Thomas F. Tedder, PhD
The Lymphoma Research Foundation (LRF) is pleased to announce the recent publication of the work of Dr. Thomas F. Tedder, LRF Mantle Cell Lymphoma Exploratory / Developmental Grant recipient (2011), in the prestigious journals, Nature and Leukemia.
Dr. Tedder's research is focused on B cells, which represent a class of lymphocytes, (white blood cells) that are part of the immune system. His recently published studies describe a type of regulatory B cells (B10 cells) in mice and humans "that are potent regulators of immune responses." His lab has been instrumental in determining the cell surface characteristics, a "mechanism of action" [how the cells work] and the molecular characteristics of B10 cell regulation when the immune system mistakenly attacks its own body [i.e. autoimmune disease] and when the immune system causes inflammation. These recently published studies are important because they help researchers identify the cellular origins of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), and they have the potential to reveal new therapeutic targets for their diagnosis and treatment.
With extensive training in microbiology, biochemistry, cellular immunology and molecular biology, Dr. Tedder received his PhD in molecular cell biology from the University of Alabama in Birmingham, and was a faculty member at the Dana-Farber Cancer Institute and Harvard Medical School before joining Duke University as a Professor of Immunology.
"There is considerable diversity among B cells, as there is considerable diversity within the human population". According to Dr. Tedder, "each small group of B cells is likely to have unique properties that make them functionally distinct and pursue different 'careers' defending us against infection". Dr. Tedder states that, "we and others have recently identified a tiny subset of normal B cells that are potent regulators of immune responses. Among all B cells, these regulatory B cells are uniquely able to produce a forceful cytokine [a cell signaling molecule], interleukin-10 (IL-10). We call these unique B cells, B10 cells. These cells are important for controlling inflammation and autoimmunity, and limit normal immune responses during infections, thereby reducing inadvertent damage to normal host tissues and limiting self-inflicted pathology."
Tedder's Leukemia paper demonstrates that 90% of CLL patients have malignant B cells that are functionally related to B10 cells, sharing their ability to express IL-10, thereby regulating immune responses. He explains that "CLL has historically been associated with suppression of the immune system, which may result from CLL cell IL-10 production." Dr. Tedder and his colleagues also found that MCL cells are functionally related to B10 cells and may also have immunosuppressive effects.
Most importantly, their lab has also recently shown that in mice, B10 cells reduce the effectiveness of immunotherapy with CD20 monoclonal antibodies. In humans, Rituximab (a CD20 monoclonal antibody) destroys B-cells, both diseased and normal B-cells, and is used to treat diseases where abnormal B-cells are present such as lymphoma. B10 cells may also inhibit Rituximab effectiveness in patients. Since B10 cells are able to inhibit immunotherapy, CLL and MCL cell production of IL-10 may explain the extraordinary resistance of these tumors to Rituximab therapy.
A major remaining question was how IL-10 production by B10 cells, and in CLL and MCL cells, is controlled to prevent nonspecific suppression of the immune system. Dr. Tedder's Nature paper, which provides the 'other half of the story', focuses on how B10 cell--IL-10 production is regulated in mice. In this study, "we show that B10 cell--IL-10 production requires physical interactions between B10 cells and a subset of T cells. Both B10 cells and these T cells must see the same foreign- and/or self-antigens leading to IL-10 production. This then limits T cell activation, immune responses and the bringing on of pathology." Now that Dr. Tedder and his team have discovered how B10 cell--IL-10 production is regulated, the next step is to determine whether the same molecular mechanisms regulate malignant B cell IL-10 production in CLL and MCL. As Dr. Tedder explains, "These studies may provide ways to inhibit malignant B cell production of IL-10, which may reduce their immunosuppressive properties and make these tumor cells more susceptible to immunotherapy."
The Nature paper also identifies a tissue culture method for expanding B10 cells as a therapy to inhibit inflammation and autoimmunity. Once isolated from patients, these rare B10 cells were given the same signals normally provided by T cells, which led to a million-fold increase in their numbers. When these expanded B10 cells were given back to mice with autoimmune disease, they shut off that disease process! This could lead to potential treatments for patients with autoimmune diseases such as Lupus, Rheumatoid Arthritis and Type 1 Diabetes.
As a current LRF grant recipient, Dr. Tedder acknowledges the important work of the Foundation in contributing towards progress in the field, "providing the resources to pursue these ideas and to generate sufficient proof that new theories and strategies will be productive and worthy of future support in a competitive landscape." Dr. Tedder adds that such an award "validates the importance of our research and provides us with the resources to further explore this disease and potentially offer new insights." Such resources are set against the backdrop of "extensive cutbacks in government funding for basic biomedical research over the past eight years, resulting in an enormous deficit in financial support for innovative and challenging ideas." It is in the context of the current funding environment, that he adds that young researchers at the beginning of their career path will only succeed if "they are committed to research and can maintain their commitment for a lifetime. Hard work is essential for success in both research and in a satisfying career."
When describing what keeps him so dedicated to lymphoma research, Dr. Tedder explains that, "while there has been remarkable progress in the treatment of lymphoma during my career, there are still major challenges and tremendous unmet needs, as in the case of both CLL and MCL. There will always be more to learn but we will remain fully engaged until effective therapies without severe side effects are available for treating these complex malignancies." Since patients are at the heart of efforts to eradicate lymphoma, according to Dr. Tedder it is important to "remain optimistic in the wake of diagnosis, as there are a large number of dedicated scientists focused on developing new treatment strategies for these diseases. Although progress has been remarkable over the past two decades, these investigators remain dedicated to the elimination of these diseases."
To view both papers and their full list of authors; click below.
To learn more about the LRF research program, or the research and investigators supported by the Foundation please click here.
To read about other Featured LRF Researchers, click here.