Type 1 diabetes mellitus: immune intervention
2012; Wiley; Volume: 66; Linguagem: Inglês
10.1111/j.1742-1241.2011.02855.x
ISSN1742-1241
Autores Tópico(s)Pancreatic function and diabetes
ResumoThis 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 may also be appropriate to consider GAD as one component of a combination therapeutic approach in T1D. Sherry N 1 , Hagopian W 2 , Ludvigsson J 3 , Jain SM 4 , Wahlen J 5 , Ferry RJ Jr 6 , Bode B 7 , Aronoff S 8 , Holland C 9 , Carlin D 9 , King KL 9 , Wilder RL 1,10 , Pillemer S 1,11 , Bonvini E 9 , Johnson S 9 , Stein KE 9 , Koenig S 9 , Herold KC 1,12 , Daifotis AG 9 ; Protégé Trial Investigator 1 Massachusetts General Hospital, Boston, MA, USA, 2 Pacific Northwest Diabetes Research Institute, Seattle, WA, USA, 3 Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden, 4 TOTALL Diabetes Hormone Research Institute, Indore, Madhya Pradesh, India, 5 Endocrine Research Specialists, Ogden, UT, USA, 6 Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children's Hospital and University of Tennessee Health Science Center, Memphis, TN, USA, 7 Atlanta Diabetes Associates, Atlanta, GA, USA, 8 Research Institute of Dallas, Dallas, TX, USA, 9 MacroGenics, Rockville, MD, USA, 10 PAREXEL International, Durham, NC, USA, 11 American Biopharma Corporation, Gaithersburg, MD, USA, and 12 Yale University, New Haven, CT, USA Lancet 2011; 378 : 487–97 Background: Previous reports have shown that, with a short course of humanised anti-CD3 monoclonal antibody (either teplizumab or otelixizumab), there was preservation of β-cell function – as measured by C-peptide – and lower insulin doses with either better or equivalent glycaemic control (7, 8). The short course of treatment, initiated soon after diagnosis, resulted in beneficial effects that extended for 2–4 years (9, 10). The current report describes a phase 3 study using teplizumab. Methods: The study randomised 516 subjects (209 assigned a 14-day course of full-dose teplizumab, 102 assigned a 14-day course of low-dose teplizumab, 106 assigned a 6-day course of full-dose teplizumab, and 99 assigned placebo). Treatment was given at baseline and at 26 weeks. Subjects were aged 8–35 and randomised within 3 months of diagnosis of T1D. The study is designed to last 2 years, with the current report giving outcome at 1 year. The primary outcome measure was a composite of the percentage of patients with insulin use of <0.5 U/kg per day and HbA1c of <6.5% at 1 year. Results: The primary outcome did not differ between groups at 1 year. However, 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p = 0.03). Moreover, exploratory analyses suggested that teplizumab could help preserve β-cell function – as measured by C-peptide – at 1 year, and might decrease the amount of insulin needed for glycaemic control, particularly in subgroups such as children. Similar proportions of patients had adverse events and serious adverse events. The most common clinical adverse event in the teplizumab groups was rash. Conclusion: Anti-CD3 therapy did not impact the primary outcome measure but exploratory analyses suggested that anti-CD3 therapy could help preserve β-cell function. The authors concluded that this should influence the design of future studies. Comment: Earlier studies had shown that relatively short courses of treatment (6 or 14 days) with an anti-CD3 monoclonal antibody can have sustained effects on β-cell function – as measured by C-peptide. Therefore, both of the anti-CD3 antibodies used (teplizumab and otelixizumab) were studied in full-scale phase 3 trials for potential commercialization for use in recent-onset T1D. The Protégé Study, discussed here, unfortunately selected a primary outcome measure that had not been used either in earlier trials of anti-CD3 or in other major immunotherapy trials discussed in this chapter or its predecessors in the previous two editions of this Yearbook. The Protégé Study also enrolled subjects in South Asia. Although these subjects met the clinical criteria used for enrolment, it is important to note that typical immune-mediated T1D (also called type 1A diabetes) is a disease principally of European Caucasians. Enrolment of Asian subjects may have confounded the results. It also turns out that the phase 3 DEFEND-1 Study using otelixizumab in T1D also did not meet its primary endpoint, as was announced by a press release on 11 March 2011 (11). The DEFEND-1 Study unfortunately selected a dose (3.1 mg total dose) dramatically lower than that used in the original teplizumab study (48 mg). Thus, there are lessons to be learned about clinical trial design, in terms of dose selection, population studied and outcome measure chosen. Nonetheless, the fact that beneficial effects were observed in the earlier studies, and suggested by the exploratory analyses in the Protégé Study, should be taken as encouraging for this therapeutic approach. Nonetheless, in the original trials with both of these antibodies, there is progressive decline in β-cell function, suggesting that there may be a need for repeated courses of administration. This was being tested in the Protégé Study and probably needs further examination. Moreover, these antibodies remain candidates to be used in combination therapy with another agent (or agents). 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 , Russell WE 13 , Schatz D 14 , Wherrett D 15 , Wilson DM 16 , Krischer JP 2 , Skyler JS 9 ; Type 1 Diabetes TrialNet Abatacept 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 Vanderbilt University, Nashville, TN, 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 : 412–19 Background: To be fully active, immune T-cells need a co-stimulatory signal in addition to the main antigen-driven signal. Abatacept modulates co-stimulation and prevents full T-cell activation. Studies in both animals and human beings have shown that interruption of the co-stimulatory second signal beneficially affects autoimmunity. Co-stimulation blockade has been effective in psoriasis, rheumatoid arthritis, juvenile rheumatoid arthritis and control of allograft rejection. This study used abatacept to modulate co-stimulation in recent-onset T1D. Methods: The study randomised 112 subjects (77 assigned to abatacept, 35 assigned to placebo), aged 6–45, 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 103 subjects included in the analysis. Intervention consisted of infusions of abatacept (or placebo) on days 1, 14 and 28, and then monthly for a total of 27 infusions. Results: At 2 years, the mean level of C-peptide was significantly higher in the abatacept group than in the placebo group, and declined at a slower rate. The difference between groups was present throughout the trial, with an estimated 9.6 months' delay in C-peptide reduction with abatacept, even though abatacept treatment was continued for the entire 2 years. The abatacept group also had significantly lower A1c levels and required less insulin in the aggregate during the total course of the study. Adverse effects were minimal and there was no increase in infections or in neutropenia. Conclusion: The co-stimulation modulator abatacept showed beneficial effects on β-cell function in recent-onset T1D. Further observation will determine whether the beneficial effect continues after cessation of abatacept infusions. Comment: This study demonstrates that treatment with the co-stimulation modulator abatacept can have beneficial effects on β-cell function – as measured by C-peptide – at 2 years. Nonetheless, there is progressive decline in β-cell function, despite continued monthly infusions of abatacept. Since abatacept works to block T-cell activation and does not impact memory T-cells, this suggests that T-cell activation lessens with time. It will be important to see what happens in the follow-up of the participants in this trial, after abatacept was discontinued. A future study might be desirable to see whether a shorter course of abatacept (e.g. 6 or 9 months) would offer similar effects. In addition, the development of a subcutaneous version of abatacept would make administration far easier, and would be mandatory if abatacept was to be explored for use in high risk subjects for delay or prevention of T1D. Abatacept might also be useful in combination therapy with another agent. Bizzarri C 1 , Pitocco D2, Napoli N3, Di Stasio E2, Maggi D3, Manfrini S3, Suraci C4, Cavallo MG5, Cappa M1, Ghirlanda G2, Pozzilli P3; IMDIAB Group 1 Department of Endocrinology and Diabetes, Bambino Gesù Children's Hospital, Rome, Italy, 2 Department of Diabetology, Catholic University, Rome, Italy, 3 Department of Endocrinology and Diabetes, University Campus Bio-Medico, Rome, Italy, 4 Department of Diabetology, Sandro Pertini Hospital, Rome, Italy, and 5 Department of Medical Therapy, University Sapienza, Rome, Italy Diabetes Care 2010; 33 : 1962–3 Background: Vitamin D deficiency has been associated with T1D, and epidemiological studies suggest that vitamin D supplementation in early childhood may decrease risk of developing T1D. A previous study (discussed in last year's Yearbook) evaluated whether 1,25(OH)2D3 (calcitriol) improves β-cell function in adults with recent-onset T1D. The current study included younger individuals. Methods: The study randomised 34 subjects, aged 11–35, and randomised within 3 months of diagnosis of T1D. Intervention consisted of calcitriol or placebo daily for 2 years. The primary endpoint was β-cell function – as measured by C-peptide – at 2 years, with 27 subjects included in the analysis (15 in the calcitriol group, 12 in the placebo group). Results: Outcome measures were assessed at 6, 12 and 24 months. HbA1c and insulin use were similar in both groups. Fasting C-peptide declined similarly in both groups. Stimulated C-peptide was measured at baseline and 12 months, and was similar in both groups. Conclusion: Calcitriol did not have a beneficial effect in recent-onset T1D. Comment: As noted in last year's Yearbook, the potential role of vitamin D as a preventative intervention for T1D has been suggested for some time. Unfortunately, in the studies conducted to date in recent-onset T1D, 1,25(OH)2D3 has failed to show a beneficial effect. The real question of whether vitamin D might have an effect in prevention of T1D has not been explored. Given the tendency towards nearly routine supplementation with vitamin D, it is uncertain whether a controlled study of its use in prevention can actually be conducted. Knip M 1,7 , Virtanen SM 3,8 , Seppä K 1,6 , Ilonen J 9,10 , Savilahti E 1 , Vaarala O 4 , Reunanen A 5 , Teramo K 2 , Hämäläinen AM 1,11 , Paronen J 1 , Dosch HM 1,12 , Hakulinen T 1,6 , Akerblom HK 1 ; Finnish TRIGR Study Group 1 Hospital for Children and Adolescents and 2 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland, 3 Nutrition Unit, 4 Immune Response Unit and 5 Department of Health and Functional Capacity, National Institute for Health and Welfare, Helsinki, Finland, 6 Finnish Cancer Registry, Helsinki, Finland, 7 Department of Pediatrics and 8 Research Unit, Tampere University Hospital, and Tampere School of Public Health, University of Tampere, Tampere, Finland, 9 Immunogenetics Laboratory, University of Turku, Turku, Finland, 10 Department of Clinical Microbiology, University of Kuopio, Kuopio, Finland, 11 Department of Pediatrics, Jorvi Hospital, Espoo, and Department of Pediatrics, University of Oulu, Oulu, Finland, and 12 Hospital for Sick Children, Research Institute, University of Toronto, Toronto, Canada N Engl J Med 2010; 363 : 1900–8 Background: Short duration of breastfeeding and/or early exposure to complex dietary proteins have been implicated as potential risk factors for β-cell autoimmunity and T1D. Methods: The study randomised 230 infants to receive either a casein hydrolysate formula or a conventional, cow's-milk based formula (control) whenever breast milk was not available during the first 6–8 months of life. Eligible infants had human leucocyte antigen (HLA) conferred susceptibility to T1D and at least one family member with T1D. Children were followed for 10 years for the development of diabetes related autoantibodies and for development of T1D. Results: The group assigned to casein hydrolysate formula had a reduced risk of development of β-cell autoimmunity (appearance of one or more antibodies). Conclusion: Dietary intervention during infancy appears to have a long-lasting effect on markers of β-cell autoimmunity. Comment: Epidemiological studies have suggested that either short duration of breastfeeding and/or early exposure to cow's milk increases the risk of T1D. It would be unethical to randomise subjects to breastfeeding vs. no breastfeeding. Thus, focus has been on avoidance of cow's milk at the time of weaning from breast milk. The Finnish TRIGR Study Group reports on the appearance of diabetes autoantibodies and has found that these are reduced by half. Under way is the full Trial to Reduce Insulin-dependent Diabetes Mellitus in the Genetically at Risk (TRIGR), a true primary prevention study (12). TRIGR has recruited 5606 newborn infants with a family member affected by T1D and enrolled 2159 eligible subjects who carried a risk-conferring HLA genotype. Eighty per cent of the participants were exposed to the study formula. The overall retention rate over the first 5 years was 87%, and protocol compliance was 94%. The full TRIGR has the development of T1D as its primary outcome. The study will conclude in 2017 when the last subject reaches age 10. To this writer, it seems appropriate to always encourage breastfeeding for as long as reasonable. TRIGR will determine whether cow's milk formulas should be avoided. If the Finnish TRIGR study results are replicated – and extended to result in reduced incidence of T1D – it will change feeding habits, probably not just for those with a family history of T1D but perhaps also for the population at large. Martin S 1 , Herder C 1 , Schloot NC 1,2 , Koenig W 3 , Heise T 4 , Heinemann L 4 , Kolb H 1 , on behalf of the DIATOR Study Group 1 Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany, 2 Departments of Medicine and Metabolic Diseases, University Hospital, Düsseldorf, Germany, 3 Department of Internal Medicine II – Cardiology, University of Ulm Medical Center, Ulm, Germany, and 4 Profil Institute for Metabolic Research, Neuss, Germany PLoS One 2011; 6 : e17554 Background: There is some evidence suggesting that the lipid-lowering agent atorvastatin also has immunomodulatory effects. Thus, the current study was undertaken to determine whether atorvastatin might alter the course of T1D. Methods: The study randomised 89 subjects (46 to atorvastatin, 43 to placebo), aged 18–39, and randomised within 3 months of diagnosis of T1D. Intervention consisted of atorvastatin or placebo daily for 18 months. The primary endpoint was β-cell function – as measured by C-peptide – at 18 months, with 63 subjects included in the analysis. Results: Outcome measures were assessed at 12 and 18 months. Fasting and stimulated C-peptide levels were not significantly different between groups at 18 months. However, in secondary analyses, both fasting and median stimulated C-peptide declined over time more slowly in the atorvastatin group than in the placebo group when the groups were considered independently. Conclusion: Atorvastatin did not have a beneficial effect in recent-onset T1D. Some secondary analyses suggest that additional studies may be warranted. Comment: This small provocative study did not meet its primary outcome (difference in C-peptide between groups at 18 months). However, when the authors examined the decline in C-peptide within the atorvastatin group, there was a non-significant decline, whereas the decline in C-peptide within the placebo group was significant. This may indicate that further evaluation of atorvastatin is warranted. Statins are widely used for the treatment of hypercholesterolaemia and reduction of cardiovascular risk. Atorvastatin will soon be generic. If an orally administered, commonly used, generic drug could slow the course of T1D that would be worthwhile. Thus, this writer would be enthusiastic to see a full-scale trial of atorvastatin in T1D. Giannoukakis N 1,2 , Phillips B1, Finegold D3, Harnaha J1, Trucco M1 1 Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, 2 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, and 3 Department of Human Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Diabetes Care 2011; 34 : 2026–32 Background: This phase 1 study investigated the safety of autologous dendritic cells, stabilised into an immunosuppressive state, in established T1D. Methods: The study randomised 10 subjects (three to unmanipulated 'control' autologous dendritic cells and seven to autologous dendritic cells engineered ex vivo toward an immunosuppressive state). Subjects were aged 18–60 and were randomised after at least 5 years of T1D, all with undetectable C-peptide. All subjects received four rounds of autologous dendritic cells administered intradermally once every 2 weeks. The primary endpoint was the proportion of patients with adverse events over 12 months, based on physician global assessment, haematology, biochemistry and immune monitoring. Results: There were no discernible adverse events in any patient during the study. The only measurable difference, compared with baseline, was a significant increase in peripheral B220+ CD11c B-lymphocytes, mainly seen in the recipients of engineered dendritic cells. Conclusion: Treatment with autologous dendritic cells, in a native state or directed ex vivo toward a tolerogenic immunosuppressive state, is safe and well tolerated. Comment: Autologous tolerogenic dendritic cells theoretically may be a major novel approach in arresting the course of T1D. The current study was initiated to determine whether administration of such cells might result in unexpected adverse effects that would limit their use. The answer is that no obvious adverse effects emerged. Hopefully this will pave the way for use of autologous dendritic cells engineered ex vivo toward an immunosuppressive state in recent-onset T1D, to see whether they have the potential to alter the course of the disease. We eagerly await the initiation of such studies. Piemonti L 1 , Maffi P 1 , Monti L 2 , Lampasona V 3 , Perseghin G 4,5 , Magistretti P 1 , Secchi A 1,6 , Bonifacio E 1,7 1 Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, Italy, 2 Cardiodiabetes and Core Lab, Division of Metabolic and Cardiovascular Sciences, San Raffaele Scientific Institute, Milan, Italy, 3 Unit of Genomics for the Diagnosis of Human Pathologies, Center for Genomics, Bioinformatics and Biostatistics, San Raffaele Scientific Institute, Milan, Italy, 4 Unit of Obesity and Metabolic Related Diseases, Division of Metabolic and Cardiovascular Sciences, San Raffaele Scientific Institute, Milan, Italy, 5 Department of Sport, Nutrition and Health Sciences, Università degli Studi di Milano, Milan, Italy, 6 Unit of Clinical Transplant, Division of Immunology, Transplantation and Infectious Diseases, Università Vita-Salute San Raffaele, Milan, Italy, and 7 Center for Regenerative Therapies Dresden, Dresden University of Technology, Dresden, Germany Diabetologia 2011; 54 : 433–9 Background: The authors sought to determine whether immunosuppression therapy can reinstate β-cell function in patients with long-term T1D. Methods: The study measured β-cell function in 22 subjects aged 30–48 with long-standing (17–35 years' duration) T1D, on a waiting list for islet transplantation, who received rapamycin monotherapy as pre-conditioning. As a comparison group, the study measured β-cell function in 14 subjects aged 20–68, with long-standing (11–22 years' duration) T1D, also on a waiting list for islet transplantation, but who did not receive rapamycin pre-conditioning. Results: During rapamycin treatment, the proportion of patients with detectable fasting C-peptide increased from 4 of 22 prior to rapamycin therapy to 13 of 22 (p = 0.01). Exogenous insulin requirement decreased in those who were C-peptide responsive. These variables remained unchanged in the 14 control patients. Conclusion: The authors concluded that therapies to reinstate β-cell function may be applicable to patients with long-term C-peptide negative T1D. Comment: This is a provocative study that found that patients who were awaiting islet cell transplantation and were pre-treated with rapamycin had an increase in β-cell function. Since it is generally not thought possible to restore β-cell function in long-standing T1D, this study raises new questions about the potential reversibility of the disease. In last year's Yearbook, we commented on an autopsy study (13) that demonstrated that some patients with long-standing apparent T1D had normal-appearing islets, intact C-peptide, absence of high risk HLA, and lack of antibodies at the time of death. Other studies also suggest that there may be persistent β-cell function in long-standing T1D. The current study suggests that such persistent β-cell function may be enhanced by immune intervention. Although such intervention is unlikely to fully restore β-cell function, studies of this type raise many new questions about our understanding of T1D. This year has raised concerns amongst many, due to the highly visible press releases concerning failure to achieve the primary outcome measure in two phase 3 studies with anti-CD3 (Protégé and DEFEND-1) and two phase 3 studies with GAD-alum. As noted in the above commentaries, all is not so bleak. As discussed, there were crucial design flaws in the anti-CD3 studies, and the GAD-alum studies perhaps used the wrong formulation (with adjuvant), by the wrong route (subcutaneous) and at the wrong time (after clinical diagnosis of T1D). To this writer, it would be premature to bury either anti-CD3 or GAD as potential interventions, particularly if they are used in prevention of T1D or as components of combination therapy. Indeed, all of the trials of immunotherapy that have achieved their primary outcome still have showed loss of effect over time, so that it is unlikely that any single therapy alone will dramatically alter the course of T1D. As discussed in a recent 'Perspective', stopping T1D will probably not only involve a combination of therapies but also require either replacement of β-cells or use of agents that stimulate β-cell regeneration or at the least enhance β-cell function (14). Fortunately, there is much progress in conducting the pre-clinical studies needed to advance such concepts into clinical trials. Over the next few years, we should begin seeing such clinical trials being conducted. The author declares no conflict of interest.
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