Advanced

Dendritic cells in allergy In vitro models for studies of the human immune response

Larsson, Kristina LU (2007)
Abstract
This thesis, which is based on four original papers, deals with human dendritic cells (DCs) in immunity and allergy. DCs play a key role in the regulation of immune responses by acting as the sentinels of the immune system, specialized in the uptake of a diverse range of antigens. These cells migrate to local lymph nodes and become highly efficient in inducing T cell proliferation, thus inducing adaptive immune responses. Therefore, DCs function as the link between innate and adaptive immune responses. Besides pathogenic microorganisms, the immune system encounters numerous proteins, many of which are harmless. A proper response against these harmless antigens is tolerance. The balance between induction of immunity or tolerance is in part... (More)
This thesis, which is based on four original papers, deals with human dendritic cells (DCs) in immunity and allergy. DCs play a key role in the regulation of immune responses by acting as the sentinels of the immune system, specialized in the uptake of a diverse range of antigens. These cells migrate to local lymph nodes and become highly efficient in inducing T cell proliferation, thus inducing adaptive immune responses. Therefore, DCs function as the link between innate and adaptive immune responses. Besides pathogenic microorganisms, the immune system encounters numerous proteins, many of which are harmless. A proper response against these harmless antigens is tolerance. The balance between induction of immunity or tolerance is in part determined by DCs. A dysfunction in the regulation of this balance may result in diseases such as allergy and autoimmunity. The incidence of allergy has reached up to 40% of the children in industrialized countries and is increasing in developing countries. The reduced quality of life in these conditions increases the need to strive for commercial products of low allergenicity. Tests to verify these products are needed, and directives from the European Union aim for a reduction of animal tests and development of alternative in vitro models. A model based on human DCs would be suitable since they have a central role in the immune system and in allergy. To address this question we studied transcriptional profiles of monocyte-derived DCs (MoDCs) and the differentiated monocytic cell line MUTZ-3 induced by pro-inflammatory signals. We could demonstrate that the cell lines expressed a wide range of molecules that are important for DC function. Thus, MUTZ-3 closely resembles DCs and is suggested to serve as an in vitro model to predict allergenicty of novel compounds. Yet, the functionality of the cell line needs to be further evaluated.The effect of an allergen (timothy) on DCs was demonstrated by transcriptional profiling of grass pollen stimulated DCs from allergic and non-allergic individuals. Furthermore, memory effector T cells were demonstrated to have an instructive role in the cross-talk between DCs and T cells in both allergic and non-allergic conditions. This education of DCs was in part specific in allergy and supports the concept of DC-mediated sustained allergic inflammation in the periphery. In addition, the reported panel of genes reveal novel molecules involved in the enhanced inflammation. The genes reported specific for allergen stimulated DCs and in the subsequent DC/T cell crosstalk in allergy may be interesting targets in the search of novel drugs.New methods for administration of vaccines are desirable to increase the speed and ease for delivery of vaccines in addition to improved safety. DCs are suitable targets for vaccine delivery since they are efficient inducers of adaptive immune responses. As they are located in mucosa and skin they can be reach by vaccine delivery to any of these tissues, e.g. via nasal administration. Nanospheres induce adaptive immune responses and function as both antigen carrier and adjuvants. Transcriptional profiling of MoDCs upon stimulation with nanospheres revealed activated pathways during uptake and processing of the antigen. Next, the efficiency of biodegradable nanospheres to induce DCs to mount adaptive immune responses needs to be identified. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Dr Gibbs, Susan, Dermatology, VU University Medical Centre, Amsterdam, The Netherlands
organization
publishing date
type
Thesis
publication status
published
subject
keywords
transplantation, serology, Immunology, vaccine, Th2, transcriptional profiling, T cell, nanosphere, Immunologi, MUTZ-3, microarray, in vitro model, Allergic rhinitis, dendritic cell, serologi
pages
131 pages
publisher
Department of Immunotechnology, Lund University
defense location
The Seminar room (Stora salen), BMC D15, Klinikgatan 32, Lund
defense date
2007-11-30 09:15
ISBN
978-91-628-7327-1
language
English
LU publication?
yes
id
e983c602-b0b6-4223-b2b9-8569d417d245 (old id 599237)
date added to LUP
2007-11-13 08:18:27
date last changed
2016-09-19 08:45:06
@misc{e983c602-b0b6-4223-b2b9-8569d417d245,
  abstract     = {This thesis, which is based on four original papers, deals with human dendritic cells (DCs) in immunity and allergy. DCs play a key role in the regulation of immune responses by acting as the sentinels of the immune system, specialized in the uptake of a diverse range of antigens. These cells migrate to local lymph nodes and become highly efficient in inducing T cell proliferation, thus inducing adaptive immune responses. Therefore, DCs function as the link between innate and adaptive immune responses. Besides pathogenic microorganisms, the immune system encounters numerous proteins, many of which are harmless. A proper response against these harmless antigens is tolerance. The balance between induction of immunity or tolerance is in part determined by DCs. A dysfunction in the regulation of this balance may result in diseases such as allergy and autoimmunity. The incidence of allergy has reached up to 40% of the children in industrialized countries and is increasing in developing countries. The reduced quality of life in these conditions increases the need to strive for commercial products of low allergenicity. Tests to verify these products are needed, and directives from the European Union aim for a reduction of animal tests and development of alternative in vitro models. A model based on human DCs would be suitable since they have a central role in the immune system and in allergy. To address this question we studied transcriptional profiles of monocyte-derived DCs (MoDCs) and the differentiated monocytic cell line MUTZ-3 induced by pro-inflammatory signals. We could demonstrate that the cell lines expressed a wide range of molecules that are important for DC function. Thus, MUTZ-3 closely resembles DCs and is suggested to serve as an in vitro model to predict allergenicty of novel compounds. Yet, the functionality of the cell line needs to be further evaluated.The effect of an allergen (timothy) on DCs was demonstrated by transcriptional profiling of grass pollen stimulated DCs from allergic and non-allergic individuals. Furthermore, memory effector T cells were demonstrated to have an instructive role in the cross-talk between DCs and T cells in both allergic and non-allergic conditions. This education of DCs was in part specific in allergy and supports the concept of DC-mediated sustained allergic inflammation in the periphery. In addition, the reported panel of genes reveal novel molecules involved in the enhanced inflammation. The genes reported specific for allergen stimulated DCs and in the subsequent DC/T cell crosstalk in allergy may be interesting targets in the search of novel drugs.New methods for administration of vaccines are desirable to increase the speed and ease for delivery of vaccines in addition to improved safety. DCs are suitable targets for vaccine delivery since they are efficient inducers of adaptive immune responses. As they are located in mucosa and skin they can be reach by vaccine delivery to any of these tissues, e.g. via nasal administration. Nanospheres induce adaptive immune responses and function as both antigen carrier and adjuvants. Transcriptional profiling of MoDCs upon stimulation with nanospheres revealed activated pathways during uptake and processing of the antigen. Next, the efficiency of biodegradable nanospheres to induce DCs to mount adaptive immune responses needs to be identified.},
  author       = {Larsson, Kristina},
  isbn         = {978-91-628-7327-1},
  keyword      = {transplantation,serology,Immunology,vaccine,Th2,transcriptional profiling,T cell,nanosphere,Immunologi,MUTZ-3,microarray,in vitro model,Allergic rhinitis,dendritic cell,serologi},
  language     = {eng},
  pages        = {131},
  publisher    = {ARRAY(0x9f504c8)},
  title        = {Dendritic cells in allergy In vitro models for studies of the human immune response},
  year         = {2007},
}