Case 1998-556
INNOVATION
Dendritic cells (DC) are a group of professional antigen presenting cells (APC) that provide a central stimulus for the generation of cell-mediated responses against foreign antigens. Dendritic cells are ubiquitously distributed throughout the body, where they pick up antigens, process them, and migrate to T-cell enriched areas of lymphoid tissue to activate corresponding antigen-specific T-cell clones.1 A major limitation in the human response to foreign challenges, including infections and tumors, is the limited number of DC and their suppression in individuals suffering from these conditions. As a result, patients often fail to respond to vaccines that might otherwise be effective.Previous in vitro data indicated that granulocyte-macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4), when used in combination, induce precursor cells, such as CD34+ stem cells and monocytes, to mature into dendritic cells. These cells were classified as DC by their expression of cell surface markers characteristic of DC cells (CD83, CD40, CD86, CD11c, etc.), by their ability to take-up and process antigens, and by their ability to stimulate the proliferation of T cells in an antigen-specific manner. The strategy of using GM-CSF AND IL-4 to enhance the number and/or function of antigen presenting cells (including dendritic cells) in the blood, tissues and lymphoid organs of patients may be employed as a mechanism to improve the immune responses of individuals with a suppressed immunity. Therefore, this method has implications in treating conditions such as cancer, infections, AIDS, malnutrition and shock. Cytokine therapy using GM-CSF and IL-4 may further be implemented into immunization and vaccination strategies for infections that respond poorly to conventional vaccine approaches. Examples of these indications include AIDS, pneumonia, and tuberculosis.This cytokine combination therapy produced promising tumor responses in Phase I testing and is currently being tested in Phase II studies in patients with prostate cancer. Additional preclinical testing is ongoing to optimize combination therapy with vaccines, to better evaluate the form and function of the dendritic cells generated, and to evaluate the use of combination cytokine therapy as a mechanism for harvesting DC for use in the production of cell-based vaccines.
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