Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen-DR4()-restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group's daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell-specific CD8 T cells, and favorable β cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation.
Antigen-specific immunotherapy is immunomodulatory strategy for autoimmune diseases, such as Type 1 diabetes, in which patients are treated with autoantigens to promote immune tolerance, stop autoimmune beta-cell destruction and prevent permanent dependence on exogenous insulin. In this study, human proinsulin peptide C19-A3 (known for its positive safety profile) was conjugated to ultrasmall gold nanoparticles (GNP), an attractive drug delivery platform due to the potential anti-inflammatory properties of gold. We hypothesised that microneedle intradermal delivery of C19-A3 GNP may improve peptide pharmacokinetics and induce tolerogenic immunomodulation and proceeded to evaluate its safety and feasibility in a first-in-human trial. Allowing for the limitation of the small number of participants, intradermal administration of C19-A3 GNP appears safe and well-tolerated in participants with Type 1 diabetes. The associated prolonged skin retention of C19-A3 GNP after intradermal administration offers a number of possibilities to enhance its tolerogenic potential, which should be explored in future studies.
Background The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials. Methods In this context, we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow. Discussion The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.
We have investigated the efficacy of conditioning skin Langerhans cells (LCs) with agents to promote tolerance and reduce inflammation, with the goal of improving the outcomes of antigen-specific immunotherapy. Topical treatments were assessed ex vivo, using excised human breast skin maintained in organ bath cultures, and in vivo in healthy volunteers by analysing skin biopsies and epidermal blister roof samples. Following topical treatment with a corticosteroid, tumour necrosis factor-α levels were reduced in skin biopsy studies and blister fluid samples. Blister fluid concentrations of monocyte chemoattractant protein-1, macrophage inflammatory proteins -1α and 1β and interferon-γ inducible protein-10 were also reduced, while preserving levels of interleukin-1α (IL-1α), IL-6, IL-8 and IL-10. Steroid pre-treatment of the skin reduced the ability of LCs to induce proliferation, while supernatants showed an increase in the IL-10/interferon-γ ratio. Phenotypic changes following topical steroid treatment were also observed, including reduced expression of CD83 and CD86 in blister-derived LCs, but preservation of the tolerogenic signalling molecules immunoglobulin-like transcript 3 and programmed death-1. Reduced expression of HLA-DR, CD80 and CD86 were also apparent in LCs derived from excised human skin. Topical therapy with a vitamin D analogue (calcipotriol) and steroid, calcipotriol alone or vitamin A elicited no significant changes in the parameters studied. These experiments suggest that pre-conditioning the skin with topical corticosteroid can modulate LCs by blunting their pro-inflammatory signals and potentially enhancing tolerance. We suggest that such modulation before antigen-specific immunotherapy might provide an inexpensive and safe adjunct to current approaches to treat autoimmune diseases.
Achieving tight glycaemic control in type 1 diabetes remains very challenging for patients. However, some individuals retain a degree of endogenous beta-cell function for 5 or more years after diagnosis, and prospective studies confirm that this is associated not only with lower glycated haemoglobin A1c levels, and less hypoglycaemia, but also a reduced incidence of long-term complications. An independent effect of insulin C-peptide may contribute to this beneficial effect. Retention of even small amounts of endogenous beta-cell function for as long as possible should therefore be a key therapeutic goal in type 1 diabetes. Tight glycaemic control from diagnosis has already been shown to help in this regard, and we argue that the introduction of novel immunotherapies which achieve this important goal should be strongly encouraged, even if they fall short of an insulin-free 'cure'.
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