Use of transgenic animals to investigate drug hypersensitivity

Toxicology 158 (2001) 75 – 83 www.elsevier.com/locate/toxicol

Use of transgenic animals to investigate drug hypersensitivity Rene Moser a, Valerie Quesniaux a, Bernhard Ryffel b,* a

Institute of Biopharmaceutical Research, Matzingen, Pharma No6artis AG, Basel, Switzerland b Department of Immunology, Uni6ersity of Cape Town, Cape Town, South Africa

Abstract Hypersensitivity reactions to drugs and environmental agents are often due to exaggerated humoral (Th2) or cell mediated (Th1) immune responses with typical cytokine profiles. Overexpression of Th2 cytokines, such as IL-4, IL-5 or IL-13 in mice, enhances an IgE antibody mediated response, while deletion of these cytokines attenuates and/or prevents allergic responses. Conversely, modulation of Th1 cytokine gene expression may affect cell-mediated immune responses. Therefore, cytokine transgenic mice are used as investigative tools to study potential chemicals and/or drug allergies. In addition to cytokines and chemokines, other factors are important for the development of allergic responses, such as IgE, Fc receptors, vasopressin and several other factors, which can be tested in transgenic mice. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Allergy; Asthma; Eczema; Cytokine transgenic mice

1. Introduction Hypersensitivity reactions to environmental agents, food, chemicals and drugs are common in man, and their incidence seems to be increasing (Woolcock and Peat, 1997; Howarth, 1998). Basically, two pathophysiological mechanisms for the development of hypersensitivity reactions can be distinguished: (1) antibody-dependent degranulation of mast cells in sensitized individuals (IgE); and (2) T cell-dependent, inflammatory responses * Corresponding author. Present address: CNRS Orleans, CDTA, UPS 44, 3B rue de la Ferollerie, 45071 Orleans, Cedex 02, France. Tel.: +33-238-255452; fax: +33-238-255435. E-mail address: [email protected] (B. Ryffel).

(Burns and Gaspari, 1996; Kimber et al., 1998a,b; Coleman and Blanca, 1998). The antigen may be a protein, a drug/chemical, or a metal. Typical clinical features of an IgE-dependent allergic reaction comprise urticaria, erythema, asthma and in severe cases, even shock (Bernstein and Bernstein, 1994). Dermal exposure to allergens may result in chronic cutaneous hypersensitivity reactions known as eczema. The question of why an inert protein causes allergy in some, but not all individuals indicates that host factors play an important role. In man, several genes have been identified on chromosome 5 (IL-3, IL-4, IL-5, IL-9, IL-13), 6 (HLA-D and TNF) and 12 (IFN-g, stem cell factor, STAT6), which are associated with allergy (Barnes and

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Marsh, 1998; Holloway et al., 1999). Genetic linkage analyses demonstrated that the development of hypersensitivity is under the control of multiple genes, the individual role of which is unknown. Experimental animal models, however, demonstrated significant roles of most of the gene products identified above, alone or in combination. In view of the complex genetic control of allergic responses and our limited understanding, hypersensitivity reactions are impossible to predict today. Small chemicals and drugs may have a reactive group allowing covalent binding to a protein and hence can be recognized by the immune system as foreign (Coleman and Blanca, 1998). In the absence of reactive groups, metabolic activation may generate haptens that sensitize T cells (Griem et al., 1999; Ewens et al., 1999). Recent evidence suggests that covalent binding may not be a prerequisite (Zanni et al., 1997; Schnyder et al., 1998). Concomitant infections, such as bacterial infections, may reduce the incidence of allergic responses (Erb et al., 1998), while parasitic infections increase it (Erb, 1999; Adams et al., 1999). In the case of mycobacterial infections, or following immunization with BCG, which is a strong Th1 response inducer, an inverse association between tuberculin responses and atopic disorders has been reported (Cookson and Moffatt, 1997; Shirakawa et al., 1997). Therefore, bacterial infections may bias the immune system to a predominantly Th1 response and reduce allergic reactions.

2. Role of cytokines and chemokines The immune system has essentially two ways of reacting to foreign substances/drugs: either the host produces antibodies of the IgE type (humoral response mediated by Th2 lymphocytes) or shows a cell mediated immune (Th1) response, as described in mouse and man (Abbas et al., 1996; Romagnani, 1997). IL-12 and IL-18 produced by antigen-presenting cells, e.g. macrophages and dendritic cells, and IFN-g, LTb and IL-2 from activated T cells,

allow the differentiation of Th1 cells. The Th1 response comprises delayed-type hypersensitivity (DTH) reaction, granuloma and eczema. IL-4, IL-5 and IL-13 from basophils and/or NK and T cells promote Th2 cell differentiation, resulting in antibody production manifested in allergic skin reactions, asthma and allergic shock. Allergic drug reactions fall into both categories. The Gell and Coombs’s classification includes four types (I–IV) of immunopathological reaction mechanisms. Type I reaction is identical with the Th2 response, while type IV coincides with the Th1 reaction. Cytotoxic antibodies (type II) and immune complex-induced reactions (type III) can be considered as special forms of antibody-mediated immune reactions resembling a Th2 response, and they are also involved in hypersensitivity reactions to drugs. Conventional drugs (chemicals) can act as haptens and act only upon binding to a protein, is an immunogenic antigen formed that is presented in the context of MHC by professional antigen presenting cells, such as dendritic cells or macrophages (Grabbe and Schwarz, 1998; Kimber et al., 1998a,b). TNF and IL-1 are apparently required for the differentiation and migration of dendritic cells to the regional lymph nodes (Kimber et al., 1998a,b), while IL-10 has an inhibitory role (Wang et al., 1999). The requirement of dendritic cells in allergic reactions has been conclusively demonstrated by eliminating dendritic cells using myeloid specific thymidine-kinase transgenic mice and ganclicovir (Lambrecht et al., 1998). The factors deciding whether a prevailing Th1 or Th2 immune response is induced, are debatable. This issue is complex and poorly understood. The initial cytokine(s) produced in DC and other cells (mast cells and NK cells) appear to determine the differentiation of so-called Th0 cells into either Th1 or Th2 cells. Bacterial and parasitic antigens are contrasting examples inducing either Th1 or Th2 responses. Mycobacterial cell walls are often used as adjuvant and are potent Th1 inducers, while schistosomal egg antigens (SEA) are potent Th2 inducers. Besides the nature of the antigen, the dose and route of presentation can also affect the Th1/Th2 differentiation. Recently another family of peptide

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factors with chemotactic functions, known as the chemokines, has been shown to have a regulatory role in the process of Thl/Th2 differentiation and hence in Th1 vs Th2 responses (Baggiolini et al., 1997). This review focuses on investigating the role of cytokines in hypersensitivity reactions. As immunological and genetic tools are available, and hypersensitivity reactions develop in mice (Kimber and Dearman, 1997; Vargaftig, 1999), the discussion will focus on genetic models in mice. The selection of inbred strains already has a substantial impact on the Th1/Th2 response pattern: for example, C57/BL6 mice have a preferential Thl response, while Balb/c mice tend to develop a Th2 response (Sun et al., 1997). Furthermore, nature has created its own discrete mutations in several genes of interest, e.g. stem cell factor, CSF-l, TLR4, FAS, lpr, and many others. Finally, overexpression and deletion of genes is now possible in mice by recombinant technology, which allows us to test for the role of a given gene in a pathophysiological process.

3. Transgenic mice The technique of modifying the mouse genome was developed in the last 10 years. Injection of DNA/gene into oocytes followed by implantation of the transfected oocyte into the uterus of pseudopregnant mice results in a progeny of mice overexpressing the randomly inserted gene. In contrast, homologous recombination in embryonic stem cells is used to generate mice deficient (knock-out, KO) for a specific gene. The latter involves generation and selection of mutant embryonic stem cells, their injection into a blastocyst, implantation into the uterus and breeding the progeny to homozygosity (Burki and Ledermann, 1995). A vast number of mutant mice has been generated (reviewed in Mak, 1998). Both types of mutants — mice overexpressing or with deletions of specific genes (KO) — proved to be valuable tools for the study of pharmacology, toxicology and disease (Wei, 1997; Ryffel, 1997; Lovik, 1997; Eynon and Flavell, 1999). The

Table 1 Cytokine deficient mice — Th1 versus Th2 KO

Phenotype

Th1/Th2

Reference

IFN-g

Reduced host resistance

Th2

IL-2 IL-12

Reduced DTH Colitis, anemia Reduced host resistance

Th2 Th2

IL-18 IL-12/18 TNF

Reduced host resistance Reduced host resistance Reduced host resistance

Th2 Th2 Th2

LT IL-10

No lymph nodes Colitis

Th2

IL-3 IL-4 IL-5 IL-13 IL-4Ra

Reduced Reduced Reduced Reduced Reduced

Th1 Th1 Th1 Th1 Th1

IL-4/13

Reduced parasite response

Dalton et al., 1993 Huang et al., 1993 Cooper et al., 1993 Sadlack et al., 1993 Magram et al., 1996 Cooper et al., 1997 Wei et al., 1999 Takeda et al., 1998 Paspararakis et al. 1996 Marino et al., 1997 De Togni et al., 1994 Sadl ack et al., 1993 Berg et al., 1995; Wang et al., 1999 Mach et al., 1998 Kopf et al., 1993 Kopf et al., 1993 McKenzie et al., 1998 Cohn et al., 1999 Brombacher et al., 1998 McKenzie et al., 1999

DTH IgE and DTH eosinophils IgE, IL-4, IL-5 BHR

77

Th1

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main phenotypic features of Th1 and Th2 cytokine KO mice are briefly reviewed in Table 1.

3.1. IFN-k KO Impaired activation of phagocytes and defective production of microbiocidal nitric oxide results in reduced host resistance to microbial antigens (Dalton et al., 1993; Huang et al., 1993). The cell-mediated immune response to microbial antigen and chemical irritants is reduced (Saulnier et al., 1995).

3.2. IL-2 KO Surprisingly IL-2 KO mice initially develop normally and have a functional immune system (Sadlack et al., 1993). However, within the first months of life, a severe autoimmune disorder develops (ulcerative colitis and anemia).

3.6. IL-5 KO These mice have reduced eosinophilia in response to nematode infections (Kopf et al., 1996).

3.7. IL-13 KO IL-13 deficient mice have reduced IgE and IL-4 responses (McKenzie et al., 1998). The IL-13 and the IL-4/IL-13 double deficient mouse (McKenzie et al., 1999) as well the IL-4-Ra deficient mouse (Cohn et al., 1999; Brombacher et al., 1999), that has an identical functional phenotype, as the IL-4 Ra chain is required for both IL-4 and IL-13 signaling, demonstrated an essential and novel role of IL-13 in allergic asthma and parasitic disease. The role of IL-13 in the drug hypersensitivity reaction has not been explored, but may open new insights.

3.3. TNF, LTh KO 4. Cytokine transgenic mice These mice confirmed that TNF plays an essential role in microbial resistance and DTH, while LTa is required for the normal development of the lymphoid organs (De Togni et al., 1994; Eugster et al., 1996; Pasparakis et al., 1996; Marino et al., 1997).

3.4. IL-12 KO Mice deficient in IL-12 have impaired IFN-g production and reduced Th1 responses: DTH responses were significantly reduced and IL-4 secretion increased (Magram et al., 1996). IL-18 may in part compensate for the absence of IL-12.

IL-4 (Tepper et al., 1990) and IL-5 (Dent et al., 1990; Tominaga et al., 1991) overexpressing mice may be of special interest as they mimic a Th2 type disorder that may be enhanced by allergens. Using a lung epithelial promotor, IL-5 (Lee et al., 1997), IL-13 (Zhou et al., 1999) and IL-9 (Dong et al., 1999) transgenic mice develop pathologic changes characteristic of asthma and may provide a sensitive model to evaluate the potential efficacy and safety of new drugs. The cutaneous allergic response to dinitrofluorobenzene is significantly increased in IL-5 transgenic mice suggesting their use in predicting the Th1 inducing potential of chemicals/drugs (Nagai et al., 1999).

3.5. IL-4 KO These mice have a normal T and B cell development, but IgG1 and IgE serum levels are reduced. In addition, they mount no antigen-specific IgE responses to the nematode Nippostrongylus brasiliensis and a predominantly Th1 cytokine response (Kuhn et al., 1991; Kopf et al., 1996). A reduced cutaneous delayed-type hypersensitivity to the hapten trinitrochloro-benzene has been demonstrated (Dieli et al., 1999).

5. Second generation transgenic mice A major limitation of the first generation mutant mice is that the gene is either randomly inserted into the genome in the case of transgenic mice, or is completely inactivated as in KO mice. If the targeted gene plays a role in the embryonic development, inactivation may be embryo-lethal or result in abnormal development, as shown for

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example in LTa KO mice, which lack lymph nodes (De Togni et al., 1994). Therefore, strategies were developed to target alterations by using the cre/lox approach (Rajewsky et al., 1996). This implies the insertion of loxP sites on both sides of the gene of interest by homologous recombination (flaxed gene). The lox sites are recognised by the cre recombinase, which cuts the inserted gene segment at the loxP sites. In vivo, the elimination of the targeted gene is performed by mating the flaxed mice with cre transgenic mice. Tissue specificity is achieved by using cre transgenic mice in which cre is expressed under a tissue-specific promotor. This allows, for example, the inactivation of genes in macrophages, lymphocytes, or lung epithelial cells. These tissue-specific KO mice will be interesting tools to investigate cutaneous and pulmonary hypersensitivity reactions. The next step of sophistication is the use of an inducible promoter, such as the tetracyclin (tet) promoter. Administration of tetracyclin in tet – crc transgenic mice allows controlled gene activation or deletion in adult mice. Furthermore, genes can be introduced into the mouse genome by the same technique of homologous recombination. The socalled ‘KO-in’ mice can express human genes, which may useful in certain experimental conditions (Taneja and David, 1998).

6. Mouse models to test drug hypersensitivity The following experimental approaches can be used to test the allergic potential of chemicals/ drugs.

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6.1.2. Restimulation of lymphocytes of local lymph nodes or splenocytes with antigen Determination of proliferation, cytokine transcripts or proteins (RNA, ELISA). 6.2. Delayed-type hypersensiti6ity reaction (DTH) In response to cutaneous challenge of sensitized mice, local oedema and inflammation develops within 24 h. The reaction is driven by Th1 cells and depends on the production of IL-12, TNF and IFN-g. Langerhans cells process the antigen/ chemical, differentiate to mature dendritic cells and migrate from the skin under the influence of IL-1 and TNF to the regional lymph node, where they exert their antigen presenting function, resulting in the recruitment and activation of effector T cells (Kimber et al., 1998a,b). Recently a role for Th2 cells and cytokines has been shown in certain forms of atopic dermatitis (Grewe et al., 1998), demonstrating that the Th1/Th2 paradigm has limitations (Kitagaki et al., 1999). In addition, a clear distinction has to be made between and irritant/toxic vs hypersensitivity reactions, such as croton oil inflammation, which does not need sensitization. A typical protocol is as follows: local challenge by epicutaneous application or intradermal injection (footpad or ear) 10 days after initial immunization by injecting antigen in Freund’s adjuvant (subcutaneously). The footpad or ear swelling is assessed at 24 and 48 h after local challenge with a micrometer. This can be combined with analysis of the response in the regional lymph node (weight, cell number, proliferation, cytokine release).

6.1. Systemic immune response after immunisation 6.3. Bronchial hyperreacti6ity (BHR) The antigen is injected parenterally with or without an adjuvant. Depending on the choice of adjuvant, a Th1 (Freund’s complete adjuvant) or Th2 response (Alum) is favoured.

6.1.1. Determination of antibody response Typically (IgG isotypes and IgE levels) IgG2a and IgG2b antibodies are induced in Th1 responses, while IgG1 and IgE are produced in Th2 responses.

For the investigation of respiratory hypersensitivity reactions, ovalbumin is commonly used, although other proteins induce identical responses (Morone, 1998; Wills-Karp, 1999). Sensitized mice challenged with the same antigen develop acute BHR, increased IgE levels, infiltration of eosinophils and mucus overproduction, which mimics bronchial asthma in man. The role of Th2 type cytokines for the development of BHR is

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established. Recent data suggest that beside IL-4 and IL-5, IL-13 plays an essential role in BHR (reviewed in Wills-Karp, 1999). Therefore, in both dermal contact and respiratory hypersensitivity reactions Th cells play a central initiating role. While the recognition is class I- and II-restricted and mediated by T cells, a role of CD1restricted T cells in allergic reactions has been suggested (Spinozzi et al., 1998). This model can be applied to any antigen or hapten to test for potential respiratory hyperreactivity and a short outline of the experimental protocol is as follows: mice are first immunized with the antigen (or hapten coupled to protein) in alum (two weekly injections) followed by respiratory challenge (intratracheal or nasal application of antigen or aerosol challenge.) A typical response to ovalbumin in mice sensitized to ovalbumin comprises of accumulation of mononuclear cells and eosinophils in peribronchial tissues and mucus hypersecretion. Sensitized mice challenged with saline instead of ovalbumin do not develop any microscopic signs.

7. Non-cytokine factors involved in allergic responses Beside cytokines and chemokines, other factors play a role in allergic responses. Transgenic mice with inactivated IgE, CD23, FcoR, lipooxygenase, cyclooxygenase, stem cell factor (SCF), might be useful in further investigations. In addition, mice that lack mast cells (w/wv), NK cells, T cells, B cells or any other effector cells of the immune system could be used.

8. Conclusion Transgenic mouse models are potentially useful models to unravel the pathophysiological mechanisms of drug hypersensitivity. As cytokines are key regulators of immune responses, the use of mice with overexpression or deletion of cytokine genes are likely to be useful. Recent highlights were obtained from IL-4Ra KO and IL-13 KO mice demonstrating the criti-

cal role of IL-13 in the development of respiratory hyperreactivity (Wills-Karp et al., 1998). Mice overexpressing Th2 cytokines, such as IL-4, IL-5 and IL-13, are likely to be of interest to design sensitive models of allergic reactions. Because the development of allergic/hypersensitivity reactions is modulated by genetic predisposition in mice as in man, allergens cause reactions in only a fraction of exposed individuals. Therefore, the development of predictive models of hypersensitivity is difficult as previously discussed (Choquet-Kastylevsky and Descotes, 1998). In conclusion, animal models only partly mirror the reactions seen in man. Extensive investigations are therefore required prior to making any recommendations on the potential predictive value of murine models in man.

Acknowledgements This work was supported by MRC grant 415 38 Harry Crossley Fund 43587 Cape Town and NRF Pretoria.

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