Perspectives on Mucosal Vaccines: Is
                                     Mucosal Tolerance a Barrier?
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5634                                                                 BRIEF REVIEW: MUCOSAL VACCINES AND TOLERANCE

The Journal of Immunology                                                                                                 ...
5636                                                                 BRIEF REVIEW: MUCOSAL VACCINES AND TOLERANCE

The Journal of Immunology                                                                                                 ...
5638                                                                                           BRIEF REVIEW: MUCOSAL VACCI...
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Mucosal Tolerance a Barrier? Perspectives on Mucosal Vaccines: Is


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Mucosal Tolerance a Barrier? Perspectives on Mucosal Vaccines: Is

  1. 1. Perspectives on Mucosal Vaccines: Is Mucosal Tolerance a Barrier? This information is current as Jiri Mestecky, Michael W. Russell and Charles O. Elson of October 20, 2010 J. Immunol. 2007;179;5633-5638 References This article cites 64 articles, 27 of which can be accessed free at: Downloaded from on October 20, 2010 4 online articles that cite this article can be accessed at: es Subscriptions Information about subscribing to The Journal of Immunology is online at Permissions Submit copyright permission requests at Email Alerts Receive free email alerts when new articles cite this article. Sign up at The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 9650 Rockville Pike, Bethesda, MD 20814-3994. Copyright ©2007 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606.
  2. 2. OF JOURNAL IMMUNOLOGY THE BRIEF REVIEWS Perspectives on Mucosal Vaccines: Is Mucosal Tolerance a Barrier?1 Jiri Mestecky,2*†§ Michael W. Russell,‡ and Charles O. Elson*† Mucosal administration of Ags induces specific Abs in ex- from mucosal surfaces, extensive studies based on the exploita- ternal secretions and systemic unresponsiveness termed tion of this principle have been conducted on the design of vac- oral or mucosal tolerance. The dominant response depends cines given by different mucosal routes (1, 2, 4 – 6). However, on the species studied, the nature, dose, frequency, route of despite its physiological and pharmacological attractiveness, Ag application, and the use of adjuvants. The temporal there have been few concerted efforts to develop mucosal vac- sequence of Ag exposure determines the quality of the en- cines. Such vaccines offer certain advantages, including the suing immune response; although initial mucosal Ag ex- stimulation of humoral responses at the site of entry of most posure results in systemic T cell hyporesponsiveness, pre- infectious agents, the simplicity of administration without the need for sterile needles and syringes, and the potential for existing systemic responses are refractory to the tolerizing prompt mass immunization. However, these advantages are effects of mucosal Ag encounter. Mucosal and systemic hu- Downloaded from on October 20, 2010 sometimes questioned on important immunologic grounds (4, moral responses may be induced concomitantly with di- 7). Due to the relatively low rates of absorption of Ags from minished systemic T cell responses, thereby permitting Ab- mucosal surfaces and their degradation by proteolytic enzymes, mediated containment of mucosal Ags without large doses of Ags may be required to induce the desired im- stimulation of the systemic immune compartment. B cell mune responses. This further prompts a frequently asked ques- Ig isotype switching and differentiation toward IgA pro- tion concerning the possible induction of oral (mucosal) toler- duction share common regulatory mechanisms with the ance by mucosal vaccines: can extended and repeated mucosal suppression of T cells. Optimization of mucosal vaccina- application of Ags decrease systemic immune responses and is tion strategies has the potential for enhancing protective this mucosal tolerance of significant importance in the devel- immune responses and suppressing systemic responses to opment and application of mucosal vaccines? In this brief re- autoantigens desirable for the treatment of autoimmune view, we have attempted to critically analyze current thoughts diseases. The Journal of Immunology, 2007, 179: 5633– concerning this topic with emphasis on its impact for the future 5638. of mucosal vaccine development. Basic observations O ne of the major functional aspects of the mucosal im- mune system can be seen as limiting the access of en- Repeated oral ingestion of large doses of Ags or haptens conju- vironmental Ags such as food and airborne materials gated to suitable carriers results in decreased or totally abrogated as well as commensal microbes to the systemic immune com- responsiveness to a subsequent systemic immunization with the partment and, hence, reducing the magnitude of systemic im- same Ag (for reviews see Refs. 8 and 9). Such oral tolerance has mune responses to such frequently encountered Ags. In view of been extensively studied in animal models, including mice, rats, the enormous antigenic challenge encountered on a daily basis, and guinea pigs; other species appear to be less prone to the particularly in the gastrointestinal tract, the survival advantage development of systemic unresponsiveness. The target of oral of effectively controlling Ag uptake and regulating the ensuing tolerance is mainly the T cell compartment and is revealed by immune responses is clear. altered delayed-type hypersensitivity (DTH)3 reactions, dimin- The induction of specific Abs at both the site of Ag stimula- ished in vitro T cell proliferation, the induction of various pop- tion and at remote mucosal tissues has been well documented ulations of regulatory T cells, and the production of suppressive (for reviews see Refs. 1– 4). Because such Abs confer protection cytokines (8, 9). Multiple mechanisms have been observed, in- against mucosal infectious agents or limit the uptake of Ags cluding deletion and/or anergy of Ag-specific T cells and the *Department of Microbiology and †Department of Medicine, University of Alabama at 1 This work was supported by the National Institutes of Health Grants U19 AI28147, Birmingham, Birmingham, AL 35294; ‡Department of Microbiology and Immunology DE06746, DK071176, DK060132, and Czech Government Grants VZ MSM 0021 and Department of Oral Biology, University at Buffalo, State University of New York, 62081 and KJ 586206106. Buffalo, NY 14214; §Department of Microbiology and Immunology, Charles University, 2 Address correspondence and reprint requests to Dr. Jiri Mestecky, University of Alabama Prague, Czech Republic at Birmingham, Department of Microbiology, Box 1, 845 19th Street South, Birmingham, Received for publication August 9, 2007. Accepted for publication August 28, 2007. AL 35294-2170. E-mail address: 3 The costs of publication of this article were defrayed in part by the payment of page charges. Abbreviations used in this paper: DTH, delayed-type hypersensitivity; CT, cholera toxin; This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. CTB, cholera toxin B; KLH, keyhole limpet hemocyanin; LT, labile toxin; pIgA, poly- Section 1734 solely to indicate this fact. meric IgA. Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00
  3. 3. 5634 BRIEF REVIEW: MUCOSAL VACCINES AND TOLERANCE induction of T regulatory cells, and these mechanisms are not in the average American diet at doses of 500 mg per day mutually exclusive (8 –11). In most reports, potential suppres- ( 180g/year), persist throughout childhood, adolescence, and sion of Ab responses was not extensively studied. An exception early adulthood, with some decrease in later life. Importantly, may be the apparent suppression of IgE responses to environ- the levels of Abs to food Ags in sera and external secretions dis- mental allergens. The induction of secretory IgA or IgG Abs play considerable mutual independence, indicating marked dif- that would successfully compete with IgE Abs for a given aller- ferences in maturation and regulation of both the magnitude gen or the selective suppression of IgE Ab responses are at the and the Ig isotype of the response within the systemic and mu- heart of these efforts. Marked differences in the efficacy of oral cosal compartments (19). immunotherapy may be ascribed to the animal species and to It is important to understand the context in which the mu- the type and purity of allergens, the Ag delivery or adjuvant sys- cosal immune system operates. In addition to the large quanti- tems, and the doses used (9, 12). ties of food Ags ingested daily, the intestine is colonized by a The ability to prevent or even to reverse experimental T cell- complex microbiota, the members of which are just beginning mediated autoimmune diseases such as experimental allergic to be identified (23). The total numbers are estimated at 100 encephalomyelitis, collagen type II-induced arthritis, or auto- trillion organisms per person, which represents 10-fold more immune diabetes in animal models (4, 8, 9) has led to renewed microbial cells than human cells present in the body (24). This interest in applying the principles of oral tolerance to the ther- is truly an enormous challenge of bacterial Ag and adjuvants for apeutic treatment of autoimmune diseases (e.g., multiple scle- the mucosal immune system, and it is present for the lifetime of rosis and rheumatoid arthritis) in humans. As explained below, the host. The mechanisms by which most of us live in peace these efforts have not been encouraging (9). This limited effec- with this microbiota are just beginning to be understood. It is tiveness in humans raises questions concerning the reasons for clear that the host is responding to this microbial challenge, as such a remarkable difference in clinical outcomes compared witnessed by the large numbers of lymphoid cells present in the Downloaded from on October 20, 2010 with results from the animal models. Although the species, age, intestine and the 3–5 g of IgA produced per day in the normal and gender under investigation as well as the type and dose of human (25). This complex microbial ecosystem, our “other Ag, the frequency of exposure, the use of adjuvants and Ag de- self”, is in dynamic communication with the intestinal epithe- livery systems, and other parameters may greatly influence the lium and with the innate and adaptive lymphoid cells present in outcome, we propose that prior exposure to the particular Ag the intestine (26). This is the context into which a mucosal vac- plays a decisive role; i.e., once an immune response is elicited cine or tolerogen is being introduced. Much of the difficulty that mode of response predominates whenever the same Ag is experienced at inducing mucosal immunity or tolerance at will encountered in the future. to a given Ag is likely due to our relative ignorance of this mi- crobiota and the resulting host-microbial interactions that are Does mucosal tolerance exist in humans? occurring continuously at the mucosal surface. The number of studies addressing this point is surprisingly lim- Despite the large cellular and humoral response to the micro- ited despite its enormous medical importance (8 –10). Lowney biota, it is commonly thought that the host is immunologically (13, 14) observed the reduced incidence and intensity of cuta- tolerant to these bacteria (27). Against this idea is the active neous sensitization in approximately one-half of humans first adaptive immune response to the microbiota that is present in given an oral application of 2,4-dinitrobenzene in acetone on mice; this response is compartmented to the intestine, i.e., there the oral mucosa. is abundant IgA to microbial Ags in the intestine but no serum It is difficult to identify an experimental Ag never previously IgG Abs or systemic T cell responses to these same Ags (28 –30). encountered in humans and to which, therefore, the population A recent study found no evidence of immunologic tolerance has no pre-existing immunity. Such an Ag must also be suitable (anergy, deletion, or regulation) of the murine immune re- both for mucosal immunization and for subsequent systemic sponse to a set of 20 recombinant microbiota protein Ags; in- challenge to test the induction of systemic unresponsiveness. stead, the systemic T cells remain naive to these Ags (30). The With these limitations in mind, we (15, 16), and others (17, 18) intestine also contains IL-10-producing CD4 T cells reactive to selected keyhole limpet hemocyanin (KLH) because of its high the Ags of the commensal microbiota (31). The mucosal im- immunogenicity as revealed by both humoral and cell-medi- mune response to these Ags appears to be tightly regulated, and ated responses to systemic immunization with small doses. Ex- details about how regulatory cells are induced and maintained tended ingestion or intranasal inhalation of KLH by volunteers in the mucosa are just emerging (32, 33). Indeed, the phenom- lacking pre-existing immunity followed by systemic challenge enon of mucosal tolerance to protein Ags delivered into the in- resulted in an unexpected outcome: decreased cell-mediated testine may be related to and be dependent upon the regulation immunity manifested by diminished DTH reactions and T cell of the immune response to the microbiota. The Ag being deliv- proliferation in vitro but priming for B cell responses. Muco- ered to a mucosal surface is, after all, encountered along with sally immunized volunteers responded to the subsequent sys- the endogenous microbes. There is much less known about the temic KLH injection by higher titers of systemic and secretory normal human mucosal immune response to the microbiota. Abs than those who received only systemic injection of KLH. Although humans produce IgA Abs to commensal bacteria, Thus, the initial mucosal immunization with high doses of a such responses do not appear to be confined to the intestine as glycoprotein Ag did not suppress the humoral arm of the im- tightly as in mice as shown by the presence of serum IgG Abs to mune response. This finding has important implications for Ags of the commensals. mucosally delivered vaccines. Furthermore, extensive studies of Certainly, strategies for the development of effective mucosal humoral and cellular immune responses to food Ags (19 –22) vaccines need to consider the large and continuous response to clearly demonstrate that humoral immune responses to impor- the Ags of the microbiota. A given vaccine Ag is in essence in tant components such as bovine -globulin, which is consumed competition for the attention of the mucosal immune system
  4. 4. The Journal of Immunology 5635 with the many thousands of these microbial Ags that occur in and properties of the vaccine Ag, contamination of the adjuvant the gut before exposure to the vaccine Ag and will continue long with endotoxin or, in the case of the B subunit, with holotoxin, after it has disappeared. The delivery of vaccine Ags by microbes and also the species of animal used. In addition, the B subunits has been tried in various forms. In some systems, commensal of enterotoxins can serve as coupled delivery agents for vaccines, bacteria themselves are used to deliver the Ag into the intestine. but the results differ from those obtained when enterotoxins are If there is already an endogenous regulation to the commensal used as admixed adjuvants. The manner of coupling, the nature vector, it is likely to be transferred to the vaccine Ag as well. of the coupled Ag, the route of administration, and the species Attenuated pathogens such as Salmonella have been used to de- affect the outcome. Ags chemically conjugated to cholera toxin liver vaccine Ags. Such vectors do induce immune responses to B (CTB) induce mucosal and systemic Ab responses to the cou- vaccine Ags in the short term, but the response to the neoanti- pled Ag when given intragastrically or intranasally in mice, but gen is overwhelmed by the response to the more immunodom- coadministration of a small adjuvant dose of intact CT may be inant Ags of the Salmonella itself. necessary especially in rats (38 – 40). In the absence of holo- In contrast to enhanced or essentially unaltered humoral re- toxin, oral administration of Ags chemically conjugated to re- sponses, the administration of Ags to human gastrointestinal or combinant CTB induces profound tolerance in mice (41). Even respiratory tracts induces a profound decrease in cell-mediated previously established systemic immune responses were sup- immunity as manifested by diminished DTH, T cell prolifera- pressed, and T cell-mediated autoimmune conditions such as tion, and secretion of cytokines with suppressor activity (15– experimental autoimmune encephalomyelitis could be reversed 18). Although most if not all of the currently available human (42). Regulatory T cells (Treg cells, both Foxp3 and Foxp3 ) vaccines generate their protective effects through the induction were induced in mice orally immunized with OVA (which of specific Abs, it is not known whether mucosal exposure to readily induces tolerance) conjugated to CTB (43). large doses of inactivated microorganisms (viruses, bacteria, or In contrast, genetically coupled recombinant chimeric pro- Downloaded from on October 20, 2010 isolated Ags) inhibits the subsequent induction of CTL by ei- teins of the form Ag-A2/B5, in which Ag is fused to the A2 sub- ther systemic immunization or infection. However, if that is the unit of the enterotoxin and assembled with B subunits, are im- case, the efficacy of vaccines whose protective function at least munogenic in mice in the absence of an intact holotoxin partially depends on CTL activity might be compromised. To adjuvant and no evidence of tolerance induction has been investigate this, Ilan (34) induced tolerance to adenoviral pro- found (44 – 46). Although the mechanisms by which these dif- teins by feeding them to experimental animals, which then dis- ferent Ag-enterotoxin constructs interact with APC to induce played markedly reduced anti-adenoviral humoral as well as cel- tolerance or immunity are not understood, clearly there are dif- lular immunity as evaluated by increased TGF , IL-4, and ferences between the molecular forms that may be amenable to IL-10 but decreased IFN- production by lymphocytes upon exploitation for the elicitation of diverse responses. However, exposure to adenoviral Ags in vitro. This finding is of consid- few trials have been conducted in humans. Oral administration erable importance for gene therapy using adenoviruses as vec- of a peptide derived from human heat-shock protein-60 fused tors; extended viral survival due to tolerance to the virus and, to CTB was found to prevent relapses of uveitis in Behcet’s dis- therefore, longer expression of the desired gene product en- ease (47). Human vaccine trials have commenced using non- coded in a recombinant adenoviral vector would be of great toxic mutants of LT-I with Helicobacter pylori or an intranasal benefit for both gene therapy and viral vector-based vaccina- influenza vaccine (48, 49). tion. Conversely, induction of tolerance to a virus as a vaccine might be an undesirable outcome. It is possible that vaccines Can an existing immune response to a foreign Ag or an autoantigen be based on live vectors involving commensal (e.g., Escherichia coli suppressed by mucosal immunization and Lactobacillus) or pathogenic (e.g., Salmonella) bacteria In animal models of type IV DTH to a hapten or of autoim- would also show differential vector survival in the gastrointes- mune diseases such as experimental allergic encephalomyelitis, tinal tract as a result of differences in the immune responses to collagen type II-induced arthritis, and autoimmune diabetes these two types of bacteria (29). mellitus, prior mucosal exposure to the relevant Ag by the oral or intranasal route diminishes or prevents the development of a The role of adjuvants in immunity or tolerance reaction or disease otherwise induced by systemic immuniza- The role of immunomodulating adjuvants is extremely impor- tion (4, 8, 9, 41– 43, 50). Based on these findings, the impor- tant in this context. Among these, the most intensively re- tant question was raised as to whether this desirable effect could searched are the heat-labile enterotoxins of Gram-negative en- be extended to the therapeutic exploitation of mucosal toler- terobacteria, such as cholera toxin (CT) and the closely related ance in the treatment of pre-existing autoimmunity or DTH. type I labile toxin (LT), LT-I, of E. coli plus the type II toxins Early empirical studies on the suppression of DTH reactions to LT-IIa and LT-IIb also from E. coli. The mucosal adjuvant environmental Ags, such as poison ivy or poison oak, provided properties of CT were first demonstrated by its ability to pre- conflicting but mostly discouraging results; feeding fresh, dried vent and even reverse the development of oral tolerance (35), or extracted leaves of these plants proved of no benefit in most and a voluminous literature has since developed demonstrating trials (51, 52). It has been demonstrated in both animals and the effectiveness of CT or LT-I as mucosal adjuvants when co- humans that pre-existing systemic immunity effectively pre- administered with a large variety of Ags delivered orally (intra- cludes the induction of mucosal tolerance. Chase (53) convinc- gastrically) or intranasally (36). The precise mechanism of ac- ingly demonstrated and explicitly stated in his now rarely cited tion of these adjuvants has not been completely elucidated, and landmark paper that animals first systemically sensitized by a controversies exist over the requirements for and roles of the A hapten (2,4-dinitrobenzene) are totally refractory to the bene- and B subunits of these toxins (37). Factors involved in the di- ficial effect of subsequent oral immunotherapy. Similarly, ani- verse findings include the route of administration, the nature mals with well-established, progressive autoimmune disease
  5. 5. 5636 BRIEF REVIEW: MUCOSAL VACCINES AND TOLERANCE (experimental allergic encephalomyelitis or collagen type II-in- duced arthritis) induced by initial systemic immunization re- spond minimally if at all to oral or intranasal immunotherapy (4). Initial systemic immunization of human volunteers with KLH followed by extended ingestion of large doses of the same Ag failed to generate tolerance (54). In this study, the measure- ment of Ag-driven T cell proliferation, KLH-specific serum and salivary Ab levels, and cutaneous DTH responses failed to reveal significant differences between subjects fed KLH or OVA as a negative control Ag. Thus, systemically induced primary re- sponses in humans were not attenuated by subsequent oral in- gestion. However, whether these data can be extended to other neo-Ags or vaccines given over a much broader range of doses is unknown. This point is important for immunization with mu- cosally administered vaccines as well as the potential treatment of autoimmune diseases. In the first case, it is unlikely that mu- cosal immunization of an individual with even a low pre-exist- ing level of systemic immunity would induce T cell-mediated FIGURE 1. Possible common regulatory pathways for the induction of mu- systemic unresponsiveness. In the second situation, it is becom- cosal tolerance and IgA production. Ags are taken up, processed, and presented ing apparent that the limited success in the treatment of existing in mucosal inductive sites, leading to the stimulation of regulatory T cells (Treg, autoimmune diseases by mucosal immunization with the au- Tr1, Th3). The main cytokine products of these cells enhance the differentia- Downloaded from on October 20, 2010 toantigen (8, 9, 55, 56) can be explained by the failure to sup- tion of B cells into pIgA-producing plasma cells in mucosal tissues (arrows press a pre-existing systemic response. pointing up) and concomitantly suppress systemic T cell responses (arrows pointing down). This concerted action achieves the common goal of preventing Functional complementarity of mucosal Ab responses and mucosal the exhaustion of the immune system by the abundance of Ags that are present tolerance: common regulatory mechanisms at mucosal surfaces. S-IgA, Secretory IgA. The IgA isotype switching of B cells and their differentiation into specific IgA Ab-producing plasma cells (57–59) and sys- temic T cell hyporesponsiveness, both of which are induced by switching, IgA B cell differentiation (TGF and IL-10), epithe- mucosal exposure to Ags (8, 9, 60), display complementary lial cell expression of the pIgA receptor and transcytosis (IL-4), functional effects and may share some common regulatory and the suppression of cell-mediated immunity (TGF , IL-4, pathways. Although specific Abs of any major Ig isotype in se- and IL-10) (8, 9, 57–59, 64, 66 – 68). Although murine B1 cells cretions prevent the uptake of inert Ags from mucosal surfaces can differentiate into IgA-producing cells that secrete Abs spe- and restrict the penetration of microorganisms into the sys- cific for intestinal microbes independently of T cells (28), this temic compartment, Abs of the IgA isotype display unique may not be the case in humans because B1 cells are not detect- functional advantages, particularly upon Ag encounter in mu- able in the intestinal lamina propria (59). We speculate that the cosal tissues. In addition to their pronounced resistance to in- inhibition of systemic T cells and the stimulation of IgA re- testinal proteolytic enzymes and the beneficial effect of multi- sponses may result concomitantly from the induction of these valency (four or eight Ag binding sites per dimer or tetramer, “inhibitory” cytokine networks. respectively), specific IgA Abs exhibit strong anti-inflammatory activity manifested by the inhibition of complement activation Unresolved questions and of the activation of inflammatory cell types (3, 5, 61– 63). This in turn reduces potential tissue damage, breakdown of the Although the parallel induction of both mucosal Ab responses mucosal barrier, and indiscriminate uptake of bystander Ags and mucosal tolerance after Ag ingestion has been demon- (63). In addition, the integral involvement of mucosal epithelial strated first in mice (60) and then in humans (15, 16), exploi- cells in receptor-mediated transcytosis of locally produced poly- tation of the potential of this phenomenon will require further meric IgA (pIgA) facilitates the clearance of Ags complexed with investigation. Ags used to date in humans have included only a specific IgA Ab (64). contact allergens (13, 14) and KLH (15–18). It is well known Despite this IgA-mediated prevention of mucosal uptake, that mucosal immunization with biologically relevant complex minute amounts of undigested Ags (e.g., bovine -globulin Ags such as inactivated viruses, bacteria, and their products in- from milk) can be detected in the circulation, usually in the duces mucosal as well as systemic Ab responses (1, 2, 4), but its form of IgA-containing immune complexes (65). In addition, impact on cell-mediated immunity, particularly the induction the parallel induction of mucosal Ab responses and the suppres- of systemic and mucosal CTL responses, has not been ade- sion of systemic cell-mediated reactions reduce stimulation of quately investigated. An important consideration in this con- the immune system. Importantly, all of these pathways, includ- text is that mucosal immunization of immunologically naive ing isotype switching to IgA and terminal differentiation of IgA subjects not previously exposed to HIV with a potential HIV plasma cells, epithelial transcytosis of pIgA and the induction of vaccine might have the undesirable effect of diminishing cell- mucosal tolerance are regulated by common cytokine networks mediated, CTL-dependent immunity. This problem may not (Fig. 1). Subsets of CD4 CD25 or CD4 CD25 regulatory apply to other mucosal vaccines (e.g., poliovirus, influenza vi- T cells secrete cytokines, including TGF , IL-4, and IL-10, rus) that, like other currently used vaccines irrespective of the that participate in surface IgM to surface IgA isotype B cell immunization route, achieve their protective effects through
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