Current perspectives and the future of disease-modifying therapies in type 1 diabetes

Table 1 List of immunotherapies that have been tried in type 1 diabetes with their mechanisms and significant trial findings

Mechanism	Agents		Significant findings from landmark trials
Agents causing generalised immunosuppression	Cyclosporine; Azathioprine; Prednisolone		Studies showed preservation of beta cells with cyclosporin; No differences in glycemic control, freedom from insulin or insulin dosage. High risk of organ toxicity
Agents targeting specific cytokines	Interleukin-1 blockers	Anakinra	No significant improvement in AUC C-peptide at 9 months; Some improvement in insulin sensitivity in type 1 diabetes with insulin resistance; High number of injection site reactions[13]
		Canakinumab	No significant improvement in AUC C-peptide at 9 months; Safe, well tolerated
	TNF-α blockers	Etanercept	Slower C-peptide decline and lower insulin requirement; Small study[14]
	Interleukin-12/23 antagonist	Ustekinumab	Marwaha et al[15]: 90 mg maintenance dose reduced proinsulin-specific IFN-γ and IL-17A-producing T cells
	Interleukin-6 blockers	Tocilizumab	EXTEND trial[16]: Reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed type 1 diabetes
Agents targeting specific immune cells	Targeting the T cells
	Anti CD3	Teplizumab	Delay in the decline of C-peptide, improvement in the C-peptide response and reduced need for insulin initiation starting from few months after initiation lasting up to seven years[38]; Approved for use in children above 8 years to postpone the onset of stage 3 T1DM[42]
		Otelixizumab	DEFEND-1,2[43,44]: No difference in 2 hours MMTT AUC C-peptide at 12 months; Reactivation of EBV
	Anti thymocyte globulin (ATG)	ATG + G-CSF	TriialNet: Slowed decline of C-peptide and reduced HbA1c in new-onset T1D[21]
	Anti CD2	Alefacept	TIDAL[45]: Significantly higher stimulated AUC C-peptide and lower insulin use in treated group
	Co-stimulation blocker	Abatacept	TrialNet[46,47]: Significantly higher stimulated C-peptide 2 hour AUC in treated group at the end of treatment and 1-year post treatment
	IL-2	Aldesleukin +/- rapamycin	Hartemann et al[48]: Dose dependent increase in the proportion of Tregs in the treatment group
	Treg infusion		Bluestone et al[49]: Subset (25% peak) of adoptively transferred T-regs still in circulation at 1 year; C-peptide preservation in those receiving lower dose
	Target antigen presenting B cells
	Anti-CD20	Rituximab	TrialNet: Higher AUC-C peptide, lower HbA1c and insulin need at 1 year; No differences in decline of C-peptide at 30 months[25]
Immunologic vaccination/antigen therapy	Insulin	Oral Insulin	Pre-POINT[50]: Increased Tregs in those who received a higher dose of oral insulin (62.5 mg)
	GAD-65 Ab	Alum-GAD 65+/- oral vitamin D	DiAPREV-IT1, DiAPREV-IT2[28,51]: Decline in total and cytotoxic T cells; No change in AUC C-peptide, oral glucose tolerance tests and HbA1c

AUC: Area under the curve; MMTT: Mixed meal tolerance test; HbA1c: Glycated hemoglobin A1c; Tregs: Regulatory T cells; TNF-α: Tumor necrosis factor-α.