A promising new therapy for
rheumatoid arthritis (RA) developed by researchers at the University of California, San Diego (UCSD) School of Medicine re-educates the body's immune system to prevent an attack against healthy joint tissue.
In patients with RA, the immune system that is supposed to protect the body, instead attacks it for unknown reasons. In a Phase I/IIa clinical trial recently described in
Proceedings of the National Academy of Sciences*, the UCSD researchers report that a peptide called dnaJP1, taken orally for six months by a group of patients with early RA, caused no side effects and actually changed the action of the immune system's T cells, preventing them from attacking the body's own tissues
The new therapy is currently in Phase II clinical trials with 160 RA patients at UCSD, Johns Hopkins University, the Mayo Clinic, and Virginia Mason Medical Center in Seattle. It is expected to be completed by the end of 2004, with enrollment still open for interested study participants.
RA is a chronic, painful disease that causes joint inflammation and destruction, progressive disability and premature death. Affecting an estimated 2.1 million Americans, RA causes substantial economic burden, with 50 percent of patients unable to work within 10 years of onset, and lifetime costs of the disease rivaling those of
coronary artery disease or
stroke.** RA is incurable, with most therapy focused on symptom relief. Unfortunately, current therapies can have serious side effects and work by suppressing the immune system, which increases the risk of infection.
While the precise cause of the disease is unknown, researchers believe that RA is influenced by an abnormal reaction to environmental factors such as infection, which initiate the autoimmune response in genetically susceptible individuals.
The immune-modulation therapy developed by Salvatore Albani, M.D., Ph.D., UCSD professor of medicine and pediatrics, takes advantage of both the genetic and environmental components of RA. In studies over the past 12 years, he has focused on the immune system's T cells, which trigger inflammation to kill and clear foreign pathogens from the body. Albani reasoned that if the immune system of RA patients could be altered, T cells might be less likely to cause chronic inflammation.
His research involved several components of the immune response, beginning with a sequence of amino acids (segments that comprise proteins) expressed on the surface of cells during an immune response. Called a human leukocyte antigen (HLA), this sequence is designed to recognize self- from non-self cells. In a normal immune response, HLA acts as a "natural dimmer" to prevent over-stimulation of the inflammatory response. In RA patients, however, the dimmer is broken and excessive inflammation ravages tissue and joints. Interestingly, researchers have determined that 70 percent of RA patients, and not normal individuals, share a specific sequence of five amino acids within their HLA.
Albani's current findings were further supported by previous studies he conducted with Dennis Carson, M.D., UCSD professor of medicine and director of the Sam and Rose Stein Institute on Aging at UCSD, that showed immune-system T cells in RA patients become confused by the body's natural HLA sequence on cell surfaces, thinking it is a foreign invader. In an attempt to protect the body, the T cells attack the HLA sequence by inducing inflammation.
To prevent T cells from attacking the body's own HLA sequence, Albani sought to develop a vaccine therapy that could re-educate the diseased immune system in RA patients to prevent rampant inflammation. He focused on a naturally occurring protein called dnaJ that is used by T cells to help initiate the inflammation process. A section of the dnaJ protein, called dnaJP1, contains the same sequence of five amino acids as those within the HLA of RA patients. Bacterial, non-human forms of the dnaJP1 peptide also contained the same sequence of RA-susceptible HLA amino acids, and were found by the UCSD team to be targets of pro-inflammatory T cell responses in RA patients.
"Therefore, we believed that if we could administer the bacterial dnaJP1 as a vaccine to patients with early RA, it would affect the autoimmune inflammation," Albani said. "A key to the treatment was oral administration of dnaJP1."