Pre-existing Autoimmunity Determines Type 1 Diabetes Outcome After Flt3-ligand Treatment

Overview

Journal J Autoimmun

Specialty Allergy & Immunology

Date 2009 Dec 17

PMID 20004555

Citations 12

Authors

Tom L Van Belle

Therese Juntti

Jeanette Liao

Matthias G von Herrath

Affiliations

Soon will be listed here.

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.

Citing Articles

Intestinal Delivery of Proinsulin and IL-10 via Combined With Low-Dose Anti-CD3 Restores Tolerance Outside the Window of Acute Type 1 Diabetes Diagnosis.

Cook D, Cunha J, Martens P, Sassi G, Mancarella F, Ventriglia G Front Immunol. 2020; 11:1103.

PMID: 32582188 PMC: 7295939. DOI: 10.3389/fimmu.2020.01103.

FLT3 ligand regulates thymic precursor cells and hematopoietic stem cells through interactions with CXCR4 and the marrow niche.

Williams K, Moore A, Lucas P, Wang J, Bare C, Gress R Exp Hematol. 2017; 52:40-49.

PMID: 28552733 PMC: 5549459. DOI: 10.1016/j.exphem.2017.05.005.

Type 1 diabetes genetic susceptibility and dendritic cell function: potential targets for treatment.

Hotta-Iwamura C, Tarbell K J Leukoc Biol. 2016; 100(1):65-80.

PMID: 26792821 PMC: 4946618. DOI: 10.1189/jlb.3MR1115-500R.

The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes.

Pearson J, Wong F, Wen L J Autoimmun. 2015; 66:76-88.

PMID: 26403950 PMC: 4765310. DOI: 10.1016/j.jaut.2015.08.019.

The Role of Dendritic Cell Subsets and Innate Immunity in the Pathogenesis of Type 1 Diabetes and Other Autoimmune Diseases.

Price J, Tarbell K Front Immunol. 2015; 6:288.

PMID: 26124756 PMC: 4466467. DOI: 10.3389/fimmu.2015.00288.

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