings about overt Type 1 diabetes is cow's milk. Formulas prepared without certain proteins normally present in cow's milk will be tested in comparison with conventional formulas.
Title: Prediction and Prevention of Type 1 Diabetes
Agency: National Institutes of Health
Description: (part of TrialNet for human trials) This application testifies to our willingness to participate in the Diabetes Prevention Trial for Type 1 Diabetes (DPT-1) now that the mandate of this trial has been renewed by the National Institutes of Health.
Dr. Trucco and his team continue their landmark research into improving the prediction of Type 1 diabetes and understanding and managing its complications. “We have some of the best researchers and clinicians in their fields, and it is conceivable that with this concentration of talent, Pittsburgh could be the place where the cure for diabetes is discovered,” says Dr. Trucco.
Published Milestones in Diabetes Research
Recently, Dr. Tucco and his colleagues published their milestone research results in the pursuit of a diabetes cure in two renowned journals. The articles are found in the June 2008 issues of Diabetes and Pediatric Diabetes.
In Diabetes: A microsphere-based vaccine prevents and reverses new-onset autoimmune diabetes. -- This study in mice was aimed at ascertaining the efficacy of microspheres formulated of antisense oligonucleotide (short DNA sequences) to prevent Type 1 diabetes and to reverse new-onset disease. The microspheres prevented Type 1 diabetes and, most importantly, exhibited a capacity to reverse clinical hyperglycemia, suggesting reversal of new-onset disease. This novel microsphere formulation represents the first diabetes-suppressive and reversing nucleic acid vaccine.
In Pediatric Diabetes: Toward a cure for Type 1 diabetes mellitus: diabetes-suppressive dendritic cells and beyond. -- In the past 20 years, bench-side research has made many promises to ‘cure’ Type 1 diabetes. Only recently has it been possible to clinically implement a limited number of bench-side successes and easier to consider immunotherapies aimed at preventing and perhaps reversing Type 1 diabetes. Key reference points (e.g., biochemical, physiologic, and immunologic profiles) and safety measurements have encouraged the adaptation of autologous (the patient’s own) immune cell therapy to reverse new-onset Type 1 diabetes and the envisioned trials with the microsphere vaccine.
“This novel microsphere approach represents for the first time a vaccine with the potential to suppress and reverse diabetes. This finding holds true promise for clinical testing in people with Type 1 diabetes,” said Dr. Trucco.
In mice with autoimmune diabetes, the scientists injected the microspheres under the skin near the pancreas. The microspheres were then captured by white blood cells known as dendritic cells which released the nucleic acid molecules within the dendritic cells. The released molecules reprogrammed these cells, and then migrated to the pancreas. There, they turned off the immune system attack on insulin-producing beta cells. Within weeks, the diabetic mice were producing insulin again with reduced blood glucose levels.
Type 1 Diabetes Vaccine in Clinical Trial
Dr. Trucco and scientists at Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center are involved in a research study where microspheres carrying targeted nucleic acid molecules fabricated in the laboratory have been shown to prevent and even reverse new-onset cases of Type 1 diabetes in animal models. This innovative scientific approach is currently in a Phase 1 clinical trial at the hospital.
In Type 1 diabetes, T cells from the immune system travel to the pancreas and destroy beta cells, which produce insulin. The scientists found that the microspheres reprogram dendritic cells to block the signaling mechanism that sends T cells to destroy beta cells.
Currently, Dr. Trucco and his colleagues are conducting a clinical trial of their leukapheresis-based dendritic cell approach in humans at Children’s. This Phase 1 clinical trial has been approved by the U.S. Food and Drug Administration (FDA). If the leukapheresis-based approach continues to show exceptional safety, the researchers hope to launch a national clinical trial that will assess the effectiveness of the dendritic cells in pediatric patients to prevent diabetes or reverse the disease right after it is clinically confirmed. The study, “Autologous Dendritic Cell Therapy for Type 1 Diabetes Suppression: A Safety Study,” is currently open for enrollment.
Leukapheresis is a process that allows for the collection of dendritic cell precursors from the patients in the study, which takes two to four hours. After the precursors are collected, they are treated in the lab with specific growth factors that turn them into dendritic cells. The growth factors are also combined with short DNA sequences that specifically block the expression of molecules that are found at the surface of dendritic cells known as CD40, CD80, and CD86. Once these reprogrammed dendritic cells are tested in the lab, they are injected back into the patient. They then orchestrate an anti-diabetic effect by suppressing the activity of T-cells which are responsible for the impairment and destruction of the pancreatic insulin-producing cells.
The McGowan Institute congratulates Dr. Trucco on all his scientific achievements and thanks are extended to him and his colleagues on behalf of all of the patients that these emerging technologies may one day help.
Illustration: McGowan Institute for Regenerative Medicine.
Dr. Trucco biography, Children’s Hospital of Pittsburgh of UPMC
Dr. Trucco on NBC’s Today Show video link
Dr. Trucco biography, University of Pittsburgh School of Medicine, Graduate Program of Immunology
Children’s Hospital of Pittsburgh of UPMC Division of Immunogenetics
Children’s Hospital of Pittsburgh of UPMC News Release
United Press International
A microsphere-based vaccine prevents and reverses new-onset autoimmune diabetes
Brett Phillips, Karen Nylander, Jo Harnaha, Jennifer Machen, Robert Lakomy, Alexis Styche, Kimberly Gillis, Larry Brown, Debra Lafreniere, Michael Gallo, Janet Knox, Kenneth Hogeland, Massimo Trucco, and Nick Giannoukakis
Diabetes 57:1544-1555, 2008.
Toward a cure for type 1 diabetes mellitus: diabetes-suppressive dendritic cells and beyond
Nick Giannoukakis, Brett Phillips, Massimo Trucco
Pediatric Diabetes 9 (3pt2), 4–13, June 2008.
The Pittsburgh Channel
Autologous Dendritic Cell Therapy for Type 1 Diabetes Suppression: A Safety Study
Children's Hospital of Pittsburgh of UPMC Studies Open for Enrollment