Current advances in using tolerogenic dendritic cells as a therapeutic alternative in the treatment of type 1 diabetes

Type 1 diabetes(T1D)is an autoimmune disease characterized by the destruction of insulin-producingβ-cells of the pancreatic islets by autoreactive T cells,leading to high blood glucose levels and severe long-term complications.The typical treatment indicated in T1D is exogenous insulin administration,which controls glucose levels;however,it does not stop the autoimmune process.Various strategies have been implemented aimed at stoppingβ-cell destruction,such as cellular therapy.Dendritic cells(DCs)as an alternative in cellular therapy have gained great interest for autoimmune disease therapy due to their plasticity to acquire immunoregulatory properties both in vivo and in vitro,performing functions such as anti-inflammatory cytokine secretion and suppression of autoreactive lymphocytes,which are dependent of their tolerogenic phenotype,displayed by features such as semimature phenotype,low surface expression of stimulatory molecules to prime T cells,as well as the elevated expression of inhibitory markers.DCs may be obtained and propagated easily in optimal amounts from peripheral blood or bone marrow precursors,such as monocytes or hematopoietic stem cells,respectively;therefore,various protocols have been established for tolerogenic(tol)DCs manufacturing for therapeutic research in the treatment of T1D.In this review,we address the current advances in the use of tolDCs for T1D therapy,encompassing protocols for their manufacturing,the data obtained from preclinical studies carried out,and the status of clinical research evaluating the safety,feasibility,and effectiveness of tolDCs.

Human CD4 ＋ effector T lymphocytes generated upon TCR engagement with self-peptides respond defectively to IL-7 in their transition to memory cells

The peripheral repertoire of CD4＋ T lymphocytes contains autoreactive cells that remain tolerant through several mechanisms. However, nonspecific CD4＋ T cells can be activated in physiological conditions as in the course of an ongoing immune response, and their outcome is not yet fully understood. Here, we investigate the fate of human naive CD4＋ lymphocytes activated by dendritic cells （DCs） presenting endogenous self-peptides in comparison with lymphocytes involved in alloresponses. We generated memory cells （Tmem） from primary effectors activated with mature autologous DCs plus interleukin （IL）-2 （Tmauto）, simulating the circumstances of an active immune response, or allogeneic DCs （Tmallo）. Tmem were generated from effector cells that were rested in the absence of antigenic stimuli, with or without IL-7. Tmem were less activated than effectors （demonstrated by CD25 downregulation） particularly with IL-7, suggesting that this cytokine may favour the transition to quiescence. Tmauto and TmaHo showed an effector memory phenotype, and responded similarly to polyclonal and antigen-specific stimuli. Biochemically, IL-7-treated Tma^o were closely related to conventional memory lymphocytes based on Erk-l/2 activation, whereas Tmauto were more similar to effectors. Autologous effectors exhibited lower responses to IL-7 than allogeneic cells, which were reflected in their reduced proliferation and higher cell death. This was not related to IL-7 receptor expression but rather to signalling deficiencies, according to STAT5 activation These results suggest that ineffective responses to IL-7 could impair the transition to memory cells of naive CD4＋ T lymphocytes recognizing self-peptides in the setting of strong costimulation.