over the past decade , many immune tolerance agents have shown promise in the non - obese diabetic mouse model for prevention and reversal of type 1 diabetes but have not been successful in clinical trials among recently diagnosed type 1 patients . the trials from decades ago using cyclosporine a in significantly lower dosages than used for organ transplantation and in similar dosages that have increased t regulatory cell populations in conditions such as atopic dermatitis , demonstrated very high initial insulin - free remission rates when administered immediately after diagnosis . over time , all newly diagnosed type 1 patients given cyclosporine a required insulin . human trials with immune tolerance agents suggest that in addition to an immune tolerance agent , a beta cell regeneration agent may also be necessary to induce long - lasting remission among patients with recent onset type 1 diabetes . a randomized , double - blind prospective trial among recent onset type 1 diabetes patients has been designed using cyclosporine a and a proton - pump inhibitor , which increases gastrin levels and has been shown to work through the reg receptor to transform pancreatic duct cells into islets . over the past three decades , there have been several trials using immune tolerance agents demonstrating both prevention and reversal of type 1 diabetes in non - obese diabetic mice , yet these results have not been translated into man . as we look at recent clinical trials among patients using immunotolerance agents , including anti - cd3 antibodies , anti - cd20 monoclonal antibody , interleukin 1-receptor antagonists , anti - thymoglobulin and others that have reversed diabetes in type 1 mouse models , the insulin - free remission rates in humans have not been seen . it is now clear that unlike the diabetes remissions seen in rodents , making peace with the immune system is not enough to generate new beta cells in humans . as we begin to understand that autoimmunity is only one aspect of type 1 diabetes in humans and the other being beta cell deficiency , we can now look at the efficacy of the immune tolerance agents in a new light . lasting insulin - free remissions in humans will only occur when beta - cell mass is sustained and regenerated over time in the milieu of immune protection . if we now examine the efficacy of immune tolerance agents based on insulin - free remissions at 1  year following initiation , some of the most promising data actually dates back 25  years . cyclosporine a had a 67.5% insulin - free remission among recent onset type 1 patients , with 50% of patients sustaining the insulin - free state after 12  months 1 . renal side effects were not seen in the many trials , including a published cohort of 285 patients with recent type 1 diabetes followed for up to 13  years after 20  months of therapy on cyclosporine 3 . the usage of cyclosporine a among patients with dermatological conditions has been associated with significantly increased t regulatory cells , both in absolute numbers and frequencies and in the reduced ability of t cells to be activated 4 . despite immune intervention , the inability to generate new beta cells has contributed to the necessity for exogenous insulin . distinct complexities of human islets , including the slower beta - cell turnover rates in humans compared with mice , may account for the need for the use of a beta cell regeneration agent in addition to an immunosuppressive or immunoregulatory agent when intervening in the disease 5 . novel therapies have emerged with a mechanism of transforming ducts into islets . for example , the reg3 gene proteins , which have been found to be upregulated in acute pancreatic ligation and in new onset human type 1 diabetes , and have been shown to generate new islets from progenitor cells found within the pancreatic ductal population . in vitro studies have shown reg peptides transform human pancreatic ducts to islets 6,7 . a recent brdu study found that two reg peptides resulted in a twofold increase in the volume of small new islets after 5  days of treatment ( p  <  0.05 ) 8 . five days of reg peptide treatment also demonstrated upregulation of pancreatic transcription factors , including ngn3 , nkx6.1 , sox9 and ins . the reg3 gamma peptide , islet neogenesis associated protein , demonstrated a 27% rise in arginine stimulated c - peptide area under the curve among 63 type 1 patients , with an average of 20  years of type 1 diabetes with no prior detectable fasting c - peptide levels ( p  =  0.0057 ) 9 . three reg peptides are currently in development . by similar mechanisms of action to the reg peptides , gastrin has been shown to stimulate islet cell hyperplasia 10 . preliminary studies combining gastrin with epidermal growth factor resulted in up to a 75% reduction in insulin requirements among existing type 1 diabetes patients 11 . proton pump inhibitors have been shown to increase gastrin levels ninefold in man . a recent study among type 2 diabetes patients demonstrated that the proton pump inhibitor , pantoprazole , given at dosage of 40  mg twice daily for 12  weeks resulted in a decrease in a1c of 7.66.8% ( p  <  0.001 ) . the decrease in a1c significantly correlated with an increase in gastrin and insulin levels and beta - cell function assessed by homeostatic model assessment 12 . thus , in type 1 diabetes , therapeutic agents that may generate new islets from ductal tissue may hold great promise when used in conjunction with an immune tolerance agent . such an approach may potentially increase beta - cell mass among type 1 patients in a muted immune environment , in order to protect and sustain both remaining beta cells and newly generated beta cells . in mice , type 1 diabetes is primarily an autoimmune disease , and rendering mice insulin independent is different than it is for humans . contributing factors may include their continuous patterns of eating , and the fact that their islets have a higher percentage of beta cells and lower percentage of alpha , delta , pancreatic polypeptide and ghrelin - secreting epsilon cells . rodents also have less complex vascular , neural and paracrine systems . perhaps , these differences and complexities help explain why diabetes can be  cured in a mouse with immunosuppression alone but not in humans , in which the reversal of diabetes requires islet regeneration in addition to immune protection . these studies posit that , in humans , type 1 diabetes is both an autoimmune disease and a disease of beta - cell deficiency , which can not be corrected with immune agents alone , as illustrated by the diagram below ( figure  1 ) . a novel proposal to tackle type 1 diabetes at diagnosis because type 1 diabetes is both an autoimmune disease and a beta - cell deficiency disease , it can not be corrected with immune dampening agents alone . our analysis of the shortcomings of the earlier therapeutic approaches to type 1 diabetes have led us to design a new proposal , utilizing the immune muting agent cyclosporine with the proton pump inhibitor , lansoprazole , a drug that markedly enhances plasma levels of gastrin . gastrin has been associated with the in vivo expansion of islet neogenesis from ductal populations acting through the reg receptor 10,13,14 . with this in mind we are now starting a novel trial http://www.clinicaltrials.gov/ct2/show/nct01762644?term=iit&rank=1 utilizing the immune agent cyclosporine a with the proton pump inhibitor , lansoprazole . each of the agents has a long enough track record so that the anticipated risks of the study are modest .