Type 1 diabetes mellitus: immune intervention

This year saw the report of several major studies of immune intervention for type 1 diabetes (T1D). Immune intervention studies have been conducted both in patients with recently diagnosed T1D and earlier during the stage of evolution of the disease in individuals found to be at increased risk. This chapter of the Yearbook of Advanced Technology and Treatments in Diabetes reviews the key papers that have appeared in this field between July 2010 and June 2011. It includes only studies conducted in human beings. Vehik K 1 , Cuthbertson D 1 , Ruhlig H 1 , Schatz DA 2 , Peakman M 3,4 , Krischer JP 1 ; DPT-1 and TrialNet Study Groups 1 University of South Florida, Pediatrics Epidemiology Center, Tampa, FL, USA, 2 University of Florida, College of Medicine, Gainesville, FL, USA, 3 Department of Immunobiology, King’s College London, London, UK, and 4 National Institutes of Health Research Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK Diabetes Care 2011; 34 : 1585–90 Background: Insulin is an important antigen in T1D. Mucosal administration of antigens is thought to stimulate regulatory T-cells in preference to effector T-cells. Thus, a number of studies have used mucosal administration of insulin in attempts to modulate the T1D disease process. These have included both oral and nasal administration of insulin. The DPT-1 Study Group had conducted a large study of oral insulin in individuals at risk of developing T1D (1). Although oral insulin did not delay the development of T1D in the group as a whole, it did show beneficial effects in a subgroup with higher levels of insulin autoantibodies (≥80 nU/ml) at the time of enrolment. The current report is a follow-up of those subjects to evaluate the long-term intervention effects of oral insulin on the development of T1D and to assess the rate of progression to T1D before and after oral insulin treatment was stopped. Methods: The follow-up included subjects who had participated in the DPT-1 oral insulin study (1994–2003) to prevent or delay T1D. In 2009, a telephone survey was conducted to determine whether T1D had been diagnosed and, if not, an oral glucose tolerance test (OGTT), HbA1c and autoantibody levels were obtained on subjects who agreed to participate. Originally, 372 subjects had been randomised, and 97 had developed T1D during the original trial. Subsequently, 75% of the remaining 272 subjects were contacted – 77 had been diagnosed with T1D and 54 others were evaluated with an OGTT. Results: In subjects in the subgroup with benefit in the original study (those with insulin autoantibodies ≥ 80 nU/ml at enrolment), the overall benefit of oral insulin remained significant (p = 0.05). However, the hazard rate in this group increased (from 6.4% to 10.0%) after cessation of therapy, which approximated the rate of individuals treated with placebo. Conclusion: The oral insulin treatment effect appeared to be maintained with additional follow-up in the subgroup with benefit in the original study. However, after therapy was stopped, the rate of developing diabetes in the oral insulin group increased to a rate similar to that of the placebo group. Fourlanos S 1,2,3 , Perry C2, Gellert SA3, Martinuzzi E4,5, Mallone R4,5, Butler J1, Colman PG3, Harrison LC1,2 1 Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VA, Australia, 2 Burnet Clinical Research Unit, Royal Melbourne Hospital, Parkville, Australia, 3 Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville, Australia, 4 INSERM, U986, DeAR Laboratory Avenir, Saint Vincent de Paul Hospital, Paris, France, and 5 Université Paris Descartes, Faculté de Médecine René Descartes, Paris, France Diabetes 2011; 60 : 1237–45 Background: A previous study (DIPP) followed genetically at-risk children from birth until the appearance of antibodies, at which point nasal insulin was administered, although without success (2). The authors of the current study had previously conducted a crossover study that suggested that nasal insulin might have beneficial effects on both the immune system and β-cell function in individuals at high risk of T1D (3). Therefore, the authors conducted this study to determine whether nasal insulin could induce immune tolerance. Methods: The study recruited subjects diagnosed with diabetes in the previous 12 months, with glutamic acid decarboxylase (GAD) antibodies and fasting C-peptide > 0.20 nmol/l, who had stable blood glucose control with diet and/or oral hypoglycaemic drug therapy but no previous insulin therapy. They randomised 52 subjects, aged 40–55 years, to nasal insulin (n = 26) or to placebo (n = 26). Intervention consisted of a metered dose nasal spray (two sprays per nostril, equivalent to 40 units of insulin) daily for 10 days and then on 2 consecutive days weekly for 12 months. Participants were assessed every 3 months for 24 months. Results: Metabolic endpoints, β-cell function, both fasting and glucagon-stimulated C-peptide, HbA1c and fasting glucose, remained similar between nasal insulin and placebo groups. At 24 months, β-cell function had declined by 35%, and 23 of 52 participants (44%) progressed to insulin treatment. Insulin antibody response to injected insulin was significantly blunted in those who had received nasal insulin. In a small cohort, the interferon-γ response of blood T-cells to proinsulin was suppressed after nasal insulin. Conclusion: The authors concluded that they had seen some evidence that nasal insulin induced immune tolerance to insulin. They assert that this provides a rationale for the use of nasal insulin to be studied to prevent diabetes in at-risk individuals. Comment: Antigen-specific therapy is thought to be a highly desirable strategy to interrupt the immune processes that result in T1D. Such therapies are generally quite safe, are specific for T1D, and are not expected to alter generalised immune responses. Mucosal administration of antigen is thought to favour protective immunity over destructive immunity. Mucosal administration of insulin has been used by both the oral and the nasal route. However, to date, in recently diagnosed T1D, three studies of oral insulin and the Fourlanos et al. study of nasal insulin discussed above have all failed to alter metabolic function. In addition, studies of both oral and nasal insulin have failed in prevention studies, although the DPT-1 oral insulin prevention study did identify a subgroup that had a beneficial effect. Follow-up of those subjects in the report by Vehik et al. discussed above showed continued effect but, after cessation of oral insulin, regression to a rate of diabetes similar to the placebo group. The TrialNet Study Group is conducting an additional study with oral insulin on subjects with similar criteria to the subgroup that showed beneficial effect. Likewise, the Australian group is performing a prevention study with nasal insulin, and a dose-ranging study of both oral and nasal insulin is being conducted in newborns at risk of T1D. Dose determination is a vexing question that has hampered many studies with antigen-specific interventions, since translation of dose from rodents to human beings is fraught with much difficulty. Despite the lack of major success with mucosally based insulin administration, there remains hope that some form of antigen-specific therapy with insulin will ultimately prove beneficial. Wherrett DK 1 , Bundy B 2 , Becker DJ 3 , DiMeglio LA 4 , Gitelman SE 5 , Goland R 6 , Gottlieb PA 7 , Greenbaum CJ 8 , Herold KC 9 , Marks JB 10 , Monzavi R 11 , Moran A 12 , Orban T 13 , J P Palmer 14 , Raskin P 15 , Rodriguez H 4 , Schatz D 16 , Wilson DM 17 , Krischer JP 2 , Skyler JS 10 ; Type 1 Diabetes TrialNet GAD Study Group 1 Hospital for Sick Children, University of Toronto, Toronto, ON, Canada, 2 University of South Florida, Tampa, FL, USA, 3 University of Pittsburgh, Pittsburgh, PA, USA, 4 Indiana University School of Medicine, Indianapolis, IN, USA, 5 University of California San Francisco, San Francisco, CA, USA, 6 Columbia University, New York, NY, USA, 7 University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora, CO, USA, 8 Benaroya Research Institute, Seattle, WA, USA, 9 Yale University School of Medicine, New Haven, CT, USA, 10 Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA, 11 Children’s Hospital Los Angeles, Los Angeles, CA, USA, 12 University of Minnesota, Minneapolis, MN, USA, 13 Joslin Diabetes Center, Boston, MA, USA, 14 University of Washington School of Medicine, Seattle, WA, USA, 15 University of Texas Southwestern Medical School, Dallas, TX, USA, 16 University of Florida, Gainesville, FL, USA, and 17 Stanford University, Stanford, CA, USA Lancet 2011; 378 : 319–27 Background: GAD is another important antigen in T1D. In animal models, GAD has been an effective agent to modulate the T1D disease process. A previous pilot study of an aluminium-hydroxide-formulated GAD (GAD-alum) vaccine had modest effect (4). The current study was designed to determine whether GAD vaccine could preserve β-cell function in recent-onset T1D. Methods: The study randomised 145 subjects (48 assigned to three injections of vaccine, 49 assigned to two injections of vaccine and one injection of placebo, and 48 assigned to three injections of placebo), aged 3–45, and randomised within 3 months of diagnosis of T1D. The primary endpoint was β-cell function – as measured by C-peptide – at 1 year, with 140 subjects included in the analysis. Results: At 1 year, the mean level of C-peptide was similar in all three groups, with no evidence of a treatment effect. HbA1c levels, insulin use, and the occurrence and severity of adverse events did not differ between groups. Conclusion: Antigen-based immunotherapy with two or three doses of subcutaneous GAD-alum did not alter the course of loss of insulin secretion during 1 year in patients with recently diagnosed T1D. Comment: This paper tested another antigen-specific immunomodulatory approach in T1D, using GAD. As noted above in discussing insulin, antigen-specific therapy is thought to be a highly desirable strategy to interrupt the immune processes that result in T1D, and generally is both safe and specific for T1D. Unfortunately, antigen-specific therapies have had more failures than successes. Indeed, in addition to this study, there have been press releases announcing the failure of two phase 3 studies using the same GAD-alum vaccine (5, 6). However, in the case of GAD, it is important to note that the benefits seen in animals used a number of routes of administration, but not as a subcutaneous vaccine. Moreover, they used GAD for prevention, not to slow the loss of β-cell function in recent-onset T1D. This raises the question of whether GAD should be considered in prevention studies in human beings. It be to GAD as one of a approach in T1D. 1 , 2 , J 3 , 4 , J 5 , 6 , B 7 , S 8 , 9 , D 9 , 9 , , S , 9 , S 9 , 9 , S 9 , Herold KC , 9 ; 1 Hospital, Boston, MA, USA, 2 Diabetes Research Institute, Seattle, WA, USA, 3 of Department of Clinical and Medicine, of Health University, 4 Diabetes Research Institute, 5 Research USA, 6 of and Children’s Hospital and University of Health Center, USA, 7 Diabetes USA, 8 Research Institute of Dallas, Dallas, TX, USA, 9 USA, 10 USA, 11 USA, and 12 Yale University, New Haven, CT, USA Lancet 2011; 378 : Background: have with a course of antibody or there was of β-cell function – as measured by C-peptide – and insulin doses with or equivalent control The course of after in beneficial effects that for The current report a phase 3 study using Methods: The study randomised subjects assigned a course of assigned a course of assigned a course of and assigned was at and at were aged and randomised within 3 months of diagnosis of T1D. The study is designed to 2 years, with the current report at 1 The primary was a of the of patients with insulin use of per and HbA1c of at 1 Results: The primary did not differ between at 1 However, of patients in the were not insulin at 1 year, with no patients in the placebo group at 1 year (p = Moreover, suggested that could preserve β-cell function – as measured by C-peptide – at 1 year, and might the of insulin for in as of patients had adverse events and adverse The adverse in the was Conclusion: therapy did not the primary but suggested that therapy could preserve β-cell function. The authors concluded that this should the of Comment: studies had that of treatment or 14 with an antibody have effects on β-cell function – as measured by Therefore, both of the antibodies used and were studied in phase 3 for for use in recent-onset T1D. The discussed a primary that had not been used in earlier of or in major immunotherapy discussed in this chapter or in the previous two of this The Study subjects in South Although subjects the criteria used for it is important to note that T1D type is a disease of of subjects have the It that the phase 3 Study using in T1D did not primary as was by a press on 11 The Study a dose than that used in the original study (48 Thus, there are to be in of dose studied and the that beneficial effects were in the earlier studies, and suggested by the in the should be as for this in the original with both of antibodies, there is in β-cell function, that there be a for of This was being tested in the Study and Moreover, antibodies to be used in therapy with another agent Orban T 1 , Bundy B 2 , Becker DJ 3 , DiMeglio LA 4 , Gitelman SE 5 , Goland R 6 , Gottlieb PA 7 , Greenbaum CJ 8 , Marks JB 9 , Monzavi R 10 , Moran A 11 , Raskin P 12 , Rodriguez H 4 , 13 , Schatz D 14 , Wherrett D 15 , Wilson DM 16 , Krischer JP 2 , Skyler JS 9 ; Type 1 Diabetes TrialNet Study Group 1 Joslin Diabetes Center, Boston, MA, USA, 2 University of South Florida, Tampa, FL, USA, 3 University of Pittsburgh, Pittsburgh, PA, USA, 4 Indiana University School of Medicine, Indianapolis, IN, USA, 5 University of California San Francisco, San Francisco, CA, USA, 6 Columbia University, New York, NY, USA, 7 University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora, CO, USA, 8 Benaroya Research Institute, Seattle, WA, USA, 9 University of Miami Diabetes Research Institute, Miami, FL, USA, 10 Children’s Hospital Los Angeles, Los Angeles, CA, USA, 11 University of Minnesota, Minneapolis, MN, USA, 12 University of Texas Southwestern Medical School, Dallas, TX, USA, 13 University, USA, 14 University of Florida, Gainesville, FL, USA, 15 Hospital for Sick Children, University of Toronto, Toronto, ON, Canada, and 16 Stanford University, Stanford, CA, USA Lancet 2011; 378 : Background: be immune T-cells a in addition to the and in both animals and human beings have that of the has been effective in and control of This study used to modulate in recent-onset T1D. Methods: The study randomised subjects assigned to assigned to placebo), aged and randomised within 3 months of diagnosis of T1D. The primary endpoint was β-cell function – as measured by C-peptide – at 2 years, with subjects included in the analysis. Intervention consisted of of on days 14 and and then for a of Results: At 2 years, the mean level of C-peptide was significantly higher in the group than in the placebo and declined at a The between was the with an delay in C-peptide with treatment was continued for the 2 The group had significantly levels and insulin in the during the course of the study. effects were and there was no in or in Conclusion: The showed beneficial effects on β-cell function in recent-onset T1D. will determine whether the beneficial effect after cessation of Comment: This study that treatment with the have beneficial effects on β-cell function – as measured by C-peptide – at 2 there is in β-cell function, continued of to and not this that with It will be important to in the follow-up of the participants in this after was A study might be desirable to whether a course of 6 or 9 similar In addition, the development of a subcutaneous of administration and be if was to be for use in high risk subjects for delay or prevention of T1D. might be in therapy with another 1 , Group 1 Department of and Diabetes, Children’s Hospital, 2 Department of University, 3 Department of and Diabetes, University 4 Department of Hospital, and 5 Department of Medical University Diabetes Care : Background: D has been with T1D, and studies that D in risk of developing T1D. A previous study in evaluated whether β-cell function in with recent-onset T1D. The current study included individuals. Methods: The study randomised 34 subjects, aged and randomised within 3 months of diagnosis of T1D. Intervention consisted of or placebo daily for 2 The primary endpoint was β-cell function – as measured by C-peptide – at 2 years, with subjects included in the in the 12 in the placebo Results: were assessed at 12 and 24 months. HbA1c and insulin use were similar in both groups. C-peptide declined in both groups. C-peptide was measured at and 12 months, and was similar in both groups. Conclusion: did not have a beneficial effect in recent-onset T1D. Comment: As noted in the of D as a intervention for T1D has been suggested for some Unfortunately, in the studies conducted to in recent-onset T1D, has failed to show a beneficial effect. The question of whether D might have an effect in prevention of T1D has not been the with it is whether a study of use in prevention be M , , K , J , 1 , 4 , A 5 , K 2 , , J 1 , , T , 1 ; Study Group 1 Hospital for and and 2 Department of and University of and University Hospital, 3 Unit, 4 Immune and 5 Department of Health and National Institute for Health and 6 7 Department of Pediatrics and 8 Research Unit, University Hospital, and School of University of 9 University of 10 Department of Clinical University of 11 Department of Hospital, and Department of University of and 12 Hospital for Sick Children, Research Institute, University of Toronto, Toronto, J : Background: of and/or to have been as risk for β-cell and T1D. Methods: The study randomised to a or a based was not during the months of had human antigen to T1D and at one with T1D. were followed for 10 for the development of diabetes autoantibodies and for development of T1D. Results: The group assigned to had a risk of development of β-cell of one or more Conclusion: intervention during to have a effect on of β-cell Comment: studies have suggested that of and/or to the risk of T1D. It be to subjects to no Thus, has been on of at the time of from The Study Group on the appearance of diabetes autoantibodies and has found that are by is the to Diabetes in the at a primary prevention study has recruited with a by T1D and subjects who a per of the participants were to the study The overall rate over the 5 was and was The has the development of T1D as primary The study will in the this it to for as as will determine whether should be the study are – and to result in of T1D – it will not for those with a of T1D but for the at S 1 , 1 , , 3 , T 4 , 4 , H 1 , on of the Study Group 1 Institute for Clinical Diabetes Center, Center for Diabetes Research at University, 2 of and Metabolic University Hospital, 3 Department of – University of Medical Center, and 4 Institute for Metabolic Research, 2011; 6 : Background: is some evidence that the agent has immunomodulatory Thus, the current study was to determine whether might alter the course of T1D. Methods: The study randomised subjects to to placebo), aged and randomised within 3 months of diagnosis of T1D. Intervention consisted of or placebo daily for months. The primary endpoint was β-cell function – as measured by C-peptide – at months, with subjects included in the analysis. Results: were assessed at 12 and months. and C-peptide levels were not significantly between at months. However, in both fasting and C-peptide declined over time more in the group than in the placebo group the were considered Conclusion: did not have a beneficial effect in recent-onset T1D. that additional studies be Comment: This small study did not primary in C-peptide between at However, the authors the in C-peptide within the there was a the in C-peptide within the placebo group was This that of is are used for the treatment of and of risk. will be an administered, drug could slow the course of T1D that be Thus, this be to a of in T1D. , J1, 1 of Department of University of School of Medicine, Pittsburgh, PA, USA, 2 Department of University of School of Medicine, Pittsburgh, PA, USA, and 3 Department of University of School of Medicine, Pittsburgh, PA, USA Diabetes Care 2011; 34 : Background: This phase 1 study the of an in T1D. Methods: The study randomised 10 subjects to and to an were aged and were randomised after at 5 of T1D, all with subjects received of every 2 The primary endpoint was the of patients with adverse events over 12 months, based on and immune Results: were no adverse events in during the study. The only with was a significant in seen in the of Conclusion: with in a or a is safe and Comment: be a major approach in the course of T1D. The current study was to determine whether administration of might result in adverse effects that The is that no adverse effects this will the for use of an in recent-onset T1D, to whether they have the to alter the course of the the of 1 , P 1 , 2 , 3 , , P 1 , A , 1 Diabetes Research Institute San Institute, 2 and of Metabolic and San Institute, 3 of for the of Center for and San Institute, 4 of and Metabolic of Metabolic and San Institute, 5 Department of and Health 6 of Clinical of Transplantation and San and 7 Center for University of 2011; 54 : Background: The authors to determine whether therapy β-cell function in patients with long-term T1D. Methods: The study measured β-cell function in subjects aged with T1D, on a for who received as As a the study measured β-cell function in 14 subjects aged with T1D, on a for but who did not Results: the of patients with fasting C-peptide increased from 4 of to therapy to 13 of (p = insulin in those who were C-peptide These remained in the 14 control Conclusion: The authors concluded that therapies to β-cell function be to patients with long-term C-peptide T1D. Comment: This is a study that found that patients who were and were with had an in β-cell function. it is generally not thought to β-cell function in T1D, this study raises the of the In on an study that that some patients with T1D had C-peptide, of high risk and lack of antibodies at the time of studies that there be β-cell function in T1D. The current study that β-cell function be by immune Although intervention is to β-cell function, studies of this type many of T1D. This year has to the highly press releases failure to the primary in two phase 3 studies with and and two phase 3 studies with As noted in the above all is not As there were in the studies, and the GAD-alum studies used the by the and at the time diagnosis of this it be to or GAD as interventions, if they are used in prevention of T1D or as of therapy. Indeed, all of the of immunotherapy that have primary have showed loss of effect over that it is that therapy will alter the course of T1D. As discussed in a T1D will not only a of therapies but of or use of that stimulate β-cell or at the β-cell function there is much in conducting the studies to the years, should being The no of

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