BGU researcher Dr. Eli Lewis and his team have discovered one of the mechanisms behind the promising treatment of Type 1 Diabetes with alpha1 antitrypsin (AAT). They discovered that AAT binds to and neutralizes another protein called gp96, which, in its outer-cellular form, induces an inflammatory response.
The study recently released by Lewis in the prestigious journal Frontiers in Immunology, demonstrates that gp96 and AAT attach to each other in the blood circulation, and that AAT thereby disables the harmful effects of gp96. Lewis is the director of BGU’s Clinical Islet Laboratory and a member of the Department of Clinical Biochemistry and Pharmacology in the Faculty of Health Sciences.
The immune system, in the case of Type 1 Diabetes patients, causes the destruction of pancreatic insulin-producing cells. A possibility for grafting these cells into patients exists, yet immunosuppression is required. Pancreatic cells are particularly sensitive to inflammation and rapidly fail to function after transplantation; in this case, the cellular injury alone behaves as an inflammatory trigger. These signals of injury are not addressed by today’s immunosuppressive drugs, and cellular injury could perhaps explain the poor outcomes of several modern immunological therapeutic approaches.
Injured cells release their proteins to the outer-cellular space; over the last twenty years it was discovered that some of these proteins, in their outer-cellular form, support the immune system. One of these outer-cellular proteins is gp96, which was found to increase in the blood of Type I Diabetes patients. It has also been demonstrated that its outer-cellular form is involved in other human diseases related to injured tissues and an adverse immune response.
Lewis’ team studies the protective attributes of another protein, alpha1 antitrypsin (AAT). Normally, blood levels of AAT rise whenever we are sick, and it then protects ‘bystander tissues’ against exaggerated inflammation and unwanted immune reactions. The mechanism for this beneficial activity is, however, yet to be determined.
The recently released study was spearheaded by doctoral student David Ochayon. According to the team’s finding, AAT directly binds to gp96 in the blood circulation and disables the harmful effects of outer-cellular gp96. The subsequent immune responses are modified in favor of cell survival. The results were generated using a series of carefully designed experiments using a large variety of cell cultures, including pancreatic cells, as well as whole animal models. Externally introduced gp96, as well as naturally occurring gp96, were assessed. The group observed a reduction in outer-cellular gp96 levels in AAT-treated mice and found that graft survival rates were enhanced by the inhibition of gp96.
Why are these findings important? The theory that deals with the development of an immune response towards damaged cells was conceived twenty years ago by Polly Matzinger. According to her theory, body cell turnover following cell death can be either programmed or not programmed. Whilst programmed cell death isn’t followed by an immune response, non-programmed cell death, for instance caused by injury or starvation, causes a strong immune response. Therefore, according to the theory one can deduce that our body has a protective mechanism against the response towards dying cells.
This knowledge may help in directing researchers towards novel medical indications for AAT treatment. For example, AAT is currently tested in Type 1 Diabetes patients in a number of clinical studies in Israel and in the USA, recruiting newly diagnosed patients and treating them with AAT. Two more trials recruit bone-marrow transplant patients, and a sixth trial recruits patients with ischemic heart conditions.
