Allergy - Can allergenicity be predicted based on dendritic cell analysis?

Research projects and aims
The focus of the allergy group is on the role of human dendritic cells (DC) and their regulatory role in allergic immune responses. We are interested in the mechanistic processes that influence DCs during an ongoing allergic response and the factors by which DCs skew the immune response toward either Th1 or Th2. The aims of our conducted research projects are to:

• assess the functional differences of blood DC subtypes in allergic and healthy individuals
• analyze the influence of allergen-specific Abs on internalisation and presentation of allergens
• delineate the molecular mechanisms involved in the cross-talk between DCs and memory T cells in the mounting of effector Th2 responses
• study the effect of drug candidates of the interaction between DCs and T cells in allergic response
• characterize the different DC subpopulations isolated blood and tonsillar tissue both functionally and transcriptionally
• determine the usefulness of in vitro-derived DC models, such as differentiated cell lines, to work as functional antigen-presenting cells
• compare our in vitro-derived DC models to in vivo DCs isolated from peripheral blood

Introduction to Dendritic Cells
DCs act as the gatekeeper between the innate and adaptive immune system. The primary function of these cells is to maintain tolerance to harmless antigens and molecules of self under immunological steady-state conditions, and trigger immunity in the presence of danger, in terms of invading pathogens or other harmful antigens. DCs are an important part of the innate immune system, since they upon triggering rapidly produce large amounts of cytokines and other mediators, which either directly activate cells in the vicinity or attract other cells to the site of inflammation or infection. Their outstanding ability to present antigen and selective respond to various pathogens and environmental factors, with a subsequent quality control and fine-tuning of the cellular communication, clearly demonstrate their deterministic role in the adaptive immunity. In allergy, it is the mounting of a Th2 response that cause the detrimental effects of e.g. induced IgE production and mast cell degranulation. Even if Th2 cells and its products induce many of the pathogenic features of allergic disease, they still depend on the instruction from antigen-presenting DCs to develop and act. DCs provide the first step of immune recognition of allergens and thus represent the decision maker of the immunological outcome. Hence, in the absence of activation signals, allergen-challenged DCs induce the proper T cell unresponsiveness and tolerance. In contrast, in the presence of these signals, the outcome of TCR-ligation may instead result in induction of T cell activation, division and Th2 differentiation. Understanding the basis of DCs in these immunological processes enables novel therapeutic approaches of allergic disease.

References

1. Larsson K, Lindstedt M, Lundberg K, Dexlin L, Wingren C, Korsgren M, Greiff L, Borrebaeck CAK (2008) CD4+ T-cells have a key instructive role in educating dendritic cells in allergy. Int Arch Allergy Immunol (in press)
2. Santegoets S, Gibbs S, Kroeze K, van de Ven R, Scheper RJ, Borrebaeck CAK, de Gruijl TD and Lindstedt M (2008) Transcriptional profiling of human skin-resident Langerhans cells and CD1a+ dermal dendritic cells: differential activation states suggest distinct functions. J Leukoc Biol 84, 143-151. (Abstract)
3. Lundberg K, Lindstedt M, Larsson K, Dexlin L, Wingren C, Ohlin M,
   Greiff L and Borrebaeck CAK (2008) Augmented Phl p 5-specific Th2 response after exposure of dendritic cells to allergen in complex with specific IgE compared to IgG1 and IgG4. Clin Immunol 128, 358-365. (Abstract)
4. Larsson K, Lindstedt M, and Borrebaeck CAK (2006) Functional and transcriptional profiling of MUTZ-3. A myeloid cell line acting as a model for dendritic cells. Immunology 117, 156.
5. Roggen EL, Lindstedt M, Borrebaeck C, Verheyen GR (2006) Interactions between dendritic cells and epithelial cells in allergic disease. Toxicol Lett 162, 71.
6. Lindstedt M, Lundberg K, and Borrebaeck CAK (2005) Gene family clustering identifies functionally associated subsets of human in vivo blood and tonsillar dendritic cells. J Immunol 175, 4839.
7. Lindstedt M, Schiött Å, Bengtsson A, Larsson K, Korsgren M, Greiff L, and Borrebaeck CAK (2005) Genomic and functional delineation of dendritic cells and memory T cells derived from grass pollen-allergic patients and healthy individuals. Int Immunol 17, 401.
8. Lindstedt M., Schiött Å, Johnsen CR, Roggen E, Johansson-Lindbom B, and Borrebaeck CAK (2005) Individuals with occupational allergy to detergent enzymes display a differential transcriptional regulation and cellular immune response. Clin Exp Allergy 35, 199.
9. Matsusaki M, Larsson K, Akagi T, Lindstedt M, Akashi M, Borrebaeck CAK (2005) Nanosphere induced gene expression in human dendritic cells. Nano Lett 5, 2168.
10. Schiött Å, Lindstedt M, Johansson-Lindbom B, Roggen E, Borrebaeck CAK (2004) The CD27- memory CD4+ T cells defines a differentiated memory population both at functional and transcriptional level. Immunology 113, 363.
11. Lindstedt M, Johansson-Lindbom B, Borrebaeck CAK (2003) Expression of CD137 (4-1BB) on Human Follicular Dendritic Cells. Scand J Immunol 57, 305. (journal cover)
12. Lindstedt M, Johansson-Lindbom B, and Borrebaeck CAK (2002) Global reprogramming of dendritic cells in response to a concerted action of inflammatory mediators. Int Immunol 14, 1203.

Contact information
Dr Malin Lindstedt
Dept. of Immunotechnology, Lund University,
BMC D13, S-22184 Lund, Sweden
e-mail
telephone: +46-46-222 9256