News and Publications
Immunology
Richard J. Ulevitch, Ph.D., Chairman
ll major diseases involve the immune system either directly or indirectly. Scientists in the Department of Immunology focus their research efforts on understanding the interactions of components of the immune system with pathogens, cancers, and each other.
Innate immunity is an ancient and powerful front line of the immune system whereby a rapid, non-specific response is mounted when a pathogen enters the body. One important area of research focuses on how the immune system responds to bacterial pathogens and what effect this response has on the body. Bruce Beutler, M.D., has identified the gene used by the innate immune system to help clear pathogens from the body. People with mutations in this gene have a higher-than-normal risk of contracting meningococcal sepsis.
Septic shock in general continues to be a major problem in U.S. hospitals. Richard Ulevitch, Ph.D., long ago recognized the importance of the CD14 protein in pathogen recognition, and his discoveries have provided the basis for a Phase III clinical trial that is currently testing anti-CD14 monoclonal antibodies as a therapy for septic shock.
Acquired immunity refers to the response that the immune systems of higher vertebrates mount against pathogens to eliminate infected cells and limit the spread of viruses or bacteria.
Immune cells of the thymus, or T cells, are one of the primary cell types responsible for acquired immunity. Jonathan Sprent, M.D., Ph.D., studies how T cells are formed in the virus and selected for their ability to recognize foreign invaders. Charles Surh, Ph.D., is studying how T cells develop and live when there is no pathogen in the body. Luc Teyton, M.D., Ph.D., studies the structures of important receptors used by T cells for immune recognition.
Wendy L. Havran, Ph.D., has found a completely new role for a population of T cells in the body called delta gamma. These T cells arise early in development and reside in the skin and gut where, when the tissue surrounding them is traumatized, they secrete a particular growth factor that helps to recruit inflammatory cells. In mice without the cells or the growth factor, wound healing is delayed or missing completely. This work has important implications for skin inflammation, wound healing, and inflammatory bowel disease.
B cells are the other important player in acquired immune defense. David Nemazee, Ph.D., studies the mechanisms by which the body discriminates between self and non-self, and how B cells that are autoreactive can be salvaged and modified through a proofreading mechanism called receptor editing. Ann Feeney, Ph.D., studies the formation of the antibody repertoire, trying to determine which genes are used more than others and why.
The department is particularly well-known for its research on autoimmunity, in which a person's own antibodies or T cells target his or her own molecules, cells, or tissues. Many of the most devastating modern diseases are caused by these immunological cases of mistaken identity.
Argyrios Theofilopoulos, Ph.D., has been working in this area at TSRI for 25 years. He has developed models for lupus, a complicated condition with a wide range of manifestations which afflicts approximately 1.4 million Americans. Theofilopoulos and Dwight Kono, M.D., have been working for several years to uncover the genes that contribute to the disease. They hope to use that knowledge to develop better, more targeted therapies than the current treatment, a regimen of non-specific drugs like cortical steroids, anti-inflammatories, and anti-malarials.
SIGNALING, CANCER, AND AUTOIMMUNE DISEASES
Tying the different parts of the immune system together are the scientists who study the signals cells exchange to communicate and carry out their work. Gary Bokoch, Ph.D., studies the signaling mechanisms that regulate how cells respond to their environment. This year, he reported the detailed mechanism of the regulation of an important enzyme, NADPH, that lies on the surface of white blood cells and destroys foreign pathogens. Wolfram Ruf, M.D., is looking for the signaling of enzymes of the blood coagulation cascade; Richard Klemke, Ph.D., is studying the basic molecular mechanisms that signal a cancer cell to metastasize.
Several researchers are interested in the potential for turning basic observations about the relationship between cancer and the immune system into new anti-cancer therapies. David Cheresh, Ph.D., has long led a program studying some of the molecules that contribute to the pathways of angiogenesis, the formation of new blood vessels. This formation is important for tumor growth, since the cancerous cells in tumors need the nutrients supplied by the new blood vessels to survive, and the cells themselves release chemicals that promote angiogenesis. Cheresh has looked at many ways of inhibiting this process and has devised some useful anti-angiogenics.
Ralph Reisfeld, Ph.D., has developed antibodies that target neuroblastoma tumors, the second leading cause of cancer in the United States after leukemia. One of his compounds is undergoing clinical trials at the National Institutes of Health.
TSRI is also home to one of the largest basic type 1 diabetes research programs in the world. Type 1, or insulin-dependent, diabetes is a chronic autoimmune disease that arises when T cells destroy the insulin-producing cells in the pancreas. Without insulin, the glucose in the bloodstream increases and is maintained at levels much greater than normal. Over time, this can lead to nerve and kidney damage, vision problems, and an increased risk of developing heart disease and vascular degeneration.
Linda Sherman, Ph.D., studies the killer T-cell repertoire and the rules that govern whether the T cells recognize "self" antigen or not. Susan Webb, Ph.D., looks at the regulation of helper T cells. Nora Sarvetnick, Ph.D., studies the causes and origins of type 1 diabetes with the goal of designing new therapies.
THE VIRAL DYNAMICS OF HIV
Several investigators in the department are molecular virologists. They aim to understand on a molecular level how viruses interact with host cells and the immune system. The department is well recognized for the efforts of its faculty to better understand the basic biology of HIV infection and the immune response to HIV.
Donald Mosier, M.D., Ph.D., has developed an elegant model to study HIV infection in living tissue. Using this model, researchers can test isolates from patients at various stages in the disease and look at how the replication and infectivity of the virus alters with mutations to its genome. They can also use the model to study basic biology and viral dynamics of HIV and to test the efficacy of vaccine and therapeutics candidates. Philippe Gallay, Ph.D., examines the role of host proteins in HIV infections.
HALTING PRION INFECTION
Dennis Burton, Ph.D., and Anthony Williamson, Ph.D., described an antibody this past year that clears prion infection in cell culture. Prions are like a molecular version of Dr. Jekyll and Mr. Hyde. The prion protein starts out with one shape that is innocuous, and ends up with another shape that is deadly. Prion infections are known to cause bovine spongiform encephalopathy (BSE), or mad cow disease, as well as one form of the same disease in humans, called variant Creutzfeldt-Jakob Disease. BSE itself is believed to have originated from a sheep form of the disease called scrapie.
Burton and Williamson originally developed antibodies to probe the structure and biochemistry of prion proteins. But one antibody they designed seems to halt the infection all together. Significantly, the normal cellular machinery degraded whatever infectious prions remained, suggesting that the antibody has the potential to cure established infection. This finding may lead to a treatment for mad cow disease and its human equivalent.
Of particular importance this year was the recruitment of Michael McHeyzer-Williams, Ph.D., one of the world's leading experts in flow cytommetry. He joins TSRI's faculty to pursue his interest in immune memory, particularly helper T-cell regulated B-cell memory.
On a final note, the department is pleased to recognize the contributions of Charles Cochrane, M.D., one of the original immunologists from the University of Pittsburgh. Cochrane celebrated his 40th year at the institute this year and continues to run an active laboratory. One of his noteworthy accomplishments is the development of a lung surfactant, which is in Phase III clinical trials as a treatment for infants with inflammatory lung problems.
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