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Mathieu et al. Metab Target Organ Damage 2022;2:15 https://dx.doi.org/10.20517/mtod.2022.16 Page 7 of 11

Another lesson learned from the anti-CD3 trials is that an intervention should not be written off too soon.
Indeed, for a long time, it was believed that anti-inflammatory interventions targeting single cytokines (e.g.,
[49]
TNF-α or IL-1) are not successful in T1D . However, the recent phase II, multicenter, placebo-controlled,
double-blind, T1GER study, where anti-TNF-α receptor antibodies were administered continuously,
showed that the decline of functional beta cell mass, as measured by stimulated C-peptide, could be arrested
[50]
by continued administration of the antibody .
Therapies targeting the restoration of tolerance of the immune system towards beta cell-related antigens,
[51]
such as insulin or GAD, have failed to be successful . However, this approach remains interesting, as it
holds the potential to induce longer-lasting beta cell protection if one could restore tolerance to the beta cell.
Hypothesizing that a combination of immune modulation (“clearing the autoimmune attack at the time of
T1D diagnosis”) and antigen administration (“restoring tolerance”) could offer the perspective of long-term
effect, several approaches have been designed, and some tested. One of these is the administration of
proinsulin (as an autoantigen) in combination with the cytokine IL-10 through a genetically engineered
Lactococcus lactis as the carrier. This approach allows administering this antigen via an oral route (a
pathway known for tolerance induction), and interim results of the phase Ib (open-label) and IIa
(randomized, double-blind), multicenter, study with this approach (AG019 Actobiotics ) demonstrate
TM
both safety and potentially interesting immune effects (NCT03751007). The investigators even brought in
[52]
an additional immune modulator in the form of teplizumab, based on successful animal studies [53,54] , which
again showed good safety and interesting immune effects. Another promising combination of immune
modulation and antigen was tested in the DIAGNODE-1 pilot trial, where GAD dissolved in alum was
administered into lymph nodes (a more targeted approach), as well as in combination with vitamin D for
low-grade immunomodulation . Based on relatively promising results, GAD in alum is now being tested
[55]
in combination with ibuprofen (DIABGAD, an interventional pilot trial; NCT01785108), etanercept
(EDCR, an interventional open-label trial; NCT02464033), or GABA (GABA/Diamyd, a randomized
placebo-controlled trial; NCT02002130) as an anti-inflammatory component.

Finally, based on the observations described above, suggesting a role in the pathogenesis of T1D for both the
beta cells and the immune system, other trials have been conducted in an attempt to combine immune
modulation with beta cell protective agents. A recent randomized, placebo-controlled, phase II trial
combined liraglutide, a GLP-1 receptor agonist, and an antibody targeting the cytokine IL-21. This
combination therapy showed a clear delay in the decline of functional beta cell mass .
[56]
FUTURE PERSPECTIVES
Why have we not succeeded in arresting T1D? In the most popular animal model, the NOD mouse, the list
of successful interventions is long, but a careful reading of the literature shows that these interventions are
particularly successful when administered early in the life of the mouse before any autoimmune attack has
[57]
started . In humans, however, this would be the equivalent of treating newborns. As long as our predictive
power is low (genetic risk scores allow enrichment in the general population of up to 25-fold, but they still
only provide a risk attribution of around 1%), only very safe interventions will be tolerated. As such, on the
GPPAD platform, the cross-sectional cohort Freder1k trial is evaluating the effect of administration of oral
insulin on the onset of autoimmunity (autoantibodies against the beta cell) (NCT03316261), and the
multicenter, randomized, placebo-controlled, SINT1A study is evaluating the impact of probiotics on islet
autoimmunity development (NCT04769037). A major issue with these early interventions is the number of
people to be screened, as well as the amount of time these people need to be followed up. Even when
individuals at later stages of T1D (such as those with autoantibodies with or without dysglycemia stage 1/2),
and thus higher risk to progress towards clinical T1D (stage 3), are studied, these trials are logistically