Spring 2008, Issue 8

Psoriasis As a Window into Immune Disorders

Alice GottliebAlice Bendix Gottlieb, MD, PhD, joined the Tufts community in 2006 as chair of dermatology and dermatologist-in-chief at Tufts Medical Center. She is also chair of the Department of Dermatology and the Harvey B. Ansell Professor of Dermatology at Tufts University School of Medicine and is a member of the clinical research and immunology programs at the Sackler School of Graduate Biomedical Sciences.

Gottlieb earned her MD from Cornell University Medical College and her PhD from Rockefeller University, where she studied in the laboratory of Henry Kunkel. She did residencies (medical and dermatology) at New York Hospital and a fellowship in rheumatic diseases at the Hospital for Special Surgery, New York, NY. Gottlieb served on the faculty of Rockefeller University for over a decade and was the associate medical director of international clinical research at Hoffmann-La Roche Inc. for two years. She has also held several positions at the University of Medicine and Dentistry of New Jersey – Robert Wood Johnson Medical School, including division chief of clinical pharmacology, chief of dermatology, director of the Psoriasis Center of Excellence, and director of the Clinical Research Center.

Gottlieb’s research group focuses on psoriasis and psoriatic arthritis (PsA), chronic inflammatory diseases linked to dysfunctional immune activity. Psoriasis is characterized by an increase in skin cell generation that leads to thickened and painful lesions covered with white scales (excess dead cells). PsA involves painful and frequently debilitating joint and connective tissue inflammation, and PsA is associated with increased risk for metabolic syndrome (hypertension, high triglycerides, or other factors linked to increased risk of cardiovascular disease and type 2 diabetes).

Gottlieb was one of the first scientists to demonstrate that psoriasis is a T lymphocyte–mediated disease. T lymphocytes or T cells normally protect the body from foreign insults such as infections and from pathologic conditions such as cancer. The cells recognize changes, become active, and respond in part by secreting soluble mediators called cytokines. Sometimes, as in psoriasis, this response can contribute to disease. Gottlieb initially demonstrated increased numbers of activated T cells and increased expression of a number of immunologic cytokines in psoriatic lesions called plaques. She then showed that treatment with a T cell–specific immunotoxin cleared psoriasis clinically and histologically.

Psoriasis is now known to be characterized by increased numbers of particular T cells, called Th1 and Th17, that are important in inflammation. Large numbers of dendritic cells, another cell type important for T cell function, are also found within psoriatic plaques. These cells work together to create an environment in which proinflammatory cytokines and cytokines that stimulate keratinocytes—cells that give rise to the skin—are present in high levels. Today’s most promising treatments for both psoriasis and PsA are recombinant biological therapies, such as monoclonal antibodies, that block proinflammatory cytokines.

Gottlieb’s research group is evaluating several biologic-response modifiers that target specific elements in cell-mediated immune reactions. The group is also exploring the basic mechanisms by which these treatments ameliorate the conditions. On average, 85% of people with chronic psoriasis for 10 years or more develop PsA. “There is some evidence from rheumatoid arthritis that if you treat with anti-inflammatories you decrease the incidence of [metabolic syndrome],” says Gottlieb. She would like to determine if treating psoriasis with agents that block either tumor necrosis factor-alpha or interleukin-12/23, two proinflammatory cytokines associated with the disease, can prevent PsA and the onset of metabolic syndrome.

Gottlieb is an active researcher who has been directly involved in over 100 clinical trials. She has five trials currently under way and five in development and review. She looks forward to collaborating with Tufts researchers on the mechanisms of action and treatment of psoriasis and related disorders. In particular she sees overlap between psoriatic arthritis and other disorders such as schistosomiasis, a parasitic disease that also involves T cell dysfunction and is being studied here at Tufts. Another opportunity involves understanding why the rampant cell proliferation that characterizes psoriasis does not lead to increased skin cancer. “The rate of replication is greatly increased in psoriasis,” says Gottlieb. “We also know there’s decreased programmed cell death. Patients don’t get increased skin cancer. Somehow there is a control on this epithelial proliferation.” Working with cancer researchers at Tufts may help her understand the underlying mechanisms involved in this control, and the research may reveal insights into skin cancer.

Besides working in both basic and clinical research, Gottlieb also works effectively with pharmaceutical companies. Her translational research on the anti-inflammatory drug infliximab was instrumental in its introduction into the psoriasis field. Her work has also contributed to the selection of psoriasis as a proof-of-concept disease for many new immunomodulators being tested by pharmaceutical companies. Gottlieb believes the accessible tissues she works with—skin and blood—could be helpful to others investigating both immune disorders and cancer. Her experience with basic research, clinical research, and drug development allows her to act as a conduit for connections between these areas.

For more information, please see http://www.tufts.edu/sackler/facultyIntros/gottliebA.html.

 

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