November 2001

From University of Pittsburgh Medical Center

University of Pittsburgh researchers define precursors to cells that control the immune response

PITTSBURGH, Nov. 11 - University of Pittsburgh researchers have identified the precursors of epidermal Langerhans cells (LCs), cells that reside in the skin and play a key role in the initiation and regulation of the immune response throughout the body. Researchers may now be able to use these cells to manipulate and control the immune response, according to the groundbreaking study to be published in the December issue of Nature Immunology, and as an advanced online publication on the journal's Web site on Monday, Nov.12.

Through genetic engineering, the cells could be targeted for the delivery of genes encoding for specific antigens and immunoregulatory molecules, signaling either the start or stop of the immune response, say the University of Pittsburgh researchers. The team also hopes to be able to use these precursors, through tissue engineering, to repopulate artificial skin with an intact immune system.

"By manipulating the function of Langerhans cells, we may be able to initiate an immune response, which could enhance vaccine development. We may also have the potential to down-regulate or turn off an immune response, creating novel treatments for asthma or other auto-immune diseases and anti-rejection therapies in transplantation," said Louis D. Falo, Jr., M.D., Ph.D., senior investigator for the study and professor and chairman, department of dermatology, University of Pittsburgh School of Medicine.

LCs are a subset of dendritic cells (DCs) present in the epidermis of the skin that show an extraordinary immunostimulatory capacity. They are antigen-presenting cells, meaning that when the LCs encounter an antigen in the presence of a "danger signal" like a pathogen or infection, they migrate from the skin to the lymph nodes, presenting a processed antigen to T-cells, initiating antigen-specific T-cell immunity.

"Scientists have known that LC precursors existed; however, the identification of an immediate LC precursor resident in the skin remained as a missing link," said Adriana T. Larregina, M.D., Ph.D., research assistant professor, department of dermatology, University of Pittsburgh School of Medicine, who led the study with Adrian E. Morelli, M.D., Ph.D., research assistant professor, department of surgery, University of Pittsburgh School of Medicine and Thomas E. Starzl Transplantation Institute. "By defining them, we gain the ability to target or retrieve the cells and study their therapeutic potential."

To identify the precursors, University of Pittsburgh researchers targeted a population of migratory cells present in the dermis of human skin, which expressed molecules that distinguish LCs from other types of DCs. They found that when these cells were cultured with transforming growth factor-beta 1, a growth factor that plays a role in differentiation and the immune response, the cells differentiated into epidermal LCs. When cultured in granulocyte macrophage-colony-stimulating factor, a protein that promotes the recovery of white cells, and interleukin-4, proteins present in inflamed skin, the precursors acquired a strong immune stimulatory function, differentiating into functionally mature DCs. By defining these precursor cells, researchers now can begin to investigate their therapeutic potential.

University of Pittsburgh researchers participating in this study, in addition to Dr. Falo, Dr. Larregina and Dr. Morelli, include: Lori A. Spencer, M.D., Ph.D., immunology program, School of Medicine; Alison Logar, Starzl Transplantation Institute; Angus W. Thomson, Ph.D., D.Sc., Starzl Transplantation Institute; and Simon C. Watkins, Ph.D., department of physiology, School of Medicine.

The study was funded by grants from the National Institutes of Health and from the Dermatology Foundation.












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