Cellular and Humoral Immune Responses in Type 1 Diabetic Patients Participating in a Phase III GAD-alum Intervention Trial

Abstract

OBJECTIVEGAD formulated in aluminum hydroxide (GAD-alum) has previously been shown to induce preservation of residual insulin secretion in recent-onset type 1 diabetes, but recent phase II and III GAD-alum trials failed to reach primary outcomes. The European phase III study was therefore closed after 15 months, and only a minority of patients completed the 30 months of follow-up.RESEARCH DESIGN AND METHODSThis study aimed to characterize cellular and humoral responses in the Swedish patients (n = 148) participating in the phase III trial, receiving four (4D) or two (2D) GAD-alum doses or placebo. Serum GAD65 antibody (GADA) levels, GADA IgG1–4 subclass distribution, cytokine secretion, and proliferative responses in peripheral blood mononuclear cells (PBMCs) were analyzed.RESULTSThe GAD65-induced cytokine profile tended to switch toward a predominant Th2-associated profile over time both in the 2D and 4D group. The groups also displayed increased GADA levels and PBMC proliferation compared with placebo, whereas GADA IgG subclass distribution changed in 4D patients.CONCLUSIONSBoth 2D and 4D patients displayed GAD65-specifc cellular and humoral effects after GAD-alum treatment, but at different time points and magnitudes. No specific immune markers could be associated with treatment efficacy.

Antigen-specific immunotherapy and influenza vaccination in type 1 diabetes: timing is everything

“…This Th2 skewing represents the anticipated response to GADalum and may have contributed to C-peptide retention in this group. It is also possible that the enhanced GAD-specific Th2 response in these individuals may have accounted for the increased humoral GAD-specific immunity observed in these participants; importantly, this observation fits with a previous report of elevated GAD antibodies in individuals treated with GAD-alum in a Phase III study [11]. However, there are some caveats to the study by Tavira et al; for example, there are no placebo comparisons and, therefore, it remains unknown whether the group vaccinated with Pandemrix >5 months before or after GAD-alum benefitted from GAD-alum as a therapeutic agent or merely avoided any non-specific adverse effects of Pandemrix on beta cell destruction pathways (see Fig.…”

Targeted immune interventions for type 1 diabetes

“…(63, 64) Some studies evaluated immune responses in participants. Patients receiving the Hsp60 peptide did have increases in IL-10 and dampened T cell responses to antigen, and those receiving GAD-alum had increases in GAD antibodies and increases in proinflammatory cytokines, T cell proliferation, as well as Tregs (65, 66) in response to GAD. Taken together, although autoantigen treatment was successful in preclinical diabetes and may modulate specific aspects of the T1D autoimmune response, after much study there is little evidence that given as a monotherapy this approach can modulate the course of disease in humans.…”

Combination Immunotherapy for Type 1 Diabetes

“…Marek-Trzonkowska and associates (46) and Bluestone and associates (47) recently reported on respective phase I trials to assess safety of using Treg adoptive immunotherapy in T1D. Participants with T1D, either within two months of diagnosis or ranging from 14-104 weeks post diagnosis, had their own Tregs isolated from peripheral blood, expanded ex vivo with anti-CD3 and anti-CD28 plus IL-2, and varying numbers of cells were adoptively transferred back into the donor (46, 47). Bluestone found a population of transferred Tregs that were long-lived and still in circulation one year post transfer (47).…”

“…Participants with T1D, either within two months of diagnosis or ranging from 14-104 weeks post diagnosis, had their own Tregs isolated from peripheral blood, expanded ex vivo with anti-CD3 and anti-CD28 plus IL-2, and varying numbers of cells were adoptively transferred back into the donor (46, 47). Bluestone found a population of transferred Tregs that were long-lived and still in circulation one year post transfer (47). Marek-Trzonkowska study participants exhibited an increase in C-peptide levels and lower exogenous insulin requirement (46).…”

“…Marek-Trzonkowska study participants exhibited an increase in C-peptide levels and lower exogenous insulin requirement (46). Bluestone study participants exhibited no decline in C-peptide levels and no worsening in HbA1c over 1 year post transfer (47). Bluestone and associates are currently investigating the combined use of adoptively transferred Tregs plus IL-2 administration (https://clinicaltrials.gov/ct2/show/NCT02772679).…”