Impaired Phagocytosis in Dendritic Cells From Pediatric Patients With Type 1 Diabetes Does Not Hamper Their Tolerogenic Potential

Abstract

Type 1 diabetes (T1D) is prompted by defective immunological tolerance, an event in which dendritic cells (DCs) are crucial as immune response orchestrators. In fact, they contribute to maintaining tolerance to self-antigens, but they can also prompt an immunogenic response against them, leading to autoimmunity. Countless factors can potentially impact on the proper functionality of the DCs, which range from altered subset distribution, impaired phagocytic function to abnormal gene expression. Moreover, in T1D, metabolic dysregulation could impair DC functions as well. Indeed, since T1D clinical course is likely to be more aggressive in children and adolescents and entails severe dysglycemia, the aim of this study was to analyze circulating DCs subpopulations in pediatric T1D at different stages, as well as to characterize their phagocytosis ability and tolerance induction potential. Thus, pediatric patients newly diagnosed with T1D, with established disease and control subjects were recruited. Firstly, DCs subsets from peripheral blood were found quantitatively altered during the first year of disease, but recovered in the second year of progression. Secondly, to study the tolerogenic functionality of DCs, liposomes with phosphatidylserine (PS) were designed to mimic apoptotic beta cells, which are able to induce tolerance, as previously demonstrated by our group in DCs from adult patients with T1D. In this study, monocyte-derived DCs from pediatric patients with T1D and control subjects were assessed in terms of PS-liposomes capture kinetics, and transcriptional and phenotypic changes. DCs from pediatric patients with T1D were found to phagocyte PS-liposomes more slowly and less efficiently than DCs from control subjects, inversely correlating with disease evolution. Nonetheless, the transcription of PS receptors and immunoregulatory genes, cytokine profile, and membrane expression of immunological markers in DCs was consistent with tolerogenic potential after PS-liposomes phagocytosis. In conclusion, T1D progression in childhood entails altered peripheral blood DCs subsets, as well as impaired DCs phagocytosis, although tolerance induction could still function optimally. Therefore, this study provides useful data for patient follow-up and stratification in immunotherapy clinical trials.

Antigen-specific immunotherapy combined with a regenerative drug in the treatment of experimental type 1 diabetes

“…PSAB-liposomes prevented T1D in the NOD mice 8 , 9 by inducing tolerogenic DCs. Furthermore, this tolerogenic effect was also validated in human DCs from subjects with T1D 10 , 11 . With the aim to combine this immunotherapy with a regenerative strategy, we previously performed a Drug Repurposing analysis to search for already-existing compounds able to promote β-cell regeneration.…”

“…Experimental data have been uploaded into the European Nucleotide Archive (EBI, https://www.ebi.ac.uk/ena ; accession number: GSE144348). Confirmation through qPCR was performed in an independent cohort of 3 patients as previously described 10 , 11 .…”

Islet-Resident Dendritic Cells and Macrophages in Type 1 Diabetes: In Search of Bigfoot’s Print

“…Several studies claim possible variation in humans. Yet, whether DC numbers are increased, decreased, or remained stable and whether this happens before, during, or after onset is inconsistent (38)(39)(40)(41)(42)(43). These inconsistences might relate to the notion that most studies focused mainly on monocyte derived DCs rather than bona fide DCs.…”

A century later, still fighting back: antigen‐specific immunotherapies for type 1 diabetes

“…The binary signal of tolerance and antigen specificity delivered by this strategy prompted the generation of tolDCs and expansion of classical FoxP3 + and nonclassical T reg cells in the experimental models of T1D and multiple sclerosis, hindering the development of their respective diseases 78,79 . Advancing in the preclinical phase pipeline, their immunomodulatory effect was also confirmed in human DCs from adult and pediatric patients with T1D, which acquired global tolerogenic features after phosphatidylserine‐liposomes phagocytosis 80,81 . Namely, these tolDCs increased the expression of tolerogenic genes such as TNFAIP3 , TNFSF14 , TGFB1 and VEGFA , and showed an immunoregulatory phenotype and functionality through the reduced expression of MHC class II, CD40, CD86 molecules; impaired capacity to induce autologous proliferation and TGF‐β and vascular endothelial growth factor A secretion.…”

“…78,79 Advancing in the preclinical phase pipeline, their immunomodulatory effect was also confirmed in human DCs from adult and pediatric patients with T1D, which acquired global tolerogenic features after phosphatidylserine-liposomes phagocytosis. 80,81 Namely, these tolDCs increased the expression of tolerogenic genes such as TNFAIP3, TNFSF14, TGFB1 and VEGFA, and showed an immunoregulatory phenotype and functionality through the reduced expression of MHC class II, CD40, CD86 molecules; impaired capacity to induce autologous proliferation and TGF-b and vascular endothelial growth factor A secretion. In the present time, this technology is being pursued with the aid of Ahead Therapeutics.…”