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Pre-existing autoimmunity determines type 1 diabetes outcome after Flt3-ligand treatment.

ABSTRACT: Redirection of immune responses by manipulation of antigen-presenting cells is an emerging strategy for immunosuppressive treatment of autoimmune diseases. In vivo expansion of dendritic cells (DC) by Fms-like tyrosine kinase-3 (Flt3)-Ligand (FL) treatment was shown to delay diabetes onset in the NOD model of autoimmune diabetes. However, we show here that Flt3 stimulation actually accelerates autoimmunity when autoreactive CD8 T cells are detectable in blood prior to treatment. With autoreactive CD8 cells present, the capacity of FL to expand DCs and induce Treg remained intact, but both numbers and the functional response of islet-specific CD8s were boosted. Also, the inhibitory receptor PD-1 on (autoreactive) CD8 T cells and its ligand PD-L1 on Treg were no longer upregulated. These data highlight the need to pre-screen for T cell autoreactivity prior to generalized DC expansion and illustrate how accelerated disease can occur when the intended initiation of regulatory mechanisms is impaired later in diabetogenesis.

SUBMITTER: Van Belle TL

PROVIDER: S-EPMC2860005 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Pre-existing autoimmunity determines type 1 diabetes outcome after Flt3-ligand treatment.

Van Belle Tom L TL Juntti Therese T Liao Jeanette J von Herrath Matthias G MG

Journal of autoimmunity 20091209 4

Redirection of immune responses by manipulation of antigen-presenting cells is an emerging strategy for immunosuppressive treatment of autoimmune diseases. In vivo expansion of dendritic cells (DC) by Fms-like tyrosine kinase-3 (Flt3)-Ligand (FL) treatment was shown to delay diabetes onset in the NOD model of autoimmune diabetes. However, we show here that Flt3 stimulation actually accelerates autoimmunity when autoreactive CD8 T cells are detectable in blood prior to treatment. With autoreactiv ...[more]

PMID: 20004555

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Project description:BackgroundIt has been estimated that 80% of cases of out-of-hospital cardiac arrest (OHCA) are due to cardiac causes. It is well-documented that diabetes is a risk factor for conditions associated with sudden cardiac arrest. Type 1 diabetes (T1D) displays a threefold to fivefold increased risk of cardiovascular disease and death compared with the general population.ObjectiveThis study aims to assess the characteristics and survival outcomes of individuals with and without T1D who experienced an OHCA. Design: A registry-based nationwide observational study with two cohorts, patients with T1D and patients without T1D. Setting: All emergency medical services and hospitals in Sweden were included in the study.ParticipantsUsing the Swedish Cardiopulmonary Resuscitation Registry, we enrolled 54 568 cases of OHCA where cardiopulmonary resuscitation was attempted between 2010 and 2020. Among them, 448 patients with T1D were identified using International Classification of Diseases-code: E10.MethodsSurvival analysis was performed using Kaplan-Meier and logistic regression. Multiple regression was adjusted for age, sex, cause of arrest, prevalence of T1D and time to cardiopulmonary resuscitation.Main outcome measuresThe outcomes were discharge status (alive vs dead), 30 days survival and neurological outcome at discharge.ResultsThere were no significant differences in patients discharged alive with T1D 37.3% versus, 46% among cases without T1D. There was also no difference in neurological outcome. Kaplan-Meier curves yielded no significant difference in long-term survival. Multiple regression showed no significant association with survival after accounting for covariates, OR 0.99 (95% CI 0.96 to 1.02), p value=0.7. Baseline characteristics indicate that patients with T1D were 5 years younger at OHCA occurrence and had proportionally fewer cases of heart disease as the cause of arrest (57.6% vs 62.7%).ConclusionWe conclude, with the current sample size, that there is no statistically significant difference in long-term or short-term survival between patients with and without T1D following OHCA.

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Pre-existing autoimmunity determines type 1 diabetes outcome after Flt3-ligand treatment.

Publications

Pre-existing autoimmunity determines type 1 diabetes outcome after Flt3-ligand treatment.

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