Mechanism(s) of alpha-1-antitrypsin monotherapy-induced immune tolerance

This proposal is about an observation we made and that, we believe, may have a major impact on islet transplantation for type 1 diabetes patients. The study is comparable to a case where human islets from an unrelated donor are transplanted to a diabetic patient with poorly controlled disease. Although the current Edmonton protocol avoids the use of immunosuppressive drugs that damage islets, there remains a life-long treatment requirement to reduce the immunological assault against the transplant. Since the therapy proposed today is life-long, the complications and loss of normal resistance to infection and malignancy is one that is particularly dangerous for young diabetic patients. We have found that a common, normal serum protein, alpha-1-antitrypsin, can be used as a therapy to prevent rejection of islet transplants in mice. Thus, our observation is one in which there is no high risk for the patient. Alpha-1-antitrypsin is a protein that inhibits enzymes, many of which are produced by inflammatory cells during islet rejection. The levels of this protein rise naturally in our blood during infections. Unfortunately, 1 out of 3,500 people are born with a genetic deficiency in alpha-1-antitrypsin and die from the consequences of chronic inflammation. However, about 20 years ago, companies were able to purify alpha-1-antitrypsin from the serum of healthy donors and administer the purified alpha-1-antitrypsin into patients with the deficiency. Safety of alpha-1-antitrypsin in humans is therefore extensively appreciated.

In initial studies during this project we have used mice that can be injected with human alpha-1-antitrypsin without forming antibodies to injected protein. We have injected these mice for over 50 days with alpha-1-antitrypsin and no other therapy; yet, mice did not reject the transplant and maintained prolonged normal blood glucose levels. Moreover, after 50 days of alpha-1-antitrypsin treatment, we stopped for three full weeks and blood sugar remained normal. To test whether mice no longer viewed the long-lasting transplant as foreign, we carefully removed the transplant and followed blood glucose. The mice now became hyperglycemic again, because they had no functional islets in them. We then performed what we call a rescue transplant, in which the mice are re-transplanted with a new transplant from the same original donor strain. The mice carrying the second graft now returned to normal blood sugar without any therapy, that is, treatment-free. This remarkable result, having foreign islets exist in a tolerant diabetic recipient without therapy, is perhaps the major goal of transplantation efforts today. In this study we will examine the mechanisms by which alpha-1-antitrypsin protects islets against rejection