Laura A. Napolitano, M.D.
Assistant Investigator
Gladstone Institute of Virology and Immunology
Assistant Professor of Medicine
University of California San Francisco
Email: Lnapolitano@gladstone.ucsf.edu
Telephone: 415-734-4814
Fax: 415-553-6299

Areas of Investigation
Our research group investigates the regulation of human T-cell production. Current efforts are focused on two enhancers of thymopoiesis: interleukin (IL)-7 and growth hormone. The dual emphasis of this work is to define the mechanisms that regulate human thymopoiesis and to use this knowledge to develop therapies to promote immune reconstitution in HIV-1 disease.

Significance
The thymus is the primary site of T-cell development and is required for the generation of a maximally diverse T-cell receptor repertoire. Consequently, the state of thymic function in an immunodeficient individual may be a pivotal factor in determining the potential for immune reconstitution. In general, the thymus atrophies with age and is considered inactive in adults. However, recent evidence suggests that a thymic reserve persists into adulthood and that thymic function may be recoverable during HIV-1 infection.
The signals that regulate thymic function are not yet well understood. Improved insight into the mechanisms that regulate T-cell production could enhance our understanding of HIV-1 immunopathogenesis and T-cell homeostasis. In addition, a more complete understanding of these regulatory processes could facilitate the development of immune-based strategies to treat immunodeficiency.

Approaches
We use a variety of in vitro systems to investigate the effects of regulatory factors on human T-cell development and function. The in vivo effects of these factors are evaluated in the SCID-hu Thy/Liv model in close collaboration with the Antiviral Drug Research Division. Conclusions drawn from these studies are extended into clinical studies of HIV-1-infected volunteers. The technical approaches to this work combine methods in cellular immunology and cell biology. Our group also works closely with the Gladstone Flow Cytometry Core and the San Francisco General Hospital Core Immunology Laboratory.

Contributions

• Demonstration that IL-7 furnishes potent anti-apoptotic and proliferative signals to early human thymocyte progenitors
• Demonstration that IL-7 may play an important role in human T-cell homeostasis
• Demonstration that therapy with human growth hormone appears to reverse thymic involution and facilitate immune reconstitution in HIV-1-infected adults

• Can positive regulators of thymopoiesis be used to enhance immune reconstitution in immunodeficient adults?
• What are the primary targets of growth hormone in the human immune system?
• What are mechanisms that regulate the production of IL-7?
• How can we better quantitate T cell production by the thymus?

Selected Publications