* Miami Valley Innovation Center, Central Product Safety Department, The Procter & Gamble Company, Cincinnati, Ohio 45253, and Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK
1 To whom correspondence should be addressed at The Procter & Gamble Company, Miami Valley Innovation Center, P.O. Box 538707, Cincinnati, OH 452538707. Fax: (513) 627-0400. E-mail: ryan.ca{at}pg.com.
Received May 10, 2005; accepted June 22, 2005
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ABSTRACT |
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Key Words: contact allergy; dendritic cells; in vitro method.
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SKIN SENSITIZATION TESTING: CURRENT STATE OF THE ART |
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However, even with the significant animal welfare benefits provided by the LLNA, there is a need to develop nonanimal test methods for skin sensitization. The mechanistic understanding of ACD has increased substantially in recent years; the challenge is to apply this knowledge to the design of predictive in vitro alternative tests. In this review, we have focused specifically on the impact of chemical exposure on dendritic cells (DC) and the potential application of such information in the development of cell-based assays for assessing skin sensitization potential of chemicals in vitro.
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IN VITRO TESTING FOR CONTACT SENSITIZATION: A NEW OPPORTUNITY IS RECOGNIZED |
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THE IMMUNOBIOLOGICAL ROLE OF DENDRITIC CELLS IN THE ACQUISITION OF CONTACT SENSITIZATION |
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Skin-sensitizing chemicals, typically lipophilic and low-molecular-weight (<500 kDa) molecules, act as haptens and need to bind to protein to form a haptenprotein complex in order to be recognized by LC (Dupuis and Benezra, 1982; Landsteiner and Jacobs, 1936
). Following encounter with a chemical allergen, LC become activated and subsequently migrate from the skin to the draining lymph nodes. This migration is stimulated by changes in the cytokine microenvironment, including up-regulated expression of tumor necrosis factor (TNF)-
by epidermal keratinocytes and IL-1ß by LC (Cumberbatch et al., 1997a
,b
). During transit from the skin to the lymph nodes, LC undergo maturation and differentiate from antigen-capture and processing cells to potent immunostimulatory DC, able to present antigen effectively to responsive T cells. Among the changes reported to occur in LC as a result of exposure to chemical allergens are internalization of surface major histocompatibility complex (MHC) class II molecules via endocytosis (Becker et al., 1992
; Girolomoni et al., 1990
), induction of tyrosine phosphorylation (Kühn et al., 1998
), the modulation of cell surface markers (Aiba and Katz, 1990
; Verrier et al., 1999
) and cytokine expression (Enk and Katz, 1992
).
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IN VITRO GENERATION OF LANGERHANS CELLLIKE DENDRITIC CELLS |
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FIRST-GENERATION APPROACHES USING DENDRITIC CELLS: CHANGES IN PHENOTYPE AND CYTOKINE EXPRESSION |
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The potential for changes in expression by DC of mRNA for other cytokines or chemokines to serve as useful markers for sensitization testing has recently been explored by Verheyen et al. (2005). Following exposure of CD34+-progenitor derived DC to allergens or irritants, mRNA expression for IL-1ß, IL-6 and IL-8, and the chemokines CCL2, CCL3, CCL3L1, and CCL4 was examined by real-time RT-PCR. Significant interindividual variations in mRNA expression in response to chemical treatment were observed. Based on their results, the authors concluded, as did Pichowski et al. (2001)
, that allergen-induced IL-1ß mRNA expression in DC was not an appropriate indicator of sensitizing potential. Neither IL-6 nor IL-8 was able to discriminate clearly allergens from irritants. However, at the 24-h time point, mRNA levels for CCL2, CCL3, and CCL4 displayed a two-fold or greater increase relative to control for the allergens, but not for the irritants. The authors suggest that further investigation of these chemokine genes is warranted.
In addition to the up-regulation of cytokine or chemokine mRNA expression, a number of other changes known to occur in LC following allergen exposure have also been investigated in DC as potential markers for the assessment of skin sensitization potential in vitro. Phenotypic alterations in DC induced by hapten treatment have been explored as a possible method for identifying potential contact allergens. The cell surface markers that have received the most attention for this purpose are MHC Class II molecule HLA-DR, the costimulatory molecules CD86 and CD80, the adhesion molecule CD54 (intercellular adhesion molecule (ICAM)-1), and CD83, a marker of mature DC, and CD40, a molecule known to play a role in several DC functions. Early investigations conducted by Degwert et al. (1997) found that incubation of monocyte-derived DC with subtoxic concentrations of contact sensitizers for periods of less than 3 h resulted in decreased HLA-DR expression, whereas incubation with irritants for the same length of time was without effect. There were no allergen- or irritant-specific effects on CD54 expression. Using LC-like DC generated from CD34+ cord blood cells, Rougier et al. (2000)
consistently observed increased expression of HLA-DR, CD83, and CD86, and decreased levels of E-cadherin following treatment with a strong allergen but not with an irritant. However, when weaker allergens were tested, changes in CD86 expression were relatively robust, whereas changes in HLA-DR or CD83 were observed only in a limited number of subjects (one or two out of eight). Other investigators have reported that 48-h treatment of PBMC-derived DC with strong contact allergens induced only modest up-regulation of HLA-DR in three out of five donors and no significant changes in CD86, CD54, or CD80 expression (Hulette et al., 2002
). Staquet et al. (2004)
examined changes in expression of a panel of cell surface markers including HLA-DR, CD1a, CD40, CD54, CD83, CD86, CCR7, and E-cadherin and intracellular HLA-DR on monocyte-derived DC following exposure to noncytotoxic concentrations of allergens of varying potencies and of irritants. They found that prolonging the exposure time from 2 to 4 days increased the number of markers impacted by most of the allergens tested. However, they noted a high degree of donor-dependent variability both in the number of markers and in which specific markers were influenced by the allergens. On the other hand, the same conditions of exposure to the irritant, SDS, never modified more than one of the markers. Other investigators have attempted to correlate chemical-induced up-regulation of CD86 and HLA-DR with cytotoxicity (Straube et al., 2005
). The strong contact allergens dinitrochlorobenzene (DNCB) and trinitrobenzene sulfonic acid (TNBS) increased CD86 and HLA-DR expression on monocyte-derived DC at dose levels that were just below the concentration that caused frank cytotoxicity. Irritants (SDS and benzalkonium chloride) were also found to up-regulate CD86 and HLA-DR expression, but only at concentrations that induced significant cytotoxicity.
Some investigators have examined cytokine secretion concurrently with cell surface marker expression. Aiba et al. (1997) reported that culture of monocyte-derived DC with chemical allergens induced a significant increase in the surface expression of HLA-DR, CD54, and CD86 compared with untreated or irritant-exposed DC. Although irritants did not provoke cytokine production, there was some induction by allergens, but the pattern of expression varied according to the particular allergen tested. Consistent with previously observed effects on IL-1ß mRNA expression (Pichowski et al., 2000
, 2001
), there were a number of nonresponders with respect to both cell surface marker expression and cytokine secretion. Coutant et al. (1999)
found that after 48 h incubation with chemical haptens, monocyte-derived DC expressed higher levels of HLA-DR, CD86, CD40, and CD54 compared with DC incubated with irritants. In addition, they observed that incubation with haptens, but not with irritants, provoked the secretion of TNF-
. They reported only small differences in responses between donors. However, the DC preparations used in their studies were prescreened; those preparations expressing high levels of HLA-DR were discarded, as they were found to respond poorly or not at all to inflammatory stimuli, possibly reflecting a higher level of maturation. Tuschl and Kovac (2001)
examined CD86, CD54, and HLA-DR cell surface expression in parallel with the induction of intracellular expression of IL-1ß in PBMC-derived DC. An up-regulation of these surface markers was observed in the majority of donors following culture with allergen but not with irritant. However, no clear results were obtained for the induction of intracellular IL-1ß. Degwert et al. (1997)
and Becker et al. (1997)
reported an increase in receptor-mediated endocytosis of HLA-DR in monocyte-derived DC exposed to several strong contact allergens. Less potent sensitizers and irritants failed to produce a significant effect on HLA-DR internalization (Becker et al., 1997
). In common with previous investigations (Aiba et al., 1997
; Pichowski et al., 2000
, 2001
), responder and nonresponder populations were identified.
On balance, the results generated to date by a number of different investigators demonstrate that measurement of allergen-induced changes in phenotype or induced cytokine expression in monocyte-, CD34+-, or PBMC-derived DC as a potential in vitro method for predicting sensitization potential has certain limitations. The parameters examined thus far apparently lack the sensitivity and dynamic range to provide a robust method for the identification of potential contact sensitizers, with the possible exception of very potent skin allergens. One other major limitation was the common finding that there was considerable donor-to-donor variation in responsiveness, such that populations could be divided into responders and nonresponders. Although it has been suggested that this problem could be circumvented by screening potential DC donors for activity, this type of approach would not lend itself easily to the development of a routine testing procedure.
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FIRST-GENERATION APPROACHES USING CELL LINES AS DC SURROGATES |
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A few commercially available human cell lines have been explored as potential surrogates for DC. Cytokine treatment of the human acute myelogenous leukemia cell line, KG-1, has been shown to induce a DC-like phenotype and morphology (Hulette et al., 2001; St. Louis et al., 1999)
. Exposure to chemical allergens had little or no effect on the expression of HLA-DR, CD54, CD80, and CD86 in these cytokine-induced cells (Hulette et al., 2002
; Yoshida et al., 2003
). However in the absence of cytokine, KG-1 cells demonstrated increased expression of CD86 and CD54 following treatment with a strong contact sensitizer (Yoshida et al., 2003
). The THP-1 cell line, derived from human monocytic leukemia cells, has also been examined for its potential as a replacement for PBMC-derived DC in the development of an in vitro predictive test for contact sensitizers (Ashikaga et al., 2002
; Yoshida et al., 2003
). Exposure to a number of skin sensitizers has been shown to enhance cell surface expression of CD86 (Ashikaga et al., 2002
; Yoshida et al., 2003
) and CD54 (Yoshida et al., 2003
). In addition, THP-1 cells demonstrated an increased internalization of MHC class II molecules in response to allergen exposure (Ashikaga et al., 2002
).
The most judicious view at present is that, with further refinement, some of these cell lines show promise as surrogates for DC in vitro assays. However, it must be noted that, in common with freshly isolated DC, the parameters of activation examined to date have shown relatively modest changes with potent allergens, thus the question of sensitivity still remains.
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SECOND-GENERATION APPROACHES USING DENDRITIC CELLS: SEARCH FOR NOVEL MARKERS BY HOLISTIC EXPRESSION PROFILING |
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Ryan et al. (2004a,b
) analyzed gene expression changes induced in DC following treatment with a low and high dose of the water-soluble analog of DNCB, dinitrobenzensulfonic acid (DNBS). Using the Affymetrix GeneChip® platform, many changes in specific transcripts were observed in both the 1 mM and 5 mM DNBS treatments. However, as expected, more genes were regulated significantly (p
0.001) by 5 mM treatment than was observed for the 1 mM dose and corresponded to approximately 10.9 and 1.6%, respectively, of the total number of genes represented on the Affymetrix U95A2 Genechip®. Many of the 118 genes that were regulated in both treatment groups at p
0.001 could be correlated with DC function and could be further validated by quantitative real-time PCR analysis. Examples include interleukin 8, CD86, CCL2, CCL4, and CD43. In addition genes not previously associated with skin sensitization or DC biology, such as AKR1C2, DUSP6, and QPCT, were identified, therefore widening the pool from which potential markers can be selected. It is anticipated that similar genomics studies using LC surrogates with different allergens and irritants may provide additional gene targets not previously discovered. However, genes that are selected as markers for skin sensitization must fit the criterion for dynamic range, robustness, sensitivity, and selectivity for a predictive model and cover a range of chemical classes (Kimber et al., 2001
).
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GENERAL CONSIDERATIONS, CURRENT CHALLENGES, AND FUTURE OPPORTUNITIES |
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If such a strategy is found to be sound, insofar as genes are identified that display selective responses to chemical allergens, then an interesting question emerges that can be framed as follows: in what ways are DC able to distinguish between encounter with a sensitizing chemical and other changes in the cellular microenvironment (such as contact with nonsensitizing skin irritants)? There is no clear answer to this question, although one possible explanation is that the changes induced, which appear to be selective for contact allergens, in fact result from the required property of sensitizing chemicals to form stable associations with proteins. The argument is that skin sensitizers might cross-link membrane proteins on target cells and that this in turn results in characteristic changes in cytokine production and/or the expression of membrane determinants. This issue is of more than theoretical importance, since resolution of the proposed selective effect of chemical allergens on the phenotype and function of DC might pave the way for a more precise approach to the identification of sensitizing potential.
The possible requirement for protein reactivity to effect changes in gene expression by DC illustrates an issue that impacts upon all proposed in vitro approaches to skin sensitization testing; the need for metabolic activation. For the acquisition of skin sensitization, there is a need for the inducing chemical allergen to form a stable association with protein. The consequence is that skin-sensitizing chemicals are either naturally protein reactive, or have to be metabolized to a protein-reactive species (i.e., pro-haptens) (Dearman and Kimber, 2003; Kimber and Dearman, 2003
). It is generally believed that in excess of 20% of skin sensitizing chemicals can be described as pro-haptens, and if a proposed in vitro method is going to be able to detect these, then there must be endogenous metabolic activity within the cell or tissue matrix used, or provision of an exogenous source of appropriate metabolizing enzymes.
Another confounding factor (which impacts on all in vitro cell assays, including those incorporating DC or DC-like cells) is delivery of the test material. Many of the chemicals are organic in nature and insoluble in an aqueous matrix that is most suitable for delivery to culture systems. There are ways of addressing this by using aqueous/organic solvent mixtures, but this nevertheless represents a significant technical challenge.
The other major issue is related to cell viability. The paradigm commonly in cell-based in vitro assays is to deliver test chemical at the maximum nontoxic concentration. This practice raises two questions. The first of these is what level of viability is deemed to be indicative of lack of toxicityand by what method should this be measured? Clearly this particular issue impacts on all types of in vitro assay systems. The second question is of greater interest, insofar as it relates more specifically to the stimulation of immune responses. This is whether there is a need for some low-level cell trauma in order for DC to respond optimally to a chemical allergen. This thinking is based upon a view that encounter with antigen is not itself sufficient to provoke a normal immune response, and that, in addition, there is a requirement for some local tissue damage or trauma to provide a necessary costimulus. This theory was first developed by Matzinger and later elaborated further by others in relation to skin sensitization (Matzinger, 2002; McFadden and Basketter, 2000
). With respect to the response by DC to chemical allergens in vitro, the speculation is that DC perhaps need a second danger signal and/or to be subject to some small amount of cellular trauma in order to mount vigorous responses. A number of investigators are exploring this currently and questioning whether some low-level cell injury induced concomitantly with, or prior to, exposure to allergen would enhance transcriptional responses induced in DC.
The need for signals additional to that provided by the allergen itself, of course, raises questions about the requirement for the presence of additional cell types within the culture system and, in particular, keratinocytes. The latter are the major cellular constituents of the epidermis and effectively surround LC. Many epidermal chemokines and cytokines that orchestrate the movement and function of LC derive from keratinocytes, and it is therefore legitimate to question whether provision of these signals by keratinocytes cocultured with LC-like DC would enhance or modify responses induced by exposure to allergen. This again is a subject of current research.
Present investigations, linked with a certain amount of ingenuity, may allow us to resolve some of these issues and uncertainties in the near future, and this would undoubtedly provide a firmer foundation for DC-based assays for skin sensitization hazard. In addition, however, it is worthwhile speculating on how some recent insights into DC and LC biology may also pay dividends in exploiting this area of science. For instance, there is a growing appreciation of the increasingly complex chemokine receptor-ligand interactions that are required for regulation of the motility and directed movement of LC and LC-like DC in health and disease, and it might be that some of the novel proteins described are selectively up-regulated during activation of DC (Partida-Sanchez et al., 2004; Qu et al., 2004
; Vermi et al., 2005
).
In the future, it may be possible to exploit DC responses in vitro not only for the identification of chemical allergens, but also for characterizing the type of allergic response that they will selectively induce. While the majority of chemical allergens are associated with skin sensitization and the development of ACD, others (fewer in number) are implicated primarily as inducers of allergic sensitization of the respiratory tract and occupational asthma. The type of allergic response a chemical allergen will provoke is largely a function of the development of discrete functional subpopulations of T lymphocytes (Kimber and Dearman, 2005). There is increasing evidence that the development of T-lymphoctyte subpopulations is in fact driven by DC of different phenotypes (either inherent or acquired) (Fujita et al., 2005
; Smits et al., 2005
). Associated with this is intriguing evidence that contact allergens and chemical respiratory allergens display differential selectivity for association with protein and a variable potential to mobilize LC in vivo (Cumberbatch et al., 2005
; Hopkins et al., 2005
). It is tempting to speculate that a more detailed understanding of the ways in which chemical allergens of different classes interact with LC and DC may yield opportunities to model this in vitro and permit not only identification of chemical allergens but also prediction of the type of sensitization they are likely to induce.
A continued investment in this exciting branch of applied immunotoxicology should see significant progress made in resolving some of the pressing technical issues. This in turn will permit a rigorous appraisal of the opportunities for hazard assessment that may be afforded by characterization of DC responses in vitro.
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ACKNOWLEDGMENTS |
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