Due to the failure of monotherapies in T1D clinical trials it is widely thought that combination treatments that can control autoimmune responses and promote -cell health and replication will be necessary for T1D intervention. As a poof-of-concept, this proposal will test the immunoregulatory agent anti-CD3 with GABA, the latter of which has both immunoregulatory actions and is a -cell mitogen/survival factor. Previous clinical studies with anti-CD3 have failed to maintain normoglycemia in newly diabetic individuals, which may have been due to 1) the chronic exhaustion of the remaining -cells, 2) the lack of sufficient -cell regeneration and 3) insufficient suppression of autoimmunity. By combining anti-CD3 with GABA, each of these deficiencies can be improved, i.e., GABA promotes mouse and human -cell survival, -cell replication and mass, and inhibits inflammatory immune cells while enhancing Treg responses. This is unlike any previously tested combination with anti-CD3 (or other immunoregulatory agent) because the second therapeutic agent used in those studies lacked the ability to inhibit autoimmunity/promote Tregs or was not a -cell mitogen/survival factor. We hypothesize that the combination of anti-CD3+GABA will sufficiently control autoimmune responses such that GABA's mitogenic and anti-apoptotic actions will be able to better preserve, and perhaps even expand -cell mass, in newly diabetic NOD mice. Since no mono- or combined therapy has yet been able to enhance -cell replication and mass in diabetic NOD mice, a successful outcome would be novel and have high potential for clinical translation. Additionally, because the actions of anti-CD3 and GABA are expected to synergize, we will test whether lower dosages of each treatment can be effective, which could be useful in the clinic to reduce potential side-effects. Finally, in addition to monitoring the effect of this combination treatment on immune responses and -cell replication, mass and function, we will determine the levels of GABA in plasma that are associated with inhibition of autoreactivity and promotion of -cell cell replication, which will be informative for GABA dosing in clinical trials. The results have high clinical potential to better preserve and perhaps increase -cell mass after T1D onset. Even a small preservation or increase of -cell mass will have clinical benefits in those newly diagnosed with T1D by virtue of lowering insulin requirements, improving glucose control and thereby reducing the long-term risk for complications. Our approach is not limited to combining GABA with anti- CD3--in the future, GABA could be combined with other safe immunoregulatory drugs, so that a proof-of- concept is likely to lead to many new possibilities for T1D intervention.
It is now generally thought that reversal of T1D will require combination therapies that can both inhibit inflammatory autoimmune responses and promote -cell mass and function. We propose a new combined therapy that should have enhanced ability to safely inhibit autoimmune responses and promote -cell survival and mass after the onset of type 1 diabetes.
