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Programmed death-1 ligands-transfected dendritic cells loaded with glutamic acid decarboxylase 65 (GAD65) inhibit both the alloresponse and the GAD65-reactive lymphocyte response

Academic Article
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Overview

authors

  • He, F. R.
  • Zhu, H. F.
  • Huang, H.
  • Dai, Yang D.
  • Shen, X.
  • Wang, M.
  • Li, L.
  • Xing, W.
  • Shen, G. X.

publication date

  • January 2008

journal

  • Clinical and Experimental Immunology  Journal

abstract

  • Type 1 diabetes (T1D) is due to a loss of immune tolerance to islet antigens, such as glutamic acid decarboxylase 65 (GAD65), for which islet transplantation is a promising therapy. Therefore, the generation of tolerance aiming at both alloantigen and GAD65 will help therapeutic intervention greatly in T1D. In this study, we tested the effect of programmed death-1 ligands (PD-L1)-transfected dendritic cells (DC) loaded with GAD65 on the alloresponse and GAD65-reactive lymphocyte response. The DC2.4 cell line was transfected with PD-L1 and co-cultured with GAD65. BALB-c mice were primed, respectively, by intraperitoneal injection with GAD65, PD-L1-transfected- or non-transfected DC (PD-L1/DC or DC), and PD-L1-transfected- or non-transfected DC loaded with GAD65 (PD-L1/DC/GAD65 or DC/GAD65). Splenocytes of treated mice were isolated and restimulated in vitro with GAD65 or the various DC populations above being used as stimulators, respectively. In the mixed lymphocyte reaction, DC/GAD65 were able to stimulate both allogeneic and GAD65-reactive lymphocytes. However, PD-L1/DC/GAD65 were poorer than DC/GAD65 at activating the GAD65-reactive lymphocyte response. Further, although PD-L1/DC could inhibit the alloresponse, PD-L1/DC/GAD65 were more effective at down-regulating the GAD65-reactive lymphocyte response. More importantly, PD-L1/DC/GAD65-primed lymphocytes exhibited the weakest proliferation when again restimulated in vitro by PD-L1/DC/GAD65. Additionally, PD-L1/DC/GAD65 down-regulated interferon-gamma and up-regulated interleukin-10 production by activated lymphocytes. Therefore, combined stimulation in vivo and in vitro by PD-L1/DC/GAD65 could inhibit both the alloresponse and the GAD65-reactive lymphocyte response, which may contribute to controlling diabetes and islet transplant rejection.

subject areas

  • Adoptive Transfer
  • Animals
  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • Cell Line
  • Cell Proliferation
  • Dendritic Cells
  • Diabetes Mellitus, Type 1
  • Endocytosis
  • Glutamate Decarboxylase
  • Immune Tolerance
  • Interferon-gamma
  • Interleukin-10
  • Isoantigens
  • Ligands
  • Lymphocyte Activation
  • Lymphocytes
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Animal
  • Programmed Cell Death 1 Receptor
  • Transfection
  • Transgenes
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Research

keywords

  • dendritic cell
  • glutamic acid decarboxylase 65
  • lymphocyte proliferation
  • programmed death-1 ligands
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Identity

PubMed Central ID

  • PMC2276913

International Standard Serial Number (ISSN)

  • 0009-9104

Digital Object Identifier (DOI)

  • 10.1111/j.1365-2249.2007.03546.x

PubMed ID

  • 18005363
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Additional Document Info

start page

  • 86

end page

  • 93

volume

  • 151

issue

  • 1

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