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PubMed2000

Nutritional and pharmacological enhancement of gut-associated lymphoid tissue.

There has been an explosion of research in the field of nutrition over the past quarter century. Clinical studies have demonstrated the effectiveness of providing nutrition by the enteral route in reducing septic morbidity in critically ill patients. These improved outcomes have been substantiated by animal models that show that enteral nutrition decreases gut permeability while maintaining the gut-associated lymphoid tissue (GALT) in mucosal immunity. Evidence points to the important immunological role of the gut in the maintenance of mucosal immunity at both intestinal and extraintestinal sites. The preservation of this mucosal immunity by enteral nutrition is consistent with the lower morbidity seen in severely injured patients who receive nutrition via the gastrointestinal tract. For patients who are unable to be fed by the enteral route and who require parenteral nutrition, several supplements show promise in enhancing the mucosal immune system defenses. The nutritional and pharmacological tactics that may enhance the GALT and thereby maintain mucosal immunity are examined.

Animals↗
PubMed2001

Immunostimulating complexes (ISCOMs) for nasal vaccination.

The immunostimulating complex (ISCOM) is documented as a strong adjuvant and delivery system for parenteral immunization. Its effectiveness for mucosal immunization has also been proven with various incorporated antigens. Lövgren et al. were the first to demonstrate the capacity of influenza virus ISCOMs to induce mucosal immune response and protection after one comparatively low nasal dose. Further studies show that similar to Cholera toxin (CT) and Escherichia coli heat-labile toxin (LT), ISCOMs break immunological tolerance and exert strong mucosal adjuvant activity, resulting in secretory IgA and systemic immune responses. Striking is the capacity of ISCOMs to induce CTL response also after nasal administration. In contrast to CT, ISCOMs initiate mucosal as well as systemic immune responses in an IL-12 dependent manner but independently of IL-4. The recombinant B subunit of cholera toxin (rCTB) was incorporated in the same ISCOM particle to explore symbiotic effects. The IgA response to rCTB in lungs was increased 100-fold when rCTB was administered nasally in ISCOMs and more than 10-fold in the remote mucosa of the genital tract. An enhanced IgA response to a passenger antigen OVA was recorded in the remote genital tract. After i.n. administration of the envelope proteins of respiratory syncytial virus in ISCOMs, high serum antibodies were induced, almost at the same levels as those following parenteral immunization and potent IgA responses were also evoked both at the local respiratory mucosa, and in the cases tested at the distant mucosae of the genital and intestinal tracts. Similar results have also been recorded with ISCOMs containing envelope proteins from Herpes simplex virus, Influenza virus and Mycoplasma mycoides. The mucosal targeting property of envelope proteins of RSV was utilized in an HIV-gp120 RSV ISCOM formulation. After nasal administration an enhanced mucosal IgA response to gp120 was observed in the female reproductive tract. In general, antigens derived from envelope viruses or cell membranes incorporated into ISCOMs retain their biological activity and conformation, encompassing the mucosal targeting and virus neutralizing properties.

Adjuvants, Immunologic↗
PubMed2001

Host determinants in HIV infection and disease. Part 1: cellular and humoral immune responses.

The course of HIV infection varies widely among individuals. Long-term nonprogressors or slow progressors may remain asymptomatic and have normal CD4 counts despite more than a decade of untreated HIV infection. In contrast, rapid progressors develop AIDS within 5 years. In addition, some persons remain uninfected despite repeated exposure to HIV. Immunologic and genetic studies of long-term nonprogressors and exposed yet uninfected persons, as well as data from studies of primary HIV infection, have helped to elucidate the mechanisms by which some persons are protected from HIV acquisition or have slow rates of disease progression. This review (the first of two parts) describes what is currently known about host factors in HIV-1 infection. Studies for inclusion were identified by a systematic search of PubMed for English-language literature published from 1988 through June 2000. Abstracts of presentations at major meetings convened in 2000 were also included if appropriate. Growing evidence suggests a crucial role of cytotoxic T cells and T-helper cells in controlling viremia, slowing disease progression, and perhaps preventing establishment of infection. Humoral and mucosal immunity, soluble inhibitory factors, the cytokine milieu, and concomitant infections also affect outcome. Genetic host factors, such as inheritance of mutant chemokine receptors or certain HLA types, affect susceptibility to infection and subsequent clinical course. The role of cellular and humoral immunity, mucosal immunity, and other local factors in determining the course of HIV infection is discussed.

Antibody Formation↗
PubMed1980

Suppression of the intestinal immune response to cholera toxin by specific serum antibody.

The possibility that preexisting specific serum antibody could suppress a defined mucosal immune response to a topically applied antigen was studied in rats. Hyperimmune serum antibody induced by parenteral immunization of rats with cholera toxoid markedly suppressed the mucosal immune response to enterically applied cholera toxin. Such antibody was far more suppressive than antibody induced by primary parenteral immunization, apparently due to its greater avidity. Transfusion of small amounts (25 to 100 microliter) of hyperimmune serum suppressed the primary mucosal antitoxin response, the development of specific memory in the mucosal immune system, and, somewhat less effectively, the secondary mucosal antitoxin response. Suppression was due largely to a direct effect of serum antibody upon the interaction of absorbed enteric antigen with lymphoid tissue in Peyer's patches and, possible, mesenteric lymph nodes; interference with antigen absorption played little or no role in the observed suppression. These results do not explain the previously reported suppressive effect of primary parenteral immunization on the mucosal immune response to cholera toxin. However, they support the notions that repeated parenteral immunization can evoke avid serum antibody without necessarily stimulating mucosa-associated lymphoid tissue and that such antibody can markedly suppress primary and secondary phases of the local immune response to mucosally applied antigen. Thus, a mechanism is demonstrated by which repeated parenteral immunization may adversely affect efforts to initiate or sustain protective mucosal immune responses.

Animals↗
PubMed2005

Recombinant poxviruses as mucosal vaccine vectors.

The majority of infections initiate their departure from a mucosal surface, such as Human immunodeficiency virus (HIV), a sexually transmitted virus. Therefore, the induction of mucosal immunity is a high priority in the development of vaccines against mucosal pathogens. The selection of an appropriate antigen delivery system is necessary to induce an efficient mucosal immune response. Poxvirus vectors have been the most intensively studied live recombinant vector, and numerous studies have demonstrated their ability to induce mucosal immune responses against foreign expressed antigens. Previous studies have demonstrated that recombinants based on the attenuated modified vaccinia virus Ankara (MVA) vector were effective in inducing protective responses against different respiratory viruses, such as influenza and respiratory syncytial virus, following immunization via mucosal routes. Recent studies performed in the murine and macaque models have shown that recombinant MVA (rMVA) does not only stimulate HIV-specific immunity in the genital and rectal tracts following mucosal delivery, but can also control simian/human immunodeficiency viraemia and disease progression. In addition, a prime-boost vaccination approach against tuberculosis emphasized the importance of the intranasal rMVA antigen delivery to induce protective immunity against Mycobacterium tuberculosis. The aim of this review is to summarize the studies employing recombinant poxviruses, specifically rMVA as a mucosal delivery vector. The results demonstrate that rMVAs can activate specific immune responses at mucosal surfaces, and encourage further studies to characterize and improve the MVA mucosal immunogenicity of poxvirus vectors.

AIDS Vaccines↗
PubMed1999

Induction of immune responses in pigs following oral administration of purified F4 fimbriae.

An effective way of stimulating the mucosal immune system was examined in piglets, using F4 fimbriae of enterotoxigenic Escherichia coli (ETEC). It was demonstrated that purified F4 fimbriae, as opposed to ovalbumin (OVA), are powerful oral immunogens. Indeed, oral administration of purified F4 induced antigen-specific antibody-secreting cells (ASC) in the Peyer's patches, mesenteric lymph nodes (LN), blood and lamina propria 4, 7, 9 and 11 days postimmunization, respectively, indicating a stimulation of the mucosal immune system, whereas upon oral administration of OVA, no immune response was observed. Moreover, the induced F4-specific IgA and IgG antibody responses were comparable with those obtained upon oral infection with viable E. coli and intramuscular (i.m.) F4 injection, respectively. Furthermore, a priming of the mucosal immune system is better obtained by oral infection (ASC localized in mesenteric LN) than by i.m. F4 injection (ASC localized in spleen and retropharyngeal LN) since an oral boost with purified F4 induced a secondary response in the orally infected animal (mainly IgA and IgG ASC, rapid increase of IgA antibodies) while in the i.m. primed animal a secondary (more circulating antigen-specific ASC than in the unprimed animal) as well as a primary IgM and IgA response (mainly IgM ASC, slow increase of IgA antibodies), suggesting a primary mucosal response, were seen. An oral challenge of the naive control displayed a primary response (mainly IgM ASC, slow increase of IgA and IgG antibodies). The capacity of purified F4 to activate the mucosal immune system on oral administration, is of importance for the development of oral vaccines against ETEC infections.

Adhesins, Escherichia coli↗
PubMed2006

Mucosal vaccines: the promise and the challenge.

Most infectious agents enter the body at mucosal surfaces and therefore mucosal immune responses function as a first line of defence. Protective mucosal immune responses are most effectively induced by mucosal immunization through oral, nasal, rectal or vaginal routes, but the vast majority of vaccines in use today are administered by injection. As discussed in this Review, current research is providing new insights into the function of mucosal tissues and the interplay of innate and adaptive immune responses that results in immune protection at mucosal surfaces. These advances promise to accelerate the development and testing of new mucosal vaccines against many human diseases including HIV/AIDS.

Animals↗
PubMed1996

Regulation of immune responses of the intestinal mucosa.

The largest lymphoid organ in the body, the intestine, is also the most intriguing and complex. At its root, the gastrointestinal immune system must permit the absorption of nutrients while protecting against invasion of pathogens. In the process, it must sort through vast antigenic challenges and orchestrate an immune response appropriate to the occasion. Whereas the general outline of mucosal immunity has been defined with respect to the phenotype of the immune cells that compose the mucosal immune system, the ontogeny of these immune cells, and the regulation of IgA responses, the details that control mucosal T cell activation and suppression that coordinate this elaborate mucosal network continue to perplex. This review highlights unique aspects of T cell regulation within the intraepithelial lymphocyte (IEL) and lamina propria lymphocyte (LPL) compartments when compared with lymphocytes in the periphery. In general, IEL are largely extrathymically derived, have a limited TCR repertoire capable of recognizing common microbiologic Ags, and demonstrate predominantly cytolytic functions. LPL are thymically derived, highly activated lymphocytes with predominantly Th2 phenotype. LPL activation is distinct from classic memory T cells in their CD2/CD28 predominance that likely contributes to limiting TCR/CD3-mediated signals in the mucosa. Ag presentation in the gut may involve nonclassical, nonpolymorphic class I-like molecules expressed by epithelial cells that may positively select extrathymically derived lymphocyte populations as well as tolerize self-reactive lymphocytes. These special features of the mucosal immune system are integrated to downregulate immune responses to ubiquitous lumenal Ags.

Animals↗
PubMed1998

Immune responsiveness of lymphotoxin-alpha-deficient mice: two reconstitution models.

The effects of lymphotoxin-alpha (LT-alpha) deficiency on mucosal immune status has not been defined. We utilized severe combined immunodeficiency (scid) mice as recipients of both mutant and wild-type whole splenocytes to determine whether lymphocytes from mutant mice had impaired homing ability. We also utilized irradiated mutant mice as recipients of wild-type whole splenocytes to determine whether lymphoid tissue anlages had, indeed, failed to develop as a consequence of LT-alpha deficiency. Subsequently, all mice were immunized orally with an attenuated strain of Salmonella typhimurium and mucosal IgA responses were monitored. The data presented here demonstrate that scid recipients generate mucosal responses equally well when reconstituted with mutant or wild-type lymphocytes. In contrast, reconstitution of mutant mice with wild-type cells failed to affect the efficiency of their mucosal immunity. The mutant phenotype, therefore, appears to involve neither impaired lymphocyte homing nor function in the generation of mucosal immunity. However, the mutant phenotype and immune responsiveness cannot be transformed merely by the provision of LT-alpha-expressing donor cell populations. The consequence of LT-alpha deficiency on mucosal immune responsiveness appears to be due to the lack of gut-associated lymphoid tissues, which may include the spleen, in mutant mice.

Animals↗
PubMed1989

Selective delivery of antigens by recombinant bacteria.

The means to attenuate Salmonella and to endow such avirulent strains with the ability to express colonization and virulence antigens from other pathogens has achieved considerable progress during the past several years. One can therefore begin to design and construct strains with specificity to a given animal host and to express in a defined way specific colonization and virulence antigens in a manner to stimulate long-lasting immunity to the Salmonella and to the pathogen supplying the genetic information for the colonization and virulence antigens. Since most pathogens colonize on or invade through mucosal surfaces, the use of recombinant bivalent Salmonella vaccine strains to stimulate a mucosal immune response would induce the development of a first line of defense against a diversity of pathogens. Mucosal immunity should therefore reduce contagious spread of many pathogens since the dose to overcome the mucosal immune barrier would be increased to result in a diminished likelihood of infection. The fact that the recombinant Salmonella vaccine strains also induce humoral and cellular immune responses justifies their use for induction of long-lasting immunity. Although considerable progress has been made in targeting antigens to the GALT by use of avirulent Salmonella, a similar strategy for delivery of antigens to the BALT has yet to be discovered and developed. In addition to constituting a system for induction of immunity against a diversity of pathogens, the recombinant avirulent Salmonella system should provide a means to explore parameters of the mucosal immune response. This would include investigation of the location and duration of memory, the age dependence of induction of mucosal immunity, and the means for the possible induction of oral tolerance with regard to either the mucosal or humoral response to an antigen expressed by the recombinant Salmonella. It is also possible to contemplate using the avirulent Salmonella to target expression of various modulators of the immune system such as interleukin-2 and interferon-gamma to the GALT and thus further enhance the immune response. Lastly, one can introduce into avirulent Salmonella strains genes for putative colonization antigens in order to investigate whether induction of an immune response against the putative colonization antigen does or does not interfere with infection. This system, therefore, permits another means to analyze the relative importance of various bacterial surface attributes in conferring pathogenicity to the microbe.

Animals↗
PubMed1989

The mucosa of the male genital tract; part of the common mucosal secretory immune system?

The selective migration of mucosal-derived lymphoid blasts to other mucosal organs is taken to be an essential part of the common secretory immune system. In rats, proliferating lymphoid cells from mesenteric lymph nodes (mLN) and peripheral lymph nodes (pLN) were labeled in vitro using two different techniques, in order to test the hypothesis that the mucosa of the male genital tract is a preferential site for mLN lymphoid blasts to home to. A low but significant migration to male genital organs was found, but with no difference between blasts from pLN and mLN. Thus there is no evidence to include the male genital tract in the common mucosal secretory immune system. Recirculating lymphocytes from the thoracic duct entered the male genital organs with a similar distribution to the pattern of lymphoid blasts. There is probably an exchange between these immigrating lymphocytes and the different subsets, which are localized in the epithelium (T suppressor) and interstitial tissue (T helper) in male genital organs. The lymphoid cells in the male genital tract might play an important role in the immune function of seminal fluid and in sexually transmissible diseases.

Animals↗
PubMed2003

Mucosal vaccination against encapsulated respiratory bacteria--new potentials for conjugate vaccines?

Polysaccharide (PS)-encapsulated bacteria such as Haemophilus influenzae type b (Hib), Streptococcus pneumoniae (pneumococcus), Neisseria meningitides (meningococcus) and group B streptococcus (GBS), cause a major proportion of disease in early childhood. Native PS vaccines are immunogenic and provide protection against disease in healthy adults but do not induce immunological memory. PSs are T-cell-independent antigens and do not elicit antibodies in infants and young children, but by conjugating PS to proteins they become T-cell dependent and immunogenic at an early age. Despite excellent efficacy of PS-protein conjugate vaccines against invasive disease, protection against mucosal infections such as pneumococcal otitis media has been less efficacious. Circulating PS-specific antibodies may protect against infections at mucosal sites, but mucosal immunoglobulin A antibodies may also contribute significantly to protection against mucosal infections. Mucosal immunization of experimental animals with conjugate vaccines against Hib, pneumococcus, meningococcus and GBS induces systemic and mucosal immune responses, which provide protection against carriage, otitis media and invasive disease in a variety of challenge models, providing new means for protection against encapsulated bacteria. In addition, mucosal immunization of neonatal mice with a pneumococcal conjugate and the nontoxic adjuvant LT-K63 has been superior to parenteral immunization in eliciting protective antibodies and PS-specific memory, and thus circumventing the limitations of antibody responses to PS that are responsible for enhanced susceptibility of neonates and infants to infections caused by encapsulated bacteria. Through T-cell dependent enhanced immunogenicity of PS-protein conjugate vaccines, mucosal immunization could be an attractive approach for early life immunization against encapsulated bacteria.

Adult↗
PubMed2005

Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria.

Animals contain an enormous load of non-pathogenic bacteria in the lower intestine, which exploit an environment with a stable temperature and abundant carbon sources. Our load of bacteria outnumbers our own cells. In order to survive with such a high number of organisms in very close proximity to host tissues the intestinal mucosa and its immune system is highly adapted. Mucosal immune responses are induced by small numbers of live commensal organisms penetrating the Peyer's patches and persisting in dendritic cells (DC). These DC can induce immunoglobulin A+ (IgA+) B cells, which recirculate through the lymph and bloodstream to populate the lamina propria and secrete protective IgA. Because DC loaded with commensal bacteria do not penetrate further than the mesenteric lymph nodes, immune induction to commensals is confined to the mucosa, allowing strong mucosal immune responses to be induced whilst the systemic immune system remains relatively ignorant of these organisms.

Adaptation, Physiological↗
PubMed2003

Upper respiratory tract immunity.

Most viral infections occur via mucosal surfaces like the respiratory, gastrointestinal, or genital epithelium. The mucosal immune system is an important component of the body's defense against such infections and consequently induction of mucosal, in addition to systemic immunity, might improve vaccine efficacy. Several orally administered vaccines, for example, against poliovirus and gastrointestinal bacterial infections, have been developed and are widely used. In contrast, to date most vaccines against respiratory pathogens are applied parenterally and thus do not induce significant mucosal immunity. For the development of effective mucosal vaccines a more profound understanding of the immune mechanisms operative at mucosal surfaces and of the interplay between different mucosal compartments is needed. Moreover, factors like the dose, form of application, and type of mucosal adjuvants are critical to the induction of effective mucosal immunity. This brief review will focus mainly on the nasal route and will summarize some recent findings concerning the function of the mucosal immune system of the upper respiratory tract. Furthermore, routes of cross-immunization between distinct mucosal compartments and how they might be relevant to vaccine development will be addressed. Finally, I will outline critical factors for the rational design of nasal vaccines and in this context highlight some recent preclinical and clinical developments in the field.

Administration, Intranasal↗
PubMed2002

Regulation of mucosal dendritic cell function by receptor activator of NF-kappa B (RANK)/RANK ligand interactions: impact on tolerance induction.

The mucosal immune system is uniquely equipped to discriminate between potentially invasive pathogens and innocuous food proteins. While the mechanisms responsible for induction of mucosal immunity vs tolerance are not yet fully delineated, recent studies have highlighted mucosal dendritic cells (DC) as being important in determining the fate of orally administered Ag. To further investigate the DC:T cell signals involved in regulating the homeostatic balance between mucosal immunity and tolerance, we have examined the expression and function of the TNFR family member receptor activator of NF-kappaB (RANK) and its cognate ligand, RANKL, in vitro and in vivo. Our data show that although DC isolated from mucosal lymphoid tissues expressed similar levels of surface RANK compared with DC isolated from peripheral lymphoid tissues, DC from the distinct anatomical sites displayed differential responsiveness to RANK engagement with soluble RANKL. Whereas splenic DC responded to RANKL stimulation with elevated IL-12 p40 mRNA expression, Peyer's patch DC instead preferentially displayed increased IL-10 mRNA expression. Our data also show that the in vivo functional capacity of mucosal DC can be modulated by RANKL. Treatment with RANKL in vivo at the time of oral administration of soluble OVA enhanced the induction of tolerance in two different mouse models. These studies underscore the functional differences between mucosal and peripheral DC and highlight a novel role for RANK/RANKL interactions during the induction of mucosal immune responses.

Adjuvants, Immunologic↗
PubMedDate not supplied

Immune cell populations within the duodenal mucosa of dogs with enteropathies.

The mucosal immune system may play a critical role in the pathogenesis of small intestinal enteropathies. The aim of the current study was to assess mucosal immune cell populations in dogs with inflammatory bowel disease (IBD), idiopathic antibiotic-responsive diarrhea (ARD), and adverse reactions to food (FR). Endoscopic biopsies were performed of the duodenum of dogs with these conditions and from a group of dogs without enteric disease. Additional control samples were collected after death from other dogs that did not have evidence of enteric disease. Immunohistochemistry and computer-aided morphometry were used to assess the distribution of immune cell subsets in both lamina propria and intestinal epithelium. Compared with controls, dogs with ARD had increased numbers of lamina propria immunoglobulin (Ig) A- plasma cells and CD4+ cells. More marked alterations were noted in dogs with IBD, with significant increases in lamina propria IgG+ plasma cells, T cells (CD3+), CD4+ cells, macrophages, and neutrophils, but with reduced mast cell numbers. Increased intraepithelial CD3+ T cells were also present in the dogs with IBD, compared with controls. However, lamina propria and epithelial populations were unaltered in dogs with FR when compared with controls. The altered mucosal immune cell populations observed in dogs with ARD or IBD may reflect an underlying immunologic pathogenesis in these disorders.

Animals↗