Antigen-based vs. systemic immunomodulation in type 1 diabetes

Figures & data

Table 1. Overview of systemic immunomodulations as an intervention or prevention therapy for T1D in humans

Systemic approach	Study name	Treatment	Subjects	Clinical or immunological outcome	Reference
Cyclosporine A	The Canadian-European randomized control trial group	10 mg/kg/d po	• 9–35 y • <6 w diagnosed	↑β-cell function ↑remission rate for 1 y	3
Cyclosporine A	French Multicenter Cyclo-sporine study	7.5 mg/kg/d po	• 15–40 y	↑remission rate	4
Cyclosporine A	French Pediatric Cyclo-sporine study	7.5 mg/kg/d po	• 7–15 y	↑remission rate	5
Anti-CD3	Phase II trial of Teplizumab for treatment of patients with recent onset T1D	14 d (34 mg/70kg) 12 d (41 mg/70kg) iv Teplizumab	• 9–30 y • <4 mo diagnosed • stimulated C-peptide >0.2 nM	better C-peptide response ↓HbA1c and insulin requirement	6
Anti-CD3	Phase II therapeutic trial with Otelixi-zumab in recently diagnosed T1D patients	6d (48 or 64 mg) iv Otelixizumab	• 12–39 y • <4 w diagnosed	better C-peptide response ↓insulin requirement	7
Anti-CD3	The Protégé study	17 mg/70 kg (14 d) 5.6 mg/70 kg (14 d) 4.6 mg/70 kg (6 d) at entry and 26 w iv Teplizumab	• 8–35 y • <12 w diagnosed	delayed ↓ C-peptide ↑glycaemic control	8
Anti-CD3	DEFEND-1	3.1 mg (8 d) iv Otelixizumab	• 12–45 y • <90 d diagnosed • ICA+ • stimulated C-peptide >0.2 nM	No change in C-peptide	Tolerx and GSK
Anakinra	AIDA	100 mg daily Sc	• 18–35 y • GADA+ • <12 w diagnosed	Still ongoing	9
Abatacept	Intravenous CTLA4-lg treatment in recent onset T1D	D 1, d 14, every 28 d Iv 10 mg/kg	• 6–45 y • <100 d diagnosed • ≥1 ICA+	Delayed β-cell decline	10
Rituximab	Effects of Rituximab on the progression of T1D in new onset subjects	D 1, d 8, d 15 and d 22 Iv 375 mg/m^2	• 8–45 y • ≥1 ICA+ • >3 w and <3 mo diagnosed	↑ C-peptide ↓ Insulin need ↓ hbA1c	11
Vitamin D	Immuno-intervention with Calcitriol in new-onset T1D	0.25 μg 1,25(OH)2D3/d for 9 mo	• 19–39 y • ICA+ • <2 min insulin treatment	No effect	12
Vitamin D	IMDIAB XI	0.25 μg 1,25(OH)2D3 every 2 d	• <4 w diagnosed • ICA+	No effect	13
Vitamin D	LADA vitamin D study	0.5 μg/d for 1 y 1-α(OH)D3 + insulin	• LADA patients • <5 y diagnosed • GADA+ • Fasting C-peptide >200 pM	↑ β-cell function	14
Vitamin D	Vitamin D in healthy individuals (MMTT and Tregs)	140 000 IU/m for 3 mo	Healthy non-diabetic	↑ Tregs	15
AHST	Safety and efficacy study of AHST for early onset T1D	cyclophosphamide (200 mg/kg) and ATG (4.5 mg/kg) + AHST	• 14–31 y • <6 w diagnosed • GADA+ • No ketoacidosis	Different periods of insulin independence	65,66

See Table 3. d, day; mo, month; LADA, latent autoimmune diabetes in adults; Tregs, regulatory T cells; y, years; ICA, islet cell antibody; GADA, GAD-associated antibodies; po, per os; MMTT, mixed meal tolerance test; AHST, autologous nonmyeloablative hematopoietic stem cell transplantation; w, weeks.

Table 3. Advantages and disadvantages of a systemic immunomodulatory approach

Advantages ▪ Due to general approach, efficacy increases Disadvantages ▪ General immune suppression ▪ Systemic side effects ▪ Extrapolation dose, timing and frequency treatment administration

Table 2. Overview of Ag-based approaches as an intervention or prevention therapy for T1D in humans

Ag	Study name	Treatment	Subjects	Clinical or immunological outcome	Reference
insulin	DPT-1 parenteral arm	0.25 U/kg/d sc + 4 d continuous infusion/y	• T1D relatives • ICA+ • 5-y risk > 50%	No effect	97
Insulin	Diabetes subcutaneous prevention trial in high risk relatives	2 × 0.05 U/kg/d Sc	• 5–39 y • IA-2 Ab+ • No protective haplotype	No effect	98
Insulin	DPT-1 oral arm	7.5 mg po	• T1D relatives • ICA+ • 5-y risk 26–50%	IAA ≥80 nU/ml delay onset	99
Insulin	EPPSCIT (European prediabetes prevention-sc insulin trial)	0.2 U/d sc	• T1D relatives • ICA+	No effect	100
Insulin	ORALE	2.5 or 7.5 mg/d po	• 7–40 y • auto-Ab+ • <2 w diagnosed	No effect	101
Insulin	IMDIAB VII	5 mg/d po	<4 w diagnosed	No effect	102
Insulin	Oral insulin	1 or 10 mg/d po	• ICA+ • <4 w diagnosed	>20 y (+ normal baseline C-peptide) slower C-peptide loss no clinical benefit	103
Insulin	DIPP (T1D prediction and prevention study)	1 U/kg/d intranasal	≥2 auto-Abs	No effect	104
insulin	INIT (intranasal insulin trial)	40 U/d first 10 d, then 80 U/w 12 mo intranasal	• <12 mo diagnosed • 30–75 y • GADA+ • fasting C-peptide ≥ 0.2 nM	Tolerance induction but no clinical effect	105
GAD-Alum	Subcutaneous GAD65	4, 20, 100 or 500 μg w 1 and w 4 sc	• LADA patients, • 30–70 y	20 µg; ↑ fasted and stimulated C-response	106
GAD-Alum	Swedish Diamyd	20 μg d 1 and d 30 sc	• 10–18 y • <18 mo diagnosed • GADA+ • fasting C-peptide >0.1 nM	<6 min diagnosed: ↑ fasted and stimulated C-response (30 min)	107
GAD-Alum	TrialNet GAD study	2 or 3 × 20 µg at d 1, 4 w and 12 w sc	• 3–45 y • <100 d diagnosed • GADA+ • stimulated C-peptide >0.2 nM	No effect	108
GAD-Alum	EU Diamyd	2 or 4 × 20 μg at d 0, d 30, d 90 and d 270 sc	• 10–20 y • <3 min diagnosed • GADA+ • fasting C-peptide >0.1 nM	No effect	109
DiaPep277 (HSP60)	Trial 420	1 mg at entry, 1, 6 and 12 m sc	• Men • 16–58 y • <6 mo diagnosed • basal C-peptide >0.1 nM	Stable C-peptide response	136

See Table 4. GAD65, glutamic acid decarboxylase 65; HSP60, heat shock protein 60; sc, subcutaneous; y, years; ICA, islet cell antibody; mo, months; d, day; GADA, GAD-associated antibodies; LADA, latent autoimmune diabetes in adults; w, weeks; po, per os.

Table 4. Advantages and disadvantages of an Ag-based approach

Advantages ▪ Epitope spreading ▪ High specificity without systemic side effects Disadvantages ▪ Time window for success ▪ Extrapolation dose, timing and frequency treatment administration ▪ Choice of adjuvants ▪ Tolerogenic route of administration requires adequate delivery system ▪ Can boost auto-reactivity

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