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Marcia F. McInerney 419-530-1981 Phone |
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Institutions/Degrees
| B.A. Biology, 1972 | University of Connecticut |
| M.S. Microbiology and Immunology, 1979 | Case Western Reserve University |
| Ph.D. Microbiology and Immunology, 1989 | University of Michigan |
| Postdoctoral Fellow Immunobiology, 1991 | Yale University School of Medicine |
| Senior Iacocca Fellow, 1998 | Joslin Diabetes Center / Harvard School of Medicine |
Medicinal / pharmaceutical chemistry. Cell-mediated autoimmune aspects of Type 1 insulin-dependent diabetes mellitus.
Click here to see article on Dr. McInerney's Research to Alleviate Gum Disease in Diabetics
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Click here to see pictures and information related to Dr. McInerney's collaborations with other research groups
Research Interests
My research is focused on the autoimmune aspects of Type 1 or insulin-dependent diabetes (T1D). The animal used for this research is the nonobese diabetic (NOD) mouse. In humans and the NOD mouse T1D is genetically inherited, autoantibodies to insulin and islet cells are produced, and T lymphocytes invade the islets in the pancreas. T-cell invasion or insulitis is associated with destruction of the insulin-secreting beta cells. In the NOD mouse, insulitis begins at 4-6 weeks of age, however the mice do not spontaneously become diabetic until 3 to 6 months of age, at which time sufficient beta cells have been destroyed to result in the loss of insulin secretion. T1D is considered to be a T cell mediated autoimmune disease, since splenic T cells, obtained from diabetic mice, but not autoantibodies (present in diabetic serum), can passage disease into irradiated, young, 6-8 week old nondiabetic NOD mice. Our published data shows that T lymphocytes, from diabetic NOD mice, that express a high density of insulin receptors (IR+ T cells) aggressively transfer insulitis and diabetes while T cells lacking IR expression (IR- T cells) are capable of neither. Other investigators have shown that the IR can function as a chemotactic receptor capable of directing cell movement in response to a gradient of insulin. Therefore, IR expression on cells, in vivo, may promote cell movement into the islet where insulin is concentrated. Once in place antigen specific T cells within the IR+ T cell population may expand and destroy beta cells. Furthermore, our research has shown that in the natural history of spontaneous T1D in NOD mice, IR+ T cells concentrated in insulitis lesions prior to diabetes onset indicating that IR expression on T cells may be an early marker for pathogenic cells. Further research has shown that IR+ T cells also have activation/memory markers equivalent to what has been observed on cells in insulitis lesions. Based on the NOD data, my laboratory is also investigating whether IR+ T cells are involved in the pathogenesis of human T1D by determining if increased numbers of IR+ T cells in the peripheral blood are associated with an increased risk for T1D. This is being tested by comparing the levels of IR+ T cells in five groups of patients: 1) new-onset diabetics, 2). relatives of diabetic patients at high risk for developing T1D [autoantibody positive], 3). relatives of diabetic patients at low risk for developing T1D [autoantibody negative], 4). patients with autoimmune diseases other than T1D and 5). normal controls. Preliminary data indicates that high risk relatives have the highest number of IR+ T cells. An association of IR+ cells with an increased risk for diabetes would provide a new target for drug therapy. Furthermore, chemotactic signaling and metabolic signaling are mediated by distinct parts of the insulin receptor and could therefore, be selectively targeted for therapeutic intervention prior to diabetes onset.
Based on the IR data a JDRF grant was submitted and funded that requested monies to generate a transgenic mouse with a FLAG tagged IR targeted to T cells. Recent data from another laboratory has shown that cells can move into the pancreas independent of T cell- MHC/Ag interactions. These grants propose to test the question of whether IR expression on T cells in a normal mouse strain (FVB) can lead to movement of T cells into the islet. If IR signaling is a delivery mechanism then therapeutic protocols designed to reduce IR expression specifically on T cells, or block IR chemotactic signaling, may delay or prevent diabetes onset in diabetes-prone individuals.
The other major focus in the laboratory involves innate immune responses to oral pathogens in diabetes. Diabetes is a risk factor for severe periodontal disease. Major pathogens associated with periodontitis are Porphyromonas gingivalis (P. gingivalis), Bacteroides forsythus (B. forsythus) and Treponema denticola (T. denticola), all gram-negative anaerobes. Previous studies suggest that both innate and adaptive immunity are involved in protection against periodontal infection. Innate immune responses are the first line of defense against an infection. Innate immune system cells, such as macrophages, react to common microbial surface molecules through newly discovered receptors on the macrophage cell surface called Toll-like receptors (TLRs). Preliminary studies have found that lipopolysaccharide (LPS) derived from Gram-negative bacteria regulate the expression of several different TLRs in macrophages and trigger cytokine production and expression of co-stimulatory molecules in macrophages. These events are essential for macrophage activation and initiation of specific adaptive immune responses for generation of antigen specific cells. The purpose of this project is to study innate immunity in type 1 diabetes, in particular, the role of TLR in the initiation of host immune responses against oral pathogens in periodontal infection, using the well established nonobese diabetic (NOD) mouse model of type I diabetes. NOD macrophage responses to live bacteria and LPS isolated from P. gingivalis, B. forsythus and T. denticola in terms of cytokine production, costimulatory molecule expression, TLR mRNA levels and TLR signal transduction will be compared to NOR mice, a diabetes resistant control strain. Our hypothesis is that a defect in innate immunity in type 1 diabetes contributes to the susceptibility to periodontal infection since it should be the interaction between the TLR and the oral pathogen that initiates immune responses. These experiments will generate novel information on innate immune responses to oral pathogens in type 1 diabetes and may lead to development of therapeutic interventions to alleviate severe periodontitis in diabetes.
Another past and current focus in the laboratory is on cytotoxic CD8+ T cells. Cytotoxic cells can directly attack and kill target cells expressing the appropriate antigen. Using my Career Development Award support from the ADA, I found that CD8+ T cells isolated directly from islets recognize insulin as an autoantigen and therefore can directly lyse islet cells. Further work on CD8+ T cells has continued in collaboration with Drs. Eli Sercarz (Torrey Pines Institute) and Anthony Quinn (UT, Biological Sciences Dept.). Other collaborative work includes research on gene therapy for islet transplantation with Dr. James Byers (UT, Pharmacology Dept) and investigation into the role of the cytokine IFN? in the development of diabetes with Drs Deborah Vestal (UT, Biological Sciences Dept), Anthony Quinn and Hermann vonGrafenstein (UT, Medicinal and Biological Chemistry Dept). Sabbatical leave research with Dr. Myra Lipes (Joslin Diabetes Center/Harvard) focused on studying beta cell surrogates for islet transplantation, showed that CD4T cells are not necessary for diabetes development if islet cells expressed costimulatory molecules and developed a new mouse model of human myocarditis.
Dr. McInerney is currently involved in collaborative USDA funded research with Dr. Sonia Najjar (The University of Toledo, College of Medicine) concerning dietary and genetic risk factors in Obesity and Insulin Resistant or Type 2 Diabetes. Diabetes is a complex disease usually involving abnormal metabolism resulting from genetic predisposition as well as environmental factors. Diet and lack of exercise play critical roles in causing obesity, often resulting in diabetes and its complications. By identifying dietary and other environmental factors that act upon genetic predisposition, strategies be developed and implemented to prevent obesity, diabetes and its associated diseases. Using appropriate bioinformatics-based analysis, a wealth of data would be extracted to identify the genetic and environmental basis for the development of obesity and diabetes. For example, we will identify genes/proteins that are commonly increased or decreased in response to certain dietary manipulations. Identified genes/proteins will become prime candidates for further functional analysis. This will lead to a better understanding of the molecular basis of obesity and diabetes, and secondary heart, brain, kidney and infertility complications. Only through this venue can we identify biomarkers and promote better diagnostics, prevention and therapeutic strategies against these alarming diseases.
More than 30% of adults and 15% of children in the United States are obese. More alarming is the 6% increase per year in obesity in young children and adolescents. Among obesity-related diseases, type 2 diabetes is dangerously close to becoming an epidemic. Based on newly released statistics from the Centers for Disease Control and Prevention (CDC) diabetes rates have risen by over 14% in just the last two years. As of November, 2005, 7% of the total population of the United States, 20.8 million Americans, have diabetes and the cost to society has increased to $150 billion a year. The death rate due to diabetes in the State of Ohio is twice the national average and four times higher for African Americans. Therefore, the impact of diabetes in Ohio as well as in the United States, is highly significant.
Representative Publications
