Abstract
Aims/hypothesis
The aim of the study was to examine the 48 month outcome of treating recent-onset type 1 diabetic patients for 6 days with humanised CD3-antibody, ChAglyCD3.
Methods
Eighty patients, aged 12–39 years, were recruited for a phase 2 multicentre trial and randomised to placebo (n = 40) or ChAglyCD3 (n = 40) treatment by a third party member; participants and care-givers were blinded. The change in insulin dose (U kg−1 day−1) over 48 months was chosen as primary endpoint and compared in 31 placebo- and 33 ChAglyCD3-treated patients. Adverse events were followed in 35 and 38 patients, respectively.
Results
Treatment with ChAglyCD3 delayed the rise in insulin requirements of patients with recent-onset diabetes and reduced its amplitude over 48 months (+0.09 vs +0.32 U kg−1 day−1 in the placebo group). Using multivariate analysis this effect was correlated with higher baseline residual beta cell function and a younger age. It was associated with better outcome variables in subgroups selected according to these variables. In the ChAglyCD3 subgroup with higher initial beta cell function, 0/11 patients became C-peptide-negative over 48 months vs 4/9 in the corresponding placebo subgroup. In the subgroup aged <27 years old, antibody treatment preserved initial beta cell function for 36 months (vs >80% decline within 24 months in the placebo subgroup <27 years old), resulted in lower HbA1c concentrations and tended to reduce glycaemic variability (p = 0.08). No long-term adverse events were observed.
Conclusions/interpretation
A 6 day ChAglyCD3 treatment can suppress the rise in insulin requirements of recent-onset type 1 diabetic patients over 48 months, depending on their age and initial residual beta cell function. In younger patients this effect is associated with reduced deterioration of metabolic variables. These observations help to define inclusion criteria for prevention trials.
Trial registration:
ClinicalTrials.gov NCT00627146
Funding:
Center grants from the Juvenile Diabetes Research Foundation (4-2001-434, 4-2005-1327) and grants from the Belgian Fund for Scientific Research-Flanders and from Brussels Free University-VUB.
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Introduction
Studies in rodents have shown that CD3-specific antibodies can induce prolonged remission of established autoimmunity by restoring immune tolerance [1]. A short course in non-obese diabetic (NOD) mice, treated within 1 week after onset, induced a long-lasting normalisation of the hyperglycaemic state and an inhibition of beta cell-specific immune activities without affecting responses to unrelated antigens [2]. Similar effects were noted in experimental allergic encephalomyelitis, a model of multiple sclerosis [3]. This treatment was also tested in recent-onset type 1 diabetic patients using humanised Fc mutated anti-human CD3 antibodies [4–6], which are less mitogenic and cytokine-releasing than murine FcR-binding CD3 antibodies such as muronomab CD3 (orthoclone OKT3) [7–9]. In a Phase 1/2 trial, a CD3-specific monoclonal antibody, hOKT3γ1 (Ala-Ala), was administered for 2 weeks [4, 6]. In our Phase 2 placebo-controlled trial, the aglycosylated recombinant ChAglyCD3 was administered for six consecutive days [5]. In both studies, an improved average beta cell function and lower average insulin dosage was seen in antibody-treated groups for at least 18 months [5, 6]. The placebo-controlled trial showed that this protective effect was most pronounced in the subgroup of patients with initial residual beta cell function at or above the 50th percentile of the 80 patients included [5]. In the present 48 month follow-up study of placebo- and antibody-treated groups, we followed this effect further to examine its correlation with baseline characteristics and its association with metabolic variables. We also assessed whether antibody treatment caused long-term adverse events.
Methods
Patient selection and treatment
Eighty recent-onset type 1 diabetic patients were included in a double-blind randomised phase 2 placebo-controlled trial [5]. They were selected according to age (12–39 years), positivity for islet-cell autoantibodies (ICA) and/or glutamic acid decarboxylase autoantibodies, random C-peptide >0.2 nmol/l (at glycaemia 10.0–13.9 mmol/l), insulin treatment for <4 weeks, polyuria for <6 months, weight loss <10% during the previous 6 months, and positivity for Epstein–Barr virus (EBV) IgG. Forty patients received i.v. ChAglyCD3 on consecutive days and 40 received a placebo. Treatment allocation by a third party was randomised according to trial centre (four in Belgium, one in Germany), age (< or ≥15 years) and presence or absence of ICA. The initial protocol had been planned for an 18 month study, with data reported by Keymeulen et al. [5]. After this period, patients re-consented to a follow-up study till month 48. Both the initial and extension study were approved by the Belgian Diabetes Registry and by the ethics committee of each participating centre. Written informed consent was obtained from each patient.
Of the initial 80 patients, 73 re-consented to the extension study (35 in the placebo group and 38 in the ChAglyCD3 group; characteristics of the participants are shown in Table 1 and the study design in Fig. 1). Reasons for not participating were withdrawal from further regular testing (placebo, n = 2), a stay abroad (ChAglyCD3, n = 3) and pregnancy (ChAglyCD3, n = 1). Both groups had demographics and baseline characteristics similar to the population at start of the study, except for a slightly higher HbA1c level in the ChAglyCD3 extension group (p = 0.02) (Table 1). There were no differences in medication with effects on insulin needs; in both groups three patients temporarily received corticoids during follow-up (Electronic supplementary material [ESM] Table 1).
Patient follow-up
Patients were on intensive insulin therapy for the entire 48 month period. At least once every 3 months, insulin doses were adjusted by the patient’s diabetologist to achieve HbA1c levels <7% as part of routine care; for 73% of patients, their diabetologist did not participate in the study. Patients adjusted pre-prandial insulin doses by carbohydrate counting and home glucose monitoring, targeting pre-prandial glycaemia at 4.4–7.8 mmol/l.
Outpatient study visits occurred at months 24 ± 3, 36 ± 3 and 48 ± 3 at the trial centre or at the local hospital. Body weight, type and dose of insulin, home blood glucose measurements, concomitant medication and adverse events were recorded. Blood samples were taken for determination of HbA1c, and residual beta cell function was measured through C-peptide release during a glucose-clamp [5, 10, 11]. The clamp was not carried out in patients who were C-peptide-negative at a previous visit; a zero value was filled in for subsequent time points and included in the analysis. Clamps consisted of a 180 min euglycaemic phase (3.3–5.0 mmol/l) followed by 146 min at 10.0–13.9 mmol/l with 1 mg glucagon injected at minute 140 [5]. C-peptide release was expressed as the AUC during sustained glucose stimulation in absence (between minutes 60 and 140) and presence (between minutes 140 and 146) of glucagon. C-peptide-negativity was defined as AUC C-peptide ≤0.03 nmol/l × min during hyperglycaemic clamp. In Belgian trial centres flow cytometry was used to quantify peripheral lymphocyte subsets. [12]
Statistical analysis
Data were stored at the Belgian Diabetes Registry and analysed by a statistician (L. Kaufman) who was not a member of the trial team. The extension study followed all variables that had been predefined for the 18 month study [5]. We did, however, change the primary endpoint (changes in baseline residual beta cell function) because only 36 of the 73 re-consented patients consented to continue clamp testing. It was replaced by changes from baseline in insulin dose/kg body weight. At baseline as well as at month 18, this variable showed a strong correlation with residual beta cell function. Evaluation of efficacy, and its multivariate analysis, was carried out on all patients for whom insulin dose and body weight were available at baseline and at 48 months. This was the case in 33 ChAglyCD3-treated and 31 placebo patients (Fig. 1). In these patient groups, 21 and 15, respectively, had re-consented to clamp tests (Fig. 1). One patient refused a clamp test at month 48 while he had remained C-peptide-positive till month 36; the clamp analysis at month 48 was thus conducted on 21 and 14 patients, respectively. Patients becoming C-peptide-negative during the study remained included in the clamp analysis with zero values filled in for the time points of C-peptide-negativity.
Multivariate analyses using stepwise multiple linear regression were performed in each group and in both groups together in order to investigate correlations between changes in insulin dose over 48 months and baseline variables. Before start of treatment, the following potentially prognostic baseline variables had been defined: age, sex, body weight and BMI, HLA-DQ genotype (protective; not protective), residual beta cell function, HbA1c, ICA (<12 JDF; ≥12 JDF), GADA (<2.6%; ≥2.6%) and baseline insulin dose (see Keymeulen et al. [5] and its supplementary appendices). A post hoc exploratory evaluation was carried out in which the effect of treatment was assessed in subgroups that differed for two of these predefined variables, namely baseline residual function (AUC C-peptide 60–140 min <50th percentile and ≥50th percentile) or age (<50th percentile and ≥50th percentile). This evaluation was performed for each time-point using the Mann–Whitney U test. Adjustments were made for multiplicity. All statistical tests were performed two-sided at the 5% level of significance. In the efficacy and multivariate analysis, country was added as variable since patients in Germany and their diabetologists were, from month 18 onwards, aware of their treatment allocation, while Belgian patients and physicians were not. In the ChAglyCD3 group 12/33 patients and in the placebo group 8/31 were German (p = 0.43).
Results
Effect of ChAglyCD3 on insulin requirements over 48 months
Mean daily insulin dose steadily increased from the start of the trial in the placebo group (+0.32 U kg−1 day−1 in 48 months) while it initially decreased in the ChAglyCD3 group and then increased only slightly above start values (+0.09 U kg−1 day−1 in 48 months) (Fig. 2a). At all time points, changes in insulin dose vs baseline were significantly different between both groups. The lower mean insulin doses after ChAglyCD3 were not caused by under-treatment since the corresponding HbA1c levels were not higher than in the placebo group (Fig. 2b). They were associated with a higher residual beta cell function as measured by the AUC during glucose clamp with glucagon (Fig. 2c). Mean beta cell function declined rapidly and steadily after placebo, but it was maintained for at least 24 months after ChAglyCD3 treatment (p > 0.05 vs baseline). At month 36, residual beta cell function in the ChAglyCD3 group was 80% higher than in the placebo group. Over the 48 month follow-up period, fewer ChAglyCD3-treated patients had become C-peptide-negative (4/21 vs 7/14 placebo patients, p = 0.07). The number of severe hypoglycaemic events was low in both groups (n = 3 in the placebo group and n = 1 in the ChAglyCD3 group), making it an insensitive variable for assessing differences in metabolic outcome at this stage.
Correlation between the effect of ChAglyCD3 on daily insulin requirements and baseline variables
In multivariate analysis two baseline variables were independently correlated with the effect of the antibody treatment on daily insulin requirements over 48 months. Analysis of the insulin dose (U kg−1 day−1) at month 48 showed that age was a significant factor in the CD3 group (p = 0.009) and baseline residual beta cell function in the placebo group (p = 0.004). When performing this analysis on both groups together, both age (p = 0.004) and baseline residual beta cell function (p = 0.019) were statistically significantly correlated, as was antibody treatment (p = 0.005).
On basis of this finding we conducted two post hoc analyses in which patients were subdivided according to one of these baseline variables, i.e. baseline residual beta cell function (C-peptide release with glucose clamping) or age. Each subdivision was then made into two categories on the basis of values below or above the 50th percentile that had been determined in the 80 patients at start of the study. Categories were denoted as initial C-peptide release <50th percentile and ≥50th percentile (Fig. 2d–f) and as age <50th percentile and age ≥50th percentile (Fig. 2g–i). Age categories were from 12 to 27 years and from 27 to 39 years, respectively.
Influence of beta cell function at baseline
The ChAglyCD3-treated subgroup with initial C-peptide release ≥50th percentile needed significantly lower insulin doses than the corresponding placebo subgroup (Fig. 2d). In the placebo subgroup, insulin requirements more than doubled during the first 24 months, while they stabilised at or below starting doses in the antibody-treated subgroup. Between months 24 and 48, mean insulin dose in the ChAglyCD3 subgroup increased progressively but remained 64–40% lower than after placebo. In the subgroups with initial C-peptide release <50th percentile, no statistically significant differences were found in the time course of insulin requirements after placebo or ChAglyCD3 treatment (p > 0.15 at all time points).
In the total group, the lower mean insulin doses in the ChAglyCD3 subgroup ≥50th percentile were not caused by inadequate dosing (Fig. 2e), but appeared to be related to higher values for mean residual beta cell function (Fig. 2f). However, the clamp test data were no longer statistically higher during the extension study, probably due to a combination of a waning effect and the small number of patients that had agreed to a continued clamp test (Fig. 2f). Nevertheless, a persistence of a higher beta cell function in the antibody-treated subgroup may explain the lower number of patients that became C-peptide-negative during the 48 month follow-up in this group (0/11 vs 4/9 in the corresponding placebo subgroup; p = 0.03). In patients with lower baseline beta cell function (C-peptide release <50th percentile), residual beta cell function was never higher following antibody treatment and the number of C-peptide-negative patients not lower (4/10 vs 3/5 in the placebo group; p = 0.61).
Influence of age
In the older subgroup (age 27–39 years), the antibody effect on mean insulin doses was only statistically significant during the first 24 months (Fig. 2g). The change in mean HbA1c levels vs baseline was similar to that in the older placebo subgroup (p > 0.39 at all time points; Fig. 2h). The antibody-treated and the placebo subgroups exhibited a similar residual beta cell function over the entire period, undergoing a 50% reduction over 48 months (Fig. 2i).
In the younger subgroup (age 12–27 years), ChAglyCD3 treatment resulted in 30–40% lower insulin doses than placebo at months 24, 36 and 48; at month 48, the dose was barely higher than at baseline (+0.03 vs +0.36 U kg−1 day−1 after placebo, p = 0.001) (Fig. 2g). This subgroup had better HbA1c levels (Fig. 2h). These antibody-induced effects were associated with a preservation of the initial beta cell function for at least 36 months, which contrasts with a >80% decline during the first 24 months after placebo (Fig. 2i). At month 48, mean beta cell function in the ChAglyCD3 subgroup had decreased by 50% but was still fivefold higher than in the placebo subgroup, although not reaching statistical significance. Similar differences were seen during the glucose clamp phase in absence of glucagon (ESM Fig. 1).
Since those in the younger age group had the most pronounced antibody-induced preservation of beta cell function, we used a post hoc analysis to examine whether this effect was associated with better glucose control as reflected by a greater number of patients with HbA1c levels <6.5% [13], with fasting blood glucose (FBG) <7.2 mmol/l [14] and with CV for FBG of <20% [15]. Table 2 shows data at start of the study and at month 48, together with the number of patients that injected <0.5 U kg−1 day−1 insulin at these time points; data are also shown for the older age group. Comparison of the two placebo subgroups at month 48 shows that a better metabolic control was achieved in the older subgroup (9/16 with HbA1c <6.5% vs 1/15 in the younger subgroup, p < 0.05); this subgroup also had more patients with FBG <7.2 mmol/l and with CV for FBG of <20% (Table 2), but the low number of patients limits statistical analysis. Antibody treatment improved metabolic control in the younger subgroup but not in the older one (Table 2).
Adverse events
Two types of side effects were noticed shortly after antibody administration but did not lead to dropouts [5]. The first consisted of mild to moderate flu-like symptoms attributed to cytokine release that rapidly disappeared under medication. The second was a transient EBV reactivation that was first observed on day 7 following the first ChAglyCD3 injection; EBV DNA copies peaked between days 21 to 28 and returned to normal pre-treatment levels between days 35 and 45. During this period of reactivation one patient presented a cervical adenopathy and fever for 12 days; in 15 other patients symptoms were mild and resolved within a few days (sore throat, n = 15; one to three enlarged cervical lymph nodes, n = 7; fever, n = 4). Over the 48 month follow-up period, no biological or clinical signs of EBV reactivation or EBV-related disease were observed; there was no higher incidence of infections, and no lymphoma or other types of cancer. No differences in CD3+ lymphocyte counts were found between months 6 and 48 (Fig. 3). The ChAglyCD3 group showed a decreased CD4+/CD8+ ratio at months 6 and 12 (p < 0.001), which appeared mainly to be the result of a slightly higher CD8+ lymphocyte count (p < 0.05); CD4+/CD8+ ratio and CD8+ counts were normalised at later time points.
The ChAglyCD3 group did not have the same weight gain and increase in BMI as the placebo group during the first 24 months, but then proceeded at the same rate. Over 48 months, the mean body weight for the ChAglyCD3 group increased by 4.4 kg (BMI +1.4 kg/m2) vs +6.6 kg (BMI + 2.1 kg/m2) in the placebo group (ESM Fig. 2).
Discussion
The present study shows that a short treatment with a CD3 antibody suppresses the rise in insulin requirements that occurs in type 1 diabetic patients during the first few years after diagnosis. This effect is correlated with a young age at onset and with higher initial residual beta cell function as independent determinants. It was associated with a prevention or reduction of further losses in beta cell mass, an effect that waned with time. In the younger subpopulation, the antibody treatment was associated with better metabolic control variables during the 48 month follow-up period.
In our placebo group, aged 12 to 39 years, mean insulin dose increased progressively from the start of the study; this can be attributed to a continued decrease in the residual beta cell function, probably the result of further beta cell losses caused by the autoimmune process or/and by the chronic hyperglycaemic state [16, 17]. The ChAglyCD3-treated group did not have a decrease in function during the first 24 months, suggesting that the antibody had suppressed the beta cell destructive process. This beneficial effect waned in time as indicated by the decline in beta cell function and the rise in insulin requirements from month 24 onwards. It is conceivable that residual beta cells are lost because the autoimmune reactivity had only been transiently suppressed; their survival and/or function may also have been affected by the chronic state of hyperglycaemia. Since the beta cell mass is already markedly reduced at clinical onset of type 1 diabetes [18, 19], it is likely that any immune-modulating intervention will have to be associated with, or followed by, a beta cell replacement therapy, as recently tested in rodents [20]; a combination with other methods for tolerance-induction should also be considered [21, 22].
Multivariate analysis indicated that the baseline residual beta cell function as well as age are two baseline variables that are independently correlated with the effect of ChAglyCD3 on insulin requirements over 48 months. The influence of the initial beta cell function has already been observed in our 18 month analysis [5]. We now show that the antibody effect is maintained throughout the 48 month follow-up in the subpopulation with initial beta cell function ≥50th percentile, while being absent in the other patients. The influence of age was also illustrated by a post hoc analysis of antibody effects in patients aged above or below the 50th percentile of the study population age, i.e. 27 years. In the younger subpopulation, aged 12–26 years, antibody treatment kept insulin requirements under baseline values for at least 3 years, which can be explained by the preservation of the initial beta cell function; in the placebo group beta cell function rapidly declined and insulin requirements increased markedly during this period. Our study is underpowered to determine whether the age effect is linear. In the older subpopulation, aged 27–39 years, no preservation of residual beta cell function was seen in the antibody-treated patients; their transient decrease in mean insulin dose may have been partly caused by some insulin under-treatment as suggested by their mean HbA1c levels, which are higher than in the placebo subgroup, although not statistically significant.
An influence of age was not detected in the trial conducted by Herold et al. This might be related to the different age range (7.5–30 years) or distribution in their study, or to its shorter follow-up [4, 6]. The present finding that the effects of ChAglyCD3 are much more pronounced in younger patients can be explained by an age-dependency of the insulitis process. In an analysis of autopsy reports at or shortly after clinical onset, we noticed that insulitis was detected in all children, but in fewer adolescents and rarely in adults [19, 23]. In clinical terms, older patients with type 1 diabetes are also presumed to undergo a less aggressive form of the disease [24, 25]. Consistent with this view is the more rapid and pronounced loss of residual beta cell function that we observed in our younger placebo subgroup compared with the older placebo subgroup.
In the younger patients, the antibody-induced preservation of beta cell function was associated with better glucose control variables. This is consistent with the DCCT study in which patients with higher beta cell function had a better glucose control and those with a loss of residual beta cell function an increased risk for severe hypoglycaemia [26, 27]. In the young placebo subgroup, virtually all patients progressed within 4 years to a metabolic state with wide variability in FBG and with HbA1c levels >6.5%, despite increased insulin doses. On the other hand, one-half of the antibody-treated patients maintained a relatively stable and normal FBG and HbA1c levels <6.5% with daily insulin doses <0.5 U/kg body weight. The antibody-induced lowering of HbA1c levels was also statistically significant when mean values were compared with those after placebo. In the study by Herold et al. an antibody-effect on HbA1c levels was reported for the first 18 months [6]. A reduction in glucose fluctuations and a lowering of HbA1c levels are clinically relevant variables as they predispose to decreased risks for hypoglycaemic events [28] and chronic diabetes lesions, respectively [29]. The latter effects could not be evaluated in the present study. During the first 4 years after onset, the number of hypoglycaemic events was low and signs of chronic lesions remained absent; moreover, the size of the subgroups would not provide the power to detect differences and to relate them to a preservation of residual beta cell function. Our observations also suggest that the improvement in metabolic variables might be limited to the first 4 years. They do, however, demonstrate that a short immune intervention can prevent losses in residual beta cell function and in metabolic control variables for at least 3 years, which supports the potential of intervention strategies at or before clinical onset of type 1 diabetes.
The prolonged effect of a short immune treatment is, to our knowledge, novel in the field of autoimmune disease. It is often assumed that an autoimmune disease will need continuous treatment to maintain efficacy; this would then increase risk of infection, as seen with TNF antagonists [30, 31] or with natalizumab [32, 33], or of nephropathy with ciclosporine [34]. In our limited follow-up period, none of the patients developed cancer or lymphoproliferative disease, or presented abnormal or more frequent infectious episodes. There were, however, side effects during and shortly after antibody administration as result of cytokine release and of EBV reactivation; although transient, their nature stresses the need to seek doses and regimens that avoid or minimise these adverse events. This will be necessary before extending anti-CD3 trials to target populations that seem most promising according to the present findings. Preservation of residual beta cell function was indeed best achieved and maintained in the younger population and in patients in an apparently early phase of the destruction process; forthcoming trials should therefore preferentially recruit young patients, including children. A safe regimen that suppresses progression of the disease at clinical onset will also stimulate trials in individuals at high risk for developing type 1 diabetes.
Abbreviations
- EBV:
-
Epstein–Barr virus
- FBG:
-
Fasting blood glucose
- ICA:
-
Islet-cell autoantibodies
References
Chatenoud L, Bluestone JA (2007) CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol 7:622–632
Chatenoud L, Thervet E, Primo J, Bach JF (1994) Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci USA 91:123–127
Tran GT, Carter N, He XY et al (2001) Reversal of experimental allergic encephalomyelitis with non-mitogenic, non-depleting anti-CD3 mAb therapy with a preferential effect on T(h)1 cells that is augmented by IL-4. Int Immunol 13:1109–1120
Herold KC, Hagopian W, Auger JA et al (2002) Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 346:1692–1698
Keymeulen B, Vandemeulebroucke E, Ziegler AG et al (2005) Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 352:2598–2608
Herold KC, Gitelman SE, Masharani U et al (2005) A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 54:1763–1769
Bolt S, Routledge E, Lloyd I et al (1993) The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties. Eur J Immunol 23:403–411
Xu D, Alegre ML, Varga SS et al (2000) In vitro characterization of five humanized OKT3 effector function variant antibodies. Cell Immunol 200:16–26
Chatenoud L, Ferran C, Reuter A et al (1989) Systemic reaction to the anti-T cell monoclonal antibody OKT3 in relation to serum levels of tumor necrosis factor and interferon-gamma. N Engl J Med 320:1420–1421
Gerlo E, Gorus F (1997) Calibration of ion-exchange HPLC measurements of glycohemoglobin: effect on interassay precision. Clin Chem 43:2353–2357
Decochez K, Tits J, Coolens JL et al (2000) High frequency of persisting or increasing islet-specific autoantibody levels after diagnosis of type 1 diabetes presenting before 40 years of age. The Belgian Diabetes Registry. Diabetes Care 23:838–844
Bachelez H, Flageul B, Dubertret L et al (1998) Treatment of recalcitrant plaque psoriasis with a humanized non-depleting antibody to CD4. J Autoimmun 11:53–62
Anonymous (2007) American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract 13(Suppl 1):1–68
Anonymous (2008) Standards of medical care in diabetes. Diabetes Care 31(Suppl 1):S12–S54
Keymeulen B, Gillard P, Mathieu C et al (2006) Correlation between beta cell mass and glycemic control in type 1 diabetic recipients of islet cell graft. Proc Natl Acad Sci USA 103:17444–17449
Eisenbarth GS (1986) Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med 314:1360–1368
Robertson RP, Harmon J, Tran PO, Poitout V (2004) Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes 53(Suppl 1):S119–S124
Gepts W (1965) Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14:619–633
Pipeleers D, Ling Z (1992) Pancreatic beta cells in insulin-dependent diabetes. Diabetes Metab Rev 8:209–227
Sherry NA, Chen W, Kushner JA et al (2007) Exendin-4 improves reversal of diabetes in NOD mice treated with anti-CD3 monoclonal antibody by enhancing recovery of beta-cells. Endocrinology 148:5136–5144
Lernmark A, Agardh CD (2005) Immunomodulation with human recombinant autoantigens. Trends Immunol 26:608–612
Sherr J, Sosenko J, Skyler JS, Herold KC (2008) Prevention of type 1 diabetes: the time has come. Nat Clin Pract Endocrinol Metab 4:334–343
Pipeleers D, In't Veld P, Pipeleers-Marichal M, Gorus F (2008) The beta cell population in type 1 diabetes. Novartis Found Symp 292:19–31
Palmer JP, Hirsch IB (2003) What's in a name: latent autoimmune diabetes of adults, type 1.5, adult-onset, and type 1 diabetes. Diabetes Care 26:536–538
Leslie RD, Williams R, Pozzilli P (2006) Clinical review: type 1 diabetes and latent autoimmune diabetes in adults: one end of the rainbow. J Clin Endocrinol Metab 91:1654–1659
Steffes MW, Sibley S, Jackson M, Thomas W (2003) Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care 26:832–836
Anonymous (1987) Effects of age, duration and treatment of insulin-dependent diabetes mellitus on residual beta-cell function: observations during eligibility testing for the Diabetes Control and Complications Trial (DCCT). The DCCT Research Group. J Clin Endocrinol Metab 65:30–36
Kilpatrick ES, Rigby AS, Goode K, Atkin SL (2007) Relating mean blood glucose and glucose variability to the risk of multiple episodes of hypoglycaemia in type 1 diabetes. Diabetologia 50:2553–2561
The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986
Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD (2003) Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 48:2122–2127
Keane J, Gershon S, Wise RP et al (2001) Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 345:1098–1104
Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D (2005) Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 353:375–381
Van Assche G, van Ranst M, Sciot R et al (2005) Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 353:362–368
Parving HH, Tarnow L, Nielsen FS et al (1999) Cyclosporine nephrotoxicity in type 1 diabetic patients. A 7-year follow-up study. Diabetes Care 22:478–483
Acknowledgements
This work was supported by Center grants from the Juvenile Diabetes Research Foundation (4-2001-434, 4-2005-1327) and by grants from the Belgian Fund for Scientific Research-Flanders and from Brussels Free University-VUB. B. Keymeulen and C. Mathieu are Senior Clinical Investigators of the Fund for Scientific-Research-Flanders (Belgium).
Duality of interest
D. Pipeleers, H. Waldmann and L. Chatenoud have received consulting fees from Tolerx; H. Waldmann is listed as co-inventor on a patent relating to ChAglyCD3 and reports holding stock options in Tolerx. The other authors declare that there is no duality of interest associated with this manuscript. The funding source, the Juvenile Diabetes Research Foundation, was not involved in the study design, in the collection, analysis and interpretation of the data, in the writing of the report and in the decision to submit the paper for publication
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Additional information
All the participating institutions were part of the JDRF Center for Beta Cell Therapy in Diabetes, Brussels, Belgium.
Electronic supplementary materials
Below is the link to the electronic supplementary material.
ESM Table 1
Corticoid administration during the study (PDF 15.5 kb)
ESM Fig. 1
Blue circles represent the placebo group and red triangles the ChAglyCD3 group. The left panel shows residual beta cell function measured as the glucose-clamp induced C-peptide release before (A) and after (B) glucagon injection. The middle panel (C–D) ranks these values according to whether residual beta cell function at baseline. The right panel (E–F) ranks them according to whether age at baseline was below or at/above the median (50th percentile) of all patients at baseline. The number of patients for whom data were available are shown for each variable and for each time point (PDF 32.6 kb)
ESM Fig. 2
BMI and body weight at baseline, 6, 12, 24, 36 and 48 months for all patients. Blue circles represent the placebo group and red triangles the ChAglyCD3 group. All values are means±SE. The difference in the changes from baseline was significant at month 24 for BMI (p = 0.03) but not for body weight (p = 0.05). The number of patients for whom data were available are shown for each variable and for each time point (PDF 57 kb)
Appendix
Appendix
The authors acknowledge the help of the following institutions and individuals for their contribution:
Diabetes Research Center, Brussels Free University-VUB: C. Hendrieckx
Belgian Diabetes Registry: I. Weets, A. Beirinckx, K. Casteels, P. Cochez, J.-L. Coolens, P. Coremans, K. Decochez, F. Defoer, L. Derdelinckx, S. Deweer, L. Emsens, A. Fassotte, F. Féry, G. Hubermont, Y. Kockaerts, G. Krzentowski, K. Laga, G. Lamberigts, C. Lemy, C. Pelckmans, D. Scarnière, G. Struelens, P. Taelman, J. Tits, K. van Acker, E. van Aken, M. Vandenbroucke, H. Vanderstappen, E. van Fleteren, L. van Gaal, S. van Imschoot, C. van Winghem, C. Vercammen, A. Verhaegen, J. Vinckx, E. Weber, M. Carpentier, H. Morobé, A. Schoonis, S. Vandenhoeck, J. van Elven
German diabetologists: W. Baumgärtner, C. Dreyer, G. Eising, K. Fischer, R. Friedrich, H. Heddaeus, H. Janka, R. Klare, P. Kreuzer, T. Lohmann, G. Meincke, J. Neinhardt, G. Schulze, M. Seebacher, C. Spiess, E. Wolff-Kruppa, V. Bacher, J. Fröhner, J. van Kooten, K. Panzer, H.-W. Paulmann, U. Trensch.
Department of Clinical Biology, Brussels Free University-VUB: P. de Pauw, I. Vermeulen, P. Goubert, T. Demesmaeker, A. Delchambre
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Keymeulen, B., Walter, M., Mathieu, C. et al. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia 53, 614–623 (2010). https://doi.org/10.1007/s00125-009-1644-9
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DOI: https://doi.org/10.1007/s00125-009-1644-9