Their conclusions, outlined in a paper to be published in the journal Blood and currently posted on the journal's Web site (www.bloodjournal.org), were based on two key discoveries about rapamycin's mechanisms.
First, while rapamycin suppresses immune system T cells, as many anti-rejection drugs do, the researchers found that the drug also inhibits the function and activation of dendritic cells, cells that play a much earlier role in the immune response as the first cells to identify foreign intruders. They in turn present these intruders to other immune system cells, including T cells.
Second, and perhaps more surprising to the study's authors, rapamycin disarms the trigger that allows dendritic cells to proliferate. This trigger, a potent, naturally occurring growth factor, also affects the proliferation of blood precursor and stem cells, which if allowed to grow unchecked, result in leukemia and other cancers.
"Rapamycin's effect on dendritic cells impairs immune reactivity at the earliest stages. Because dendritic cells are important for the initiation and regulation of immune response, this effect is very important. Our findings provide novel insight into the pharmacology of this agent and have significant implications for the development of new therapeutic strategies in disease processes in which dendritic cells play a crucial immunopathological role," stated Angus W. Thomson, Ph.D., D.Sc., professor of surgery and immunology at the Thomas E. Starzl Transplantation Institute and the University of Pittsburgh School of Medicine.
"Dendritic cells are of pivotal importance in conditions such as atherosclerosis and various autoimmune diseases where these cells perpetuate chronic immune responses. As such, one disease that may be especially amenable to rapamycin's inhibitory action on dendritic cells is systemic lupus erythematosus because dendritic cells accumulate in lupus lesions and are thought to drive the immunopathologic process in this disease" noted Holger Hackstein, M.D., Dr.Med., a research associate at the Institute of Clinical Immunology and Transfusion Medicine at Justus-Liebig University.
While their studies were performed in the laboratory and in mice, Dr. Hackstein and co-authors propose a human clinical trial be done to evaluate the effectiveness of rapamycin as a treatment for lupus. Additionally, they believe studies in patients with acute myeloid leukemia should be explored because of the potential that rapamycin could arrest the growth factor signals that are involved in that disease.
"Not only do our findings have implications for dendritic cell-triggered autoimmune diseases and blood malignancies, but there are important implications for transplant tolerance as well," added Timucin Taner, M.D., a pre-doctoral fellow working in Dr. Thomson's lab and co-lead author with Dr. Hackstein.
Drs. Taner and Thomson and their colleagues at the Starzl Institute in Pittsburgh plan to continue their work to harness the dendritic cells' potential to promote tolerance of transplanted organs. Further studies will look at how rapamycin affects dendritic cells and the transplant tolerance process.
In addition to Drs. Hackstein, Taner and Thomson, other authors include Alan F. Zahorchak, M.S., Adrian E. Morelli, M.D., Ph.D., and Alison J. Logar, M.S., all of the Thomas E. Starzl Transplantation Institute; and Andre Gessner, M.D., Ph.D., of the University of Erlangen, Erlangen, Germany.
Their research was supported by grants from the National Institutes of Health and the German Foundation of Hemotherapy Research.
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Journal
Blood