June 25, 2001 PITTSBURGH, June 5 -- University of Pittsburgh researchers have identified a new cellular target for aspirin, shedding light on the mechanisms of the most widely used drug in the world and raising a set of intriguing questions, including whether aspirin could be useful for preventing organ rejection.
In the June 15 issue of the Journal of Immunology, the researchers report for the first time that aspirin has a profound effect on bone-marrow derived dendritic cells -- the powerful immune system cells that are responsible for initiating an immune response -- by preventing their maturation and hence, their ability to signal other cells to attack.
The findings help to explain why aspirin taken in high doses significantly reduces inflammation and provides relief to patients with various autoimmune diseases, including arthritis and rheumatic fever, says lead author Holger Hackstein, M.D., a visiting research fellow at the University of Pittsburgh's Thomas E. Starzl Transplantation Institute, who is working in the lab of Angus Thomson, Ph.D., D.Sc., professor of surgery and molecular genetics and biochemistry and senior author on the paper.
And while the research used a mouse model to look at aspirin's effect on myeloid dendritic cells, the findings point to possible novel therapies for patients with autoimmune diseases as well as approaches that could induce tolerance in organ transplant recipients. The researchers plan a series of animal studies to determine if aspirin can help prevent organ rejection. Specifically, they will be looking to see what role aspirin has in preventing dendritic cells from calling in the troops of T and B lymphocytes that directly attack transplanted organs.
"These findings provide new insight into the immunopharmacology of aspirin. Moreover, exposure to this readily available drug provides a simple, inexpensive and highly effective means to manipulate the immunostimulatory capacity of dendritic cells," wrote the authors.
"While these results are very intriguing, it would be premature to advise patients to ingest large quantities of aspirin. For many transplant patients, this could be medically dangerous,” warns Dr. Hackstein, whose primary appointment is with the Institute of Clinical Immunology and Transfusion Medicine at Justus-Liebig University of Giessen in Giessen, Germany.
Dendritic cells are rare immune system cells that originate in bone marrow and are present in all tissue. Myeloid dendritic cells initiate immune system attack, whereas lymphoid-related dendritic cells are believed to temper the immune system, according to other studies performed by Dr. Thomson and colleagues. Essentially, myeloid dendritic cells initiate an immune response by recognizing something that is foreign and then calling out signals that serve to present the foreign antigen to other immune system cells that do their part to destroy it.
Despite its discovery more than 100 years ago, little is known about how aspirin actually works to control pain and inflammation, or how it is beneficial for patients with autoimmune diseases. What is known is that it acts on two pathways, one involving prostaglandins, and the other, a more recent discovery, involving nuclear factor –K(kappa)B (NF-KB). Aspirin inhibits the activation of NF-KB, molecules that activate chemicals to trigger inflammation. More specifically, according to the Pittsburgh team, aspirin disables NF-KB inside dendritic cells.
Without NF-KB activation, the dendritic cells are hindered from performing the normal function of a mature cell. They no longer have the capability to place molecular signals on the outside of their cells that serve as warnings to the T and B cells that an attack is warranted against a transplanted organ, or in the case of autoimmune disease, a patient's own tissue. The potential for an immune response is stopped in its tracks.
The researchers also found aspirin to have a surprising effect on the precursor or progenitor dendritic cells. They assumed that if aspirin inhibited maturation of normal dendritic cells that it would prevent their development altogether when progenitor cells were exposed to aspirin. Instead, aspirin enabled the robust production of pure dendritic cells that remained immature, never developing the capacity to present antigens.
Among other things, this finding proves that aspirin does not have a toxic effect on dendritic cells, the authors note.
In addition to Drs. Hackstein and Thomson, other authors include Adrian E. Morelli, M.D., Ph.D.; Adriana T. Larregina, M.D., Ph.D.; Raymond W. Ganster, Ph.D.; Glenn D. Papworth, Ph.D.; Alison J. Logar, B.S.; Simon C. Watkins, Ph.D.; and Louis D. Falo, M.D., Ph.D. The research was supported by grants from the National Institutes of Health.
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