Overview:
Research in my laboratory is focused on defining mechanisms that regulate T lymphopoiesis. We also seek to apply this knowledge towards the development of therapies that may promote immune reconstitution during immunodeficiency. Our work is particularly focused on rebuilding the immune system of those with HIV infection, although our research also has significant applications to other states of immune deficiency such as bone marrow transplantation and advanced age.

Background:
Acquired immunodeficiencies, such as those caused by HIV infection or bone marrow transplantation, are frequently characterized by T cell loss and an increased risk of illness or death from infection. Since the thymus is the primary site of T cell development, the state of thymic function in an immunodeficient individual may be a pivotal factor in determining the potential for T cell recovery. Although the thymus is generally thought to be active only early in life, accumulating evidence suggests that a thymic reserve persists into adulthood and that it can be summoned in times of need. We have previously hypothesized that therapies designed to enhance T lymphopoiesis might facilitate immune restoration. In prospective studies of adults with HIV infection, we have found that the administration of immune-based therapy is associated with reversal of thymic involution and an increase in circulating naive CD4+ T cells These data offer promising evidence that new T cell production might be inducible during immunodeficiency.

Our research efforts are directed towards the study of three interesting enhancers of T lymphopoiesis: the somatotropic hormones growth hormone and insulin-like growth factor-1; and an important homeostatic regulator of T cells, interleukin-7. Each of these factors are important immune regulators that are capable of enhancing the production and function of T cells, yet the mechanism of their action is not completely understood . Our overall objective is to identify targets of these regulators within the central and peripheral immune tissues and to understand their mechanisms of immune regulation. This information will enhance our understanding of the processes that regulate T lymphopoiesis and could be directly applicable to the future development of targeted therapies to enhance immune reconstitution in immunodeficient individuals.

Experimental Approaches:
We use a variety of in vitro and in vivo systems to investigate the effects of regulatory factors on thymopoiesis and peripheral immune function. Our approach is broad and includes the culture and analysis of human and mouse immune tissues; utilization of murine models; and clinical studies of HIV-infected volunteers. The technical approaches to this work combine diverse methods in cellular immunology, cell biology, molecular biology, and small animal imaging

Active Interests:

• Investigation of the specific effects of immune modulators on thymopoiesis and peripheral immune function. How is thymic involution reversed?
• Clinical studies using immune-based therapies to enhance T lymphopoiesis in adults with HIV. Can we improve the quantity and quality of T cells in immunodeficient hosts?
• Development of innovative methods to quantitate thymic function
• Investigation of the impact of gender and age on T lymphopoiesis