Beyond inflammation: tolerance, immunotherapy and more

ARTICLE

A well regulated inflammatory reaction comprises a quick elicitation phase followed by an effective elimination of the noxious agent and subsequent healing of the lesion. For such a successful inflammatory reaction to occur, strong pro-inflammatory mechanisms must be in place. In recent decades, pro-inflammatory mechanisms have been thoroughly investigated in molecular and cellular terms and in animal models of human disease.

Besides pro-inflammatory mechanisms, however, inborn and acquired anti-inflammatory mechanisms are also required to maintain the integrity of an organism, especially at the interface to the environment, i.e. in the skin and in the respiratory and gastrointestinal tracts. It is absolutely essential to prevent unnecessary inflammatory reactions to foreign substances that do not endanger the respective organism, to spatially and/or temporally confine inflammatory reactions once elicited, and to guarantee down-regulation and restitutio ad integrum. Glucocorticoids are the best-known players in physiological as well as in pharmacological anti-inflammation [1]. Besides glucocorticoids, some cytokines have been ascribed anti-inflammatory activities, among them interleukin (IL)-4, transforming growth factor (TGF)-ß, and IL-10. However, it is easily predictable that these findings are only the tip of the iceberg. Chronic inflammatory diseases and allergies may not only be due to an aberrant overwhelming pro-inflammatory reaction, but might also be caused by a dysfunction or failure of anti-inflammatory mechanisms. This notion was only very recently confirmed by the still unpublished finding by Peter Souef and colleagues that certain mutations (38A) in Clara cell protein 16, a novel anti-inflammatory molecule of bronchial epithelium, are associated with a tremendous increase in the risk of developing asthma [2-4]. Interestingly, Clara cell protein 16 inhibits both interferon-gamma (IFN-gamma) production and biological activity [3] indicating that pro-inflammatory reactions are ­ by necessity ­ closely interconnected with counter-regulatory anti-inflammatory pathways.

Vis-à-vis these non-specific anti-inflammatory mechanisms, the functional and cellular mechanisms active in preventing immune-mediated inflammation have been studied for a long time under the acronym "tolerance". After a period of neglect in the late eighties and early nineties, tolerance phenomena and alongside suppressor T cells and suppressor macrophages [5, 6] mediating them, have again attracted attention since a better understanding of tolerance is now thought to be the basis of improvements in immunotherapy of autoimmune diseases, allergies, and cancer. In this review, we will discuss tolerance and immunotherapy; beyond this, the advent of immunoprophylaxis [7] might revolutionise current concepts in the handling of genetically co-determined immune-mediated diseases.

Central tolerance

Tolerance to self-antigens is the absolute pre-requisite for the undisturbed functioning of the immune system. Problems in establishing or maintaining self-tolerance will lead to autoimmune phenomena and in the worst case to autoimmune diseases such as lupus erythematodes, scleroderma, autoimmune bullous diseases, Goodpasture's syndrome, Wegener's granulomatosis, and ­ presumably ­ multiple sclerosis. The mechanisms of self-tolerance have been well analyzed; unfortunately, clarification of the causes and pathogenesis of most of the autoimmune diseases has lagged behind. In this section, we will give a short overview of the mechanisms active in establishing self-tolerance.

Depending on whether tolerance is induced in primary or secondary lymphoid organs, it is called central or peripheral tolerance, respectively. Since little is known about B cell tolerance and B cell tolerance might be dependent on T cell tolerance to the same antigens, central tolerance is often equated with negative selection during thymic education. While peripheral tolerance [8] may also be directed to non-harmful environmental agents such as foods, pollens and cutaneous contact substances, and may even be induced in an organism already sensitized (hyposensitisation), central tolerance mechanisms are exclusively devoted to establish self-tolerance.

Thymic education of bone marrow-derived precursor T cells (thymocyte) comprises several steps including migration to the thymus, differentiation with expression of T cell receptor (TCR) molecules and TCR complex molecules such as CD3, and CD4 or CD8, and positive or negative selection. Positive selection is a process in which a low affinity interaction between the TCR complex of a thymocyte and a self-peptide self-MHC complex on a thymic antigen-presenting cell leads to activation, proliferation, and further maturation of the thymocyte involved. Surprisingly, self-peptides are required for positive selection, however they seem to play a rather non-specific role in these low affinity interactions. Failure of a thymocyte to express a functional TCR or of a functional TCR complex to recognize self-MHC molecules leads to a lack of positive selection ultimately resulting in the intra-thymic death of the thymocyte involved. On the contrary, negative selection is a process in which a high affinity interaction between the TCR complex of a thymocyte and a self-peptide self-MHC complex on a thymic antigen-presenting cell leads to induced cell death, i.e. apoptosis of the thymocyte involved. Apoptosis of thymocytes recognizing self-peptide self-MHC molecular complexes with high affinity results in the elimination of self-reactive T cell clones (clonal deletion), i.e. self-tolerance. The fundamental difference, however, between thymocytes and mature T cells, i.e. induction of apoptosis by antigen recognition in the former and of activation and expansion in the latter, remains to be elucidated. Presumably, intracellular signaling events differ in thymocytes and mature T cells; for example, CD3 does not seem to be coupled to the TCR heterodimers in immature thymocytes.

Peripheral tolerance

In contrast to central tolerance, the mechanisms for the induction of peripheral tolerance are multifold [9] and apply both to organisms still naive or already sensitized towards a particular antigen. In the latter situation, tolerance induction is a goal much harder to achieve since it must circumvent immune activation in an organism eagerly prepared to react. Tolerance induction in a sensitized organism (hyposensitisation), however, is the clinical situation in which immunotherapy is most often required. Furthermore, peripheral tolerance mechanisms guarantee tolerance induction towards self-antigens not represented in the thymic microenvironment as well as to common environmental antigens such as food and contact allergens. Peripheral tolerance is either induced by directly inhibiting activation of antigen-specific T cells, a process also called anergy induction, by deleting antigen-specific T cells through activation-dependent programmed cell death, or by activating antigen-specific regulatory "suppressor" T cells.

Anergy is a state of a T cell in which it cannot be activated by the usually appropriate signals. In vitro, this state may last for several weeks; in contrast, it is not clear whether anergy occurs in vivo at all and for which period of time it might ­ if any ­ persist in the intact organism. Thus, the contribution of anergy to peripheral tolerance is not yet well defined. Anergy is thereby due to defective antigen recognition and signaling processes on naive or memory T cells; and it has mostly been investigated in CD4⁺ helper T cells. Interestingly, however, it has been shown that memory T cells are much more easily anergized than naive T cells in vitro and this may raise some hope for improvements in immunotherapy of established autoimmune or allergic diseases. Two signals are needed for the activation of an antigen-specific T cell, i.e. antigen recognition and signaling through the TCR complex (signal 1), and interactions of and signaling through co-stimulatory molecules (signal 2). Anergy induced by a defective signal 2 has been extensively studied. The most important pair of co-stimulatory molecules is CD28 on the T cell and B7-1/B7-2 (CD80/CD86) on an antigen-presenting cell. B7 molecules are constitutively expressed on most dendritic cells known to excel at activating naive T helper cells to differentiate into mature Th1 cells, while they occur only at a low density on all other resting antigen-presenting cells such as macrophages which need to be activated by IFN-gamma to express functionally active numbers of co-stimulatory molecules. Thus, if macrophages that have not been pre-activated by pro-inflammatory cytokines present an antigen to a T cell, signal 1 will be delivered while signal 2 will be defective leading to anergy of the T cell involved. Whether special antigen-presenting cells or special activational states of antigen-presenting cells exist that particularly favor anergy induction in T cells and what role the presumptive down-regulatory T cell co-stimulatory molecule CTLA-4, a close homologue of CD28, might play is currently a matter of debate [10] and will be discussed later in this review. Anergy may also be induced when signal 1 is defective while signal 2 is correctly delivered. Signal 1 may be defective when an antigen is presented that is subtly altered compared to the antigen used for immunization or when the TCR is downregulated. Altered peptide ligands allow only low affinity interactions with the TCR complex on the antigen-specific T cell which does not suffice for correct signaling through the TCR. Anergy induction by a defective signal 1 is one of the basic mechanisms for tolerance induction during tolerogenic peptide immunotherapy.

Tolerance induction by activation-dependent programmed cell death is less well established than anergy induction. As already discussed, central tolerance depends on negative selection followed by programmed cell death. Whether activation of the respective T cells is a prerequisite of this process, however, is presently not clear. Recent results suggest that high affinity interactions between thymocytes and thymic antigen-presenting cells depend on the proper activating function of a co-stimulatory molecule called CTLA-4 on the T cells. This has been deduced from the high affinity of CTLA-4 to its ligands CD80/CD86 that exceeds that of CD28 by a factor of 10-100 and from the finding that a fatal lymphoproliferative syndrome develops in CTLA-4-deficient mice while results concerning the positive or negative function of CTLA-4 in T cell activation are rather controversial.

In peripheral tolerance induction, evidence for a role of activation-dependent programmed cell death is rather circumstantial. Lupus erythematosus is a prime human autoimmune disease, and several mouse models of this disease have been identified including the NZB and NZBxNZW F1 mice, as well as the BXSB, lpr (lymphoproliferation), gld (generalized lymphoproliferative disease), and viable motheaten strains. In both the lpr and gld homozygous mice, activation-dependent cell death of CD4⁺ T cell is defective due to mutations in the death proteins Fas and Fas ligand, respectively. Unfortunately, Fas or Fas ligand abnormalities have not been found in true human lupus erythematodes raising some questions about the actual involvement of activation-dependent programmed cell death in establishing or maintaining peripheral self-tolerance in humans.

In general, induction of tolerance is a dose-dependent phenomenon. High as well as low doses of antigen are able to induce peripheral tolerance under certain conditions. High zone tolerance is thought to be mediated by anergy induction and activation-dependent programmed cell death while low zone tolerance is thought to be mediated preferentially by induction of antigen-specific regulatory "suppressor" T cells. Concerning tolerance induction by regulatory T cells, two pathways have gained importance in recent years, i.e. oral tolerance [11] and contact tolerance [12], and these will be discussed in the following sections in greater detail.

Oral tolerance

Oral tolerance is a state of specific immunological hyporesponsiveness towards a previously fed antigen. Oral tolerance was first shown to occur in hen egg protein-induced anaphylaxis and hapten-mediated contact dermatitis. Interestingly, these early models showed oral tolerance induction in both Th1- and Th2-mediated immune reactions. In the meantime, however, it has become clear that oral tolerance is primarily induced in Th1-associated disease models and human diseases such as experimental allergic encephalomyelitis (EAE) and multiple sclerosis (MS), collagen-induced arthritis and rheumatoid arthritis, and diabetes in the non obese diabetic mouse (NOD) or type I diabetes in humans. In light of the fact that all immune reactions in the gut are skewed towards a Th2 response, this may actually be no great surprise. While the mechanisms, i.e. antigen-presenting cell differentiation and cytokine milieu, responsible for this preferential Th2 response have not yet been well elucidated, it is well known that the major Th2 cytokine, i.e. IL-4, is the major suppressive cytokine for Th1 activation. Thus, it is conceivable that once antigen-specific memory Th2 cells have been induced, development of Th1 cells specific for the same antigen must be severely impaired. In addition to the Th2 subset, a novel T helper cell subset, the Th3 cell subset, has been identified in the gut [13]. Th3 cells are characterized by preferential expression and synthesis of the anti-inflammatory cytokine transforming growth factor (TGF)-ß. TGF-ß plays an important role in the local immune system in the gut since it serves as an isotype switch factor for mucosal IgA production. The anti-inflammatory properties of TGF-ß have been clearly demonstrated in TGF-ß-deficient mice showing inflammation in several organ systems. Th3 cells have been induced through oral administration of antigen in EAE and in MS patients [14] and may have a suppressive role in experimental inflammatory colitis. Th3 cells specific for myelin basic protein (MBP) one of the antigens used for immunization in EAE have been cloned and further analyzed. Th3 cells use IL-4 as their prime growth and differentiation factor although they do not express it. IL-10 and TGF-ß itself may also support development of Th3 cells. Th3 clones were found not to differ from Th1 or Th2 cells in TCR usage, MHC restriction, or epitope recognition. However, Th3 clones do not proliferate well. This may account for the relative resistance of Th3 cells to anergy induction/deletion by high doses of antigen. Thus, established Th1 disease could possibly be broken by first anergizing/deleting antigen-specific Th1 cells by administration of high doses of antigen and afterwards inducing long-lasting oral tolerance through activation of the surviving Th3 cells. However, this hypothesis has not yet been tested. On the contrary, it has been shown that tolerance induction and treatment of established disease is not easily possible by oral administration of an antigen, but that the antigen must be coupled to special antigen-presenting cells that are administered via the i.v. route [15]. In concordance with these findings and considerations, human trials for treatment of autoimmune diseases by the induction of oral tolerance alone have so far failed, despite the fact that antigen-specific Th3 cells were obviously induced.

Contact tolerance

In contrast to the mucosal surfaces, immunization via the skin normally leads to strong Th1 responses, i.e. to delayed type hypersensitivity (DTH) or contact dermatitis. Contact dermatitis is usually induced by small molecules, haptens, that bind to self proteins to yield strong antigens. While DTH reactions are caused by the induction of CD4⁺ effector T cells secreting cytokines intended to activate macrophages eliminating the causative agent, contact sensitivity differs from this general model in several aspects [16]. Although MHC class II⁺ Langerhans cells are induced to emigrate from the epidermis and enter the regional lymph node, it is not the CD4⁺, but the CD8⁺ T cell population that is preferentially activated [17]. It has been shown in MHC class II-deficient mice that contact sensitivity is strongly enhanced while MHC class I-deficient mice fail to mount a contact sensitivity (CS) response. In CD4-deficient mice, contact sensitivity is impaired indicating an additional regulatory role for CD4⁺ T cells in contact sensitivity. The predominance of CD8⁺ effector T cells [18] is reflected in the effector phase of contact dermatitis by the occurrence of spongiosis; spongiosis is the histological correlate of a cytolytic attack of CD8⁺ T cells against MHC class I⁺ keratinocytes presenting antigen. Most haptens, however, are ubiquitously occurring environmental or occupational substances that normally do not elicit contact sensitivity. This may be due to the low concentration of the haptens normally encountered on the skin that could favor low zone tolerance rather than sensitization. Careful titration of contact sensitizers in mouse models of contact sensitivity has proven that sensitization occurs in a medium range of hapten concentration while high and low concentrations of hapten induce contact tolerance. Mechanisms of low zone contact tolerance have been further elucidated and it has been shown that low zone contact tolerance is mediated by CD8⁺ T cells secreting Th2-associated cytokines IL-4 and IL-10 [12] and these results have been confirmed in mouse models of UVB-induced contact tolerance [5,6]. Unfortunately and in unwanted concordance with oral tolerance, contact tolerance could not yet be induced in already sensitized organisms so that the question of the therapeutic applicability of the contact tolerance concept in a clinical situation remains unresolved. As in oral tolerance, it may be hoped that specialized antigen-presenting cells might be able to break an established sensitization.

Antigen-presenting cells and tolerance induction

Antigen-presenting cells (APC) are required both for the induction of T cell activation as well as tolerance, especially in the case of CD4⁺ T cells which need contact to MHC class II molecules. The APC that mediate Th1 induction are mature dendritic cells and IFN-gamma-induced, classically activated macrophages as well as B cells. These APC express high levels of MHC class II molecules as well as co-stimulatory molecules such as CD86. How differential induction of Th1, Th2, and Th3 subsets is regulated by APC is not yet resolved. It is also not clear which APC can effectively deliver a tolerogenic signal to T cells. In this situation, a concept of alternative immunological activation of APC, especially macrophages has been proposed [19]. Alternative activation of APC is mediated by cytokines such as IL-4, IL-10, and TGF-ß as well as by glucocorticoids. Alternatively activated macrophages and, less so, alternatively activated immature dendritic cells have been shown not only to be deactivated with respect to pro-inflammatory cytokine secretion, but to actively express anti-inflammatory molecules and functions. We have shown recently that alternatively activated macrophages express novel antigens recognized by monoclonal antibodies [20-27] and occur in vivo in chronic inflammatory reactions such as rheumatoid arthritis [28] and psoriasis [29]. Alternatively activated macrophages furthermore actively promote healing by expression of angiogenic factors [30] and suppress mitogen-induced lymphocyte proliferation by yet unknown mediators [31]. In addition, we have been able to clone a novel CC-chemokine, alternative macrophage activation-associated CC-chemokine (AMAC)-1 [32], which attracts naive T cells [33]. How are alternatively activated macrophages involved in tolerance induction? While the antigen-presenting cells mediating low zone contact tolerance are still elusive, UVB-induced contact tolerance has been shown to be mediated by alternatively activated macrophages [6, 34, 35]. By secreting AMAC-1, alternatively activated macrophages may attract CD4⁺ naive T cells that are induced to differentiate into suppressor/inducer T cells by TGF-ß derived from the alternatively activated macrophages. In turn, these suppressor/inducer CD4⁺ T cells which are defective in IL-2 receptor expression induce naive CD8⁺ T cells to differentiate into tolerogenic Th2-like CD8⁺ suppressor lymphocytes, the above mentioned effector cells of contact tolerance.

Specific immunotherapy

Tolerance induction utilizing the oral or contact routes has primarly been shown to be effective in animal models of Th1-associated diseases, but has not yet been successfully introduced as a therapeutic approach for established human autoimmune or allergic diseases [13]. In contrast, Th2-associated atopic diseases such as atopic rhinoconjunctivitis and allergic asthma have been successfully treated by allergen-specific immunotherapy (SIT) since 1900. SIT is widely used today throughout the USA and continental Europe and is thought effective and safe when clear guidelines are followed for allergen extract preparation and standardization, regarding indications and contraindications, and in securing patient compliance [36]. While it was originally hypothesized that SIT ­ similar to vaccination against viral disease ­ might induce neutralizing antibodies against the unknown agent causing hayfever, later researchers have claimed that SIT might exert its effects by inducing blocking antibodies against IgE. At present, it is generally thought that SIT might preferentially influence the T helper cell compartment by inducing a shift from Th2 predominance to Th1 predominance in the immune reaction toward a specific allergen. This assumption has been corroborated in numerous studies showing that SIT may suppress allergen-dependent proliferation of allergen-specific T cells, reduce FcepsilonRII expression on B cells, enhance IFN-gamma secretion by allergen-specific T cells, and may in fact induce development of allergen-specific Th0 and Th1 cells [37, 38]. Recently, it has been more and more recognized that Th1-like CD8⁺ suppressor T cells (Tc1) that secrete considerable amounts of IFN-gamma are the most potent tolerizing immunoregulatory cells induced by SIT [39, 40]. This latter finding is among those now being exploited to design optimized SIT strategies.

In general, despite the well documented clinical effects, there is ample room for improvement of the traditional methods used in SIT including routes and formulations. In order to circumvent subcutaneus application of allergen insuing regular weekly to monthly visits of patients in the allergologist's office, sublingual and oral application of allergen have been explored [41-43]. While some studies indicate that sublingual SIT may also be effective, oral SIT has not been well established and, in addition, uses huge amounts of allergen. For theoretical reasons, however, the intradermal route still seems preferable. In contrast to mucosal sites, it has been shown that Th2 cells cannot home to the skin rendering the skin an immunologically previleged site for Th1 reactions [44]. Regarding formulations [45], allergen extracts are usually applied as aqueous solutions, or adsorbed to depot adjuvants such as aluminium hydroxide. While aqueous preparations carry a higher risk of anaphylactic reactions, aluminium hydroxide is known to be a potent Th2-inducing agent and to stimulate IgE synthesis. In so far, SIT is in search of better depot adjuvants that support preferential development of Th1 reactions. Adjuvants that show these characteristics are MPL^® and immunomodulatory DNA sequences (ISS/ODN); ISS thereby exert their effects via induction of interferon-alpha, ß expression and secretion [46].

And more? From epitopes to genetic tolerization to immunoprophylaxis

With the advent of molecular cloning of the allergens relevant in atopic disease, SIT is about to make further progress. Not only will it be possible to produce better standardizable SIT products with the recombinant protein allergens. Molecular techniques are also currently being used to decipher the epitope structure of these allergens and to subdivide it into anaphylactic IgE-binding B cell epitopes and non-anaphylactic T cell epitopes [47]. Immunization with T cell epitope peptides is deemed to be safer than SIT with the intact protein and is thought to be able to induce the necessary Th2-to-Th1 shift especially in case of slightly altered peptide ligands. An essential obstacle to broad applicability of immunization with T cell epitope peptides is the MHC-restriction of the T cell response. Detailed analysis of the house dust mite-reactive T cell repertoire has shown that MHC class II restriction is heterogeneous, involving HLA-DP, -DQ, and -DR molecules, and that multiple T cell epitopes are recognized [36]. Allelic polymorphism and inter-species variation of house dust mite allergens pose additional problems [48, 49]. On the other hand, there is evidence for a bias in T cell receptor gene usage possibly alleviating the problems caused by MHC restriction [36]. Thus, SIT with major T cell epitopes may well be a promising approach that should be further elucidated.

Even more promising, however, is tolerance induction by genetic vaccination with cDNA of cloned allergens and this therapeutic approach may become the ultimate form of SIT [40, 46, 50-53]. Genetic SIT has been shown in animal models of atopic disease not only to be able to protect the non-sensitized organism against sensitization [40], but to substantially reduce preexisting allergen-specific IgE plasma levels [50]. "Naked" plasmid DNA encoding an antigen is readily taken up by keratinocytes, fibroblasts, muscle cells and other cell types including antigen presenting cells when injected intradermally or intramuscularly. These naturally "transfected" cells express and synthesize the encoded antigen in considerable quantity and the immune system easily mounts a humoral as well as cellular immune response against the respective antigen. Interestingly, the antibodies produced are predominantly of the IgG2a subclass associated with B cell help by Th1 cells while no IgE is made. Th1 skewing by genetic SIT is presumably due to plasmid encoded bacterial-derived ISS. On the cellular side, allergen-specific Th1-like CD8⁺ T cells (Tc1) have been shown to predominantly mediate allergen-specific tolerance induction [40]. Allergen-specific Tc1 predominance in the cellular immune response induced by genetic SIT is not surprising since intracellular expression, synthesis, and processing of allergen is coupled with peptide antigen presentation in the context of MHC class I molecules exclusively interacting with TCR plus CD8. Compared to SIT with T cell epitope peptides, genetic SIT offers profound advantages. Since genetic SIT can be performed with plasmids containing full length cDNAs of relevant allergens, MHC restriction will pose no problem. Since no free antigen is injected and only processed antigen is produced, genetic SIT should perform to highest safety standards, even for highly anaphylactic allergens such as latex Hev b 5 [53]. Since intracellular plasmids may persist for long time periods, weekly to monthly booster injections will not be necessary adding substantially to the ease and cost effectiveness of genetic SIT and securing patient compliance. When potential biohazards of genetic SIT, especially cancerogenicity and loss of function caused by integration of plasmid DNA into the human genome, can be effectively excluded, genetic SIT may become the upshot in molecular therapy paving the way for broad acceptance of somatic gene therapy.

SIT, even as genetic SIT, carries one severe disadvantage, i.e. specificity. Obviously, specificity in combination with the huge number of possible allergens precludes preventive treatment of individuals genetically and/or environmentally at risk of developing severe atopic disease. Recently, it has been shown, however, that SIT in monosensitized asthmatic patients may prevent the development of new sensitizations in all treated individuals [54]. Even if concepts such as cross epitope suppression and bystander tolerance [13] designed to balance epitope spread phenomena may find more experimental and clinical support in the future, it would take a long time to develop SIT formulations that might guarantee broad and longlasting tolerance toward the whole allergen spectrum. Therefore, development of immunoprophylactic strategies for atopic diseases in the form of antigen-independent, non-specific immunotherapies is mandatory. Researchers and pharmaceutical companies, however, in the short term have preferentially turned to master more clearly defined routes to anti-allergic drug development even if this might mean intermittent oblivion of causative therapeutic approaches. Recent progress in symptomatic treatment of atopic disease, especially asthma, has thus been achieved at the far end of the inflammatory cascade, e.g. by the development of 5-lipoxygenase inhibitors and leukotriene receptor blockers. In addition, humanized anti-IgE antibodies blocking Fc epsilonRI and II binding or IgE crosslinking without mediating mast cell mediator release are already tested in clinical trials. While these antibodies will give only symptomatic relief subsiding dependent on their half-lives, immunization with appropriate IgE mimotopes ­ based on the same principle mechanism ­ might secure longlasting therapeutic success via therapeutically active anti-IgE auto-antibodies, this being an appealing new form of non-specific immunotherapy [55]. Since better hygiene and fewer severe bacterial and viral infections are thought to play a role in the ever increasing incidence of atopic diseases in western countries, vaccination with Th1-inducing infectious agents including mycobacteria are discussed as non-specific, immunoprophylactic measures in atopic infants ("Give us this day our daily germs") [56-60]. Soluble IL-4 receptor molecules or other pharmacological IL-4 or IL-4-receptor antagonists may even come closer to correcting the basic defect in atopy and might reverse the genetically determined and environmentally triggered Th2 preponderance [61]. If given in the atopy-sensitive phase of the life cycle, i.e. newborn to early childhood, this kind of treatment may turn out to be true immunoprophylaxis of atopy by non-specific immunotherapy.

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