Department of Immunology and Microbial Science

Investigators in the Department of Immunology and Microbial Science direct their research efforts towards understanding the interactions of components of the immune system with pathogens, cancers, and with cells and tissues in other parts of the body. These scientists follow the behavior of immune cells–where and how they move; how the body maintains them; how they become activated; how they clear pathogens from the body; and how they die or turn into resting cells.

One important area of research focuses on the innate immune system, the front-line broad defense our bodies use to mount a quick response to pathogens. Investigators are interested in the signals that mediate this response, the genes that are involved in recognizing pathogens, and what effect our responses have on the body. One investigator 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, one of the leading causes of infant mortality in the United States and a major problem in U.S. hospitals. Another investigator long ago recognized the importance of the CD14 protein in pathogen recognition, and his discoveries have provided the basis for using anti-CD14 monoclonal antibodies as a therapy for septic shock.

Also related to the innate immune system is the work of a TSRI research team that reported the detailed mechanism of the regulation of an important pathogen-destroying enzyme, called NADPH oxidase, which lies on the surface of phagocytic leukocytes--the white blood cells that destroy foreign pathogens in an innate immune response. The mechanism may be relevant to several diseases because non-inflammatory cells also carry NADPH oxidases. The capability to modulate oxidant production without totally disarming the protective leukocyte immune response could provide an improved therapeutic approach to diseases such as arthritis, cardiac tissue damage associated with heart attack, and atherosclerosis.

There is an unusual population of T cells in the body, called δγ T cells, that arise early in development and reside in the skin and gut. One group in the department has found a completely new role for these T cells. When the tissue surrounding them is traumatized, they secrete a particular growth factor that helps to recruit inflammatory cells and repair the damage. This work has important implications for skin inflammation, wound healing, and inflammatory bowel disease.

Another focus of the department is the study of B cells, which mature in the bone marrow and produce antibodies against pathogenic invaders. One research group 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. Another group studies the formation of the antibody repertoire, trying to determine which genes are used more than others and why.

Tying the different parts of the immune system together are the scientists who study the chemical signals cells exchange to communicate, carry out their work, and respond to their environments. One investigator pioneered research in how the immune system connects with thrombosis during coagulation and was the first to clone and sequence the molecule, called tissue factor (TF), that starts the cascade. Another group has followed this research by looking at signals that are turned on downstream of enzymes in the blood coagulation cascade and by investigating how these signals are relevant to diseases like cancer and sepsis.

Integrin research has a long history in the department, and one group has looked at how these molecules contribute to the pathways of angiogenesis, the aberrant growth of new blood vessels induced by cancerous cells. The group has looked at many ways of inhibiting this process and has devised some breakthrough anti-angiogenics that specifically target cells to shut down the tumor-promoting process.

Another of the department's research groups has taken a different approach to fighting cancer tumors, developing antibodies that target neuroblastoma tumors, the second leading cause of cancer in the United States after leukemia. One of their compounds is undergoing clinical trials at the National Institutes of Health. Also in clinical trials is a lung surfactant developed by a member of the department. It is in Phase III clinical trials as a treatment for infants with inflammatory lung problems.

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 this virus. One investigation is trying to determine the role of host proteins in HIV infections, looking at the attachment of the virus to target cells and trying to determine how to target the host proteins that HIV uses to enter cells. Another research team has developed an elegant model to study HIV infection in living tissue, which can be used to test isolates from patients at various stages of the disease and look at how the replication and infectivity of the virus alters with mutations to its genome. Scientists can also use the model to study basic biology and viral dynamics of HIV and to test the efficacy of vaccine and therapeutic candidates.

Scientists in the department also described an antibody that in cell culture clears infection by prions, which start out with one shape that is innocuous, and ends up with another shape that is deadly--a molecular version of Dr. Jekyll and Mr. Hyde. 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. The antibody they designed seems to halt the infection, 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.

The interactions of viruses and cells and the pathways by which DNA viruses, like adenoviruses, enter cells is the subject of research by another group within the department. Adenoviruses are ancient viruses with a long evolutionary tree--even some bacterial viruses are similar--and understanding how they enter cells gives insight into the biology of other viruses, like HIV. Also, adenoviruses are one of the primary vehicles for delivering genes into cells in the fledgling field of gene therapy.

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.

Lupus, for instance, is a complicated condition with a wide range of manifestations that afflicts approximately 1.4 million Americans. Two research groups have been working for several years to uncover the genes that contribute to the disease. The scientists have developed models for lupus, and these aid them in cloning the genes responsible. They hope to use this knowledge to develop better, more targeted therapies that can improve on the current treatment, a regimen of non-specific drugs like cortical steroids, anti-inflammatories, and anti-malarials.

TSRI is also home to one of the largest basic Type 1, or insulin-dependent, diabetes research programs in the world. Type 1 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.

Investigators study a variety of topics related to diabetes, including the killer T-cell repertoire and the rules that govern whether the T cells recognize "self" antigen or not; the regulation of helper T cells; and the causes and origins of Type 1 diabetes. Their goal, similar to all the other investigators in the Department of Immunology and Microbial Science, is to understand the underlying mechanisms of the disease and contribute to the design of new therapies.

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