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Sensitization or Tolerance?

Dendritic cells and cytokines

Bart N. Lambrecht
Department of Pulmonary Medicine
Erasmus University Medical Center
Rotterdam, The Netherlands

DCs control the pulmonary immune response and are critical in asthma pathogenesis
This presentation will demonstrate the essential role of DCs in the pulmonary immune response leading to polarization of Th responses into Th1 (producing IL2, IFN ), Th2 (IL4, IL5, IL9, IL-13) and Th3 (IL10 and/or TGF ). Dendritic cells are very sensitive to the effects of microbial products through their high level expression of evolutionary conserved pattern recognition receptors such as Toll like receptors (TLR) and C-type lectin receptors. These antigen-derived and microbial signals are translated by the DC into a stimulus that can be read by T cells and consists of a particular density of MHCII-peptide (signal 1), a particular expression (or absence) of costimulatory molecules (signal 2) and a particular expression (or absence) of polarizing cytokines and/or chemokines (signal 3). The way in which these signals are integrated over time by the DC are incompletely understood but are essential to understand the process of sensitization.

If we are to understand the influence of environment on sensitization to inhaled allergens, we need to know how sensitization to inhaled allergen is induced. It was shown that a network of airway DCs is responsible for the recognition and uptake of inhaled allergens leading to sensitization (1, 2). When instilled in the airways, fluorescent ovalbumin (OVA) antigen was taken up by endogenous DCs which migrated to the draining lymph nodes of the lung and induced T cell proliferation in naive OVA-specific T cells (3). These T cells were induced to become effector T cells by the induction of a division-related differentiation program that culminated in the expression of inflammatory chemokine receptors and cytokines. When only antigen-pulsed DCs were injected into the trachea, a T cell differentiation program was induced that was very similar to the program induced by the endogenous DCs (4).

To immediately relate these findings to a disease model, we have systematically studied the role of DCs in the pathogenesis of atopic asthma, a disease caused by a dysregulated adaptive immune response to inhaled allergens leading to eosinophilic airway inflammation. To prove that a cell is important in a particular disease process, ideally Koch's postulates have to be fulfilled. As a proof of the first postulate, we demonstrated in an animal model of asthma that the airways, lymph nodes and bone marrow of mice and rats with eosinophilic airway inflammation contain grossly increased amounts of myeloid DCs (5). The second postulate was proven by demonstrating that intratracheal administration of myeloid DCs to the airways of healthy naive animals induced Th2-dependent eosinophilic airway inflammation (5, 6). This was further supported by observing strong Th2 responses to house dust mite (HDM) allergen in humanized SCID mice immunized with HDM-pulsed syngeneic human monocyte-derived DCs (7). To prove the third and most important postulate, we have shown that transgene-based conditional removal of DCs from the airways of diseased animals cured all the features of allergic disease (8). By fulfilling Koch's postulates we are confident that DCs have an essential role in the pathogenesis of asthma in this mouse model, and that we have identified this cell type as a good target for therapeutic and preventive intervention in asthma.

Dendritic cells and the hygiene theory
The incidence of atopic diseases has risen dramatically over the last 50 years, possibly due to altered microbial load from the environment and conditions of increased hygiene. By recognising allergens and by stimulating naive T cells, dendritic cells (DC) are responsible for sensitisation to inhaled allergen. Through high level expression of pattern recognition receptors (PRR), these cells are also uniquely sensitive to microbial products.

As DCs are also paramount to mounting immune responses to bacteria, viruses and parasites (9), we used this model to study the effect of environmental factors such as LPS exposure on sensitization. When DCs were exposed to bacterial LPS in vitro, they induced a polarized Th1 response (high IFN , low IL-4, IL-5, IL-13) that suppressed the development of airway eosinophilia and goblet cell hyperplasia. To our surprise, we found that LPS had a similar Th1 inducing in IL-12p40-/- mice, illustrating that Th1 responses can be induced by DCs through factors distinct from the classical Th1 polarizing signals (Kuipers et al, in press). In addition, Akbari and Umetsu demonstrated that immature lung DCs could also be responsible for the induction of tolerance to inhaled allergens by induction of IL-10 producing regulatory Th3 cells that suppressed allergic airway features (10). Schistosoma mansoni infected atopic patients have anti-inflammatory IL-10 producing regulatory cells (11). We have been able to show that OVA-pulsed DCs exposed synthetic PGD2-like molecules, also found in Schistosoma mansoni, induced a population of IL-10 producing regulatory T cells with an inherent capacity to suppress airway inflammation. Thus the senitization induced by DCs can be profoundly influenced by microbial products in this mouse model.

Dendritic cells of atopic donors are uniquely sensitive to the house dust mite allergen Der p 1.
In humans, DCs have also been shown to differentiate naive T cells into either Th1, Th2, or Th3 cells. The factors that determine the outcome of the T cell differentiation process are very similar to the ones described in mice and include the developmental origin of DCs (myeloid versus plasmacytoid), the degree of maturity of the DC, the nature and dose of the antigen, and the type of microbial pattern used for maturation of DC function.

Allergy to house dust mite (HDM) is the most commonly found sensitization in atopic asthmatics. However, in vitro T cell responses to HDM can also be found in non-allergic individuals, illustrating that it is not the lack of immune recognition that is discriminating between atopics and non-atopics. It is increasingly clear that monocyte-derived (mo-)DCs derived from HDM atopics are uniquely sensitive to Der p 1, a major allergen of HDM (12). Studies by Hammad have shown that mo-DCs from atopics respond to Der p 1 by producing IL-10, IL-6 and TNF- but no IL-12, and by upregulating the expression of the co-stimulatory molecule CD86. On the contrary, mo-DCs derived from non-atopic or pollen-sensitive donors produce mainly IL-12, IL-6 and TNF- and increase expression of CD80 (7, 13). Not surprisingly, mo-DCs exposed to Der p 1 induced a preferential Th2 response in naive allogeneic T cells, whereas those from non-allergic donors induced mainly Th1. These effects were completely dependent on the cysteine protease activity of Der p 1, as pro-Der p 1 did not skew the response towards Th2. Increasing evidence also suggests that Der p 1 acts on mo-DCs to recruit Th2 cells in allergic donors, and Th1 cells in non-allergic donors by inducing the production of Th2 prone chemokines MDC and TARC in allergic donor DCs, and of the Th1-prone chemokine IP-10 in non-allergic DCs (14). Together these findings suggest that DCs from HDM allergic individuals are uniquely sensitive to the effects of Der p 1 allergen, thus inducing and attracting Th2 cells preferentially. This mechanism might prove to be essential in the sensitization process.

References

  1. Lambrecht, B. N. 2001. The dendritic cell in allergic airway diseases: a new player to the game. Clin. Exp. Allergy 31:206.,
  2. Holt, P. G., and P. A. Stumbles. 2000. Regulation of immunologic homeostasis in peripheral tissues by dendritic cells: the respiratory tract as a paradigm. J. Allergy Clin. Immunol. 105:421.
  3. Vermaelen, K. Y., I. Carro-Muino, B. N. Lambrecht, and R. A. Pauwels. 2001. Specific migratory dendritic cells rapidly transport antigen from the airways to the thoracic lymph nodes. J.Exp.Med. 193:51.
  4. Lambrecht, B. N., R. A. Pauwels, and B. Fazekas de St.Groth. 2000. Induction of rapid T cell activation, division and recirculation by intratracheal injection of dendritic cells in a TCR-transgenic model. J. Immunol. 164:2937.
  5. van Rijt, L. S., J. B. Prins, V. C. deVries, P. J. Leenen, K. Thielemans, H. C. Hoogsteden, and B. N. Lambrecht. 2002. Allergen-induced accumulation of airway dendritic cells is supported by an increase in CD31hi Ly-6Cneg hematopoietic precursors. Blood 100:3663.
  6. Lambrecht, B. N., M. De Veerman, A. J. Coyle, J. C. Gutierrez-Ramos, K. Thielemans, and R. A. Pauwels. 2000. Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation. J Clin Invest 106:551.
  7. Hammad, H., B. N. Lambrecht, P. Pochard, P. Gosset, P. Marquillies, A. B. Tonnel, and J. Pestel. 2002. Monocyte-derived dendritic cells induce a house dust mite-specific Th2 allergic inflammation in the lung of humanized SCID mice: involvement of CCR7. J Immunol 169:1524.
  8. Lambrecht, B. N., B. Salomon, D. Klatzmann, and R. A. Pauwels. 1998. Dendritic cells are required for the development of chronic eosinophilic airway inflammation in response to inhaled antigen in sensitized mice. J. Immunol. 160:4090.
  9. Lambrecht, B. N., J. B. Prins, and H. C. Hoogsteden. 2001. Lung dendritic cells and host immunity to infection. Eur Respir J 18:692.
  10. Akbari, O., R. H. DeKruyff, and D. T. Umetsu. 2001. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat. Immunol. 2:725.
  11. van Den Biggelaar, A. H., J. L. Grogan, Y. Filie, R. Jordens, P. G. Kremsner, F. Koning, and M. Yazdanbakhsh. 2000. Chronic Schistosomiasis: Dendritic Cells Generated from Patients Can Overcome Antigen-Specific T Cell Hyporesponsiveness. J.Infect.Dis. 2000.Jul;182(1):260-265. 182:260.
  12. Lambrecht, B. N., and H. Hammad. 2002. Myeloid dendritic cells make it to the top. Clin Exp Allergy 32:805.
  13. Hammad, H., A. S. Charbonnier, C. Duez, A. Jacquet, G. A. Stewart, A. B. Tonnel, and J. Pestel. 2001. Th2 polarization by Der p 1--pulsed monocyte-derived dendritic cells is due to the allergic status of the donors. Blood 98:1135.
  14. Hammad, H., H. H. Smits, E. A. Wierenga, S. G.A., A. B. Tonnel, and J. Pestel. 2002. Monocyte-derived dendritic cells exposed to Der p1 allergen enhance the recruitment of Th2 cells: major involvement of the chemokines TARC and MDC. Eur Cytokine Netw in press.

Slide presentation

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