For individuals with type 1 diabetes, current treatment revolves around insulin administration. But despite nearly a hundred years of clinical use, injections of insulin are still far from attaining control over glucose levels; in fact, patients exhibit dangerously high blood glucose levels over 60% of their day. Pancreatic islets are where our insulin is made, and these become the target of an immune attack during type 1 diabetes. For the past decade, human islets have been isolated from human donors and given to diabetic hosts in a rather simple and non-invasive surgical procedure. Under these conditions, perfectly stable glucose levels are achieved, mostly with no need for further injections of insulin. However, the problem of the immune attack against the grafts is yet unresolved, and even if it were to be soon resolved, we simply don’t have enough donors to go around. As a solution to the shortage in organs, non-human donors have been considered, such as the pig, and regulatory authorities (FDA for example) have recently approved clinical trials using pigs as islet donors. However, with today’s abundance in pig islets for human grafting, one has to tackle a much more aggressive immune response, the response mounted against another species.
Researchers from BGU lead by Dr. Eli Lewis, have had success in protecting islet grafts between strains of the same species for some time now by using a natural protein in our blood, called alpha-1 antitrypsin (in short, alpha1). It is an anti-inflammatory circulating protein that is driven to higher levels when we’re sick with, say, the flu. Luckily, the material is available for use and has a remarkable safety record when administered to a small population of individuals with a rare genetic deficiency in the very same protein.
In a recent report published by Dr. Lewis’ team in PLoS ONE, the initial attempt to apply alpha1 in order to protect inter-species islet transplants had failed; even extending the treatment protocol to provide greater doses of alpha1 for longer durations did not grant islet graft acceptance. However, the team at BGU found some highly interesting microscopic changes inside explanted graft samples that hinted at a positive trend during alpha1 treatment, and suggested that alpha1 might need help from other immune-related therapies in order to overcome the immune response to inter-species grafts. They turned to a newly-appreciated niche in the Pharma industry, combination therapy. Aiming again, as with alpha1, at superior patient safety, the team turned to a pre-existing safe regimen: temporary T-cell depletion is a therapy given just prior to organ transplantation (sometime referred to as ATG). Upon introduction of this specific cocktail of antibodies, the recipient’s T-cells are abolished and new T-cells spontaneously re-populate the individual after about two weeks. BGU’s team found that, on its own, temporary T-cell depletion affords merely a delay in graft rejection. However, unexpectedly, when alpha1 was administered to animals in combination with the temporary T-cell depletion approach, islet grafts were accepted between species.
The approach is unique in multiple aspects, as the immunology behind these observations focuses on pathways rarely tested. For example, it has been noted that the profile of re-populating immune cells is prone to manipulation, in this case, in favor of islet graft acceptance. Also, the synergy between the anti-inflammatory alpha1 and a pure T-cell drug ATG, points at some under-examined aspects of the mechanism of action of alpha1.
“This approach may be applicable in the near future for the purpose of pig-to-human islet transplantation, a procedure currently examined in several clinical trials around the world,” says Lewis.
