Bacteria and gut immunity
`
`Shobha Char, PhD, and Michael J.G. Farthing, MD, FRCP
`
`The Medical College of St. Bartholomew's Hospital, London, UK
`
`The interaction between the intestinal microflora and the host
`mucosal im mune system is complex. Intestina l bacteria are considered
`vital for the maturatio n and maintenance of intestinal immunity in
`healthy individuals but may have harmful effects when the flo ra
`is modified by d rugs such as the proton p ump inhibitors, wh ich
`suppress gastric acid. Research continues to support the concept that
`a healthy flora can be maintained by certain bacterial species suc h
`as Lactobacillus, although their therapeutic role in disease states has
`not yet been estab lished. Translocatio n of bacteria across the gut
`wall occurs in certain d isease states in which epithelial integrity is
`disrupted, particularly during intravenous nutrition and small bowel
`transplantation. Impairment of mucosal imm unity has recently been
`documented in HIV infection and AI DS, including a deficit in antige n
`presentation. Modulatio n of gut immune responses is the cornerstone
`of vaccine development for intestinal infections. New antige n delivery
`systems are being developed that may assist in promoting protective
`immune responses rather than the development of oral tolerance.
`
`Current Opinion in Gastroenterology 1994, 10:659-663
`
`Intestinal microflora
`
`The human gastrointestinal tract contains 1014 bacte(cid:173)
`rial cells (an equivalent of 1 kg). There is a marked
`variation in the n umber and pattern of bacterial flora
`at different levels of the tract. The number of ingested
`bacteria is reduced dramatically by gastric acid. A low
`concentration of organisms is maintained in the small
`bowel by intestinal motility that ensures that nonadher(cid:173)
`ent organisms are constantly cleared from the small in(cid:173)
`testine. Despite this clearing, the concentration of bac(cid:173)
`teria increases from the jejunum through the ileum,
`with a marked increase in the colon. The bacterial
`content of duodenal fluid following acid inhibition by
`the p roton pump inhibitor omeprazole was examined
`in a controlled prospective study (1 •]. Duodenal bac(cid:173)
`terial overgrowth of both oral- and fecal-type bacte(cid:173)
`ria occurred frequently in ambulatory patients treated
`with omeprazole. Further studies are needed to deter(cid:173)
`mine the clinical significance during long-term treat(cid:173)
`ment with omeprazole. Shin do et a/. (2•) found evi(cid:173)
`dence of overgrowth of bacteria capable of deconjugat(cid:173)
`ing bile salts in the jejunum of seven of 27 patients with
`liver cirrhosis who had a positive bile acid breath test.
`Bacterial overgrowth in these patients was attributed to
`the sh ift to alkaline pH in the gastric juice.
`
`The dominant populations of bacteria in the intes(cid:173)
`tine are members of the genera Bacteroides, Eubac-
`
`terium, Bifidobacterium, Clostridium, Lactobactllus,
`and Fusobacterium. Escherichia coli and aerotoler·
`ant streptococci constitute the accompanying flora.
`Various microorganisms are eliminated from the in(cid:173)
`testine by a "barrier effect" exerted by the normal
`microflora. The normal microflora thus supports the
`immune system by providing colonization resistance
`against pathogenic exogenous microorganisms. Lacto(cid:173)
`bacillus sp has been shown to inhibit the growth of
`potentially pathogenic organisms such as Staphylococ(cid:173)
`cus, Pseudomonas, Salmonella, and Helicobacter py(cid:173)
`lori in vitro. It has been suggested that Lactobacil(cid:173)
`lus migh t contribute to the maintenance of coloniza(cid:173)
`tion resistance through the production of lactic and
`acetic acids, hydrogen peroxide, and antimicrobial sub(cid:173)
`stances. It is thus considered important to maintain the
`levels of Lactobacillus in the intestinal flora because
`several other studies also indicate a protective effect
`against potential pathogens (3••].
`
`Bacterial translocation
`
`In normal situations, the only bacteria that readily
`transloc:ate from the intestinal lumen to mesenteric
`lymph nodes (MLNs) and other viscera are facultative
`intr.tcellular pathogens such as Salmonella spp and Lis(cid:173)
`teria spp. It is well known that this tendency is in(cid:173)
`creased in patients with impaired T-cell function, such
`
`Abbreviations
`GVHD-graft-versus-host disease; MLN- mesenteric lymph node; TNF- tumor necrosis factor.
`
`© 1994 Current Science ISBN 1-85922-611·6 ISSN 0267- 1379
`
`659
`
`

`

`660
`
`Immunology
`
`as those with AIDS or lymphomas, or organ transplant
`recipients. Lim et at. [4•) studied the effect of HIV in(cid:173)
`fection on intestinal lamina propria macrophage sub(cid:173)
`sets in 4I patients at various stages of HIV infection.
`The results show that there was no difference in over(cid:173)
`all density of macrophages, but there was a significant
`decrease in dendritic cells in all clinical stages of HIV.
`Thus, the antigen-presenting arm of mucosal immune
`defenses may be seriously compromised in HIV infec(cid:173)
`tion, and this loss represents a further insult to mucosal
`immunity already impaired as a result of loss of CD4+
`T lymphocytes. These factors may contribute to the de(cid:173)
`velopment of opportunistic infection in the gut.
`
`In the context of mechanisms involved in immune re(cid:173)
`sponse, bacterial translocation through specialized ab(cid:173)
`sorptive cells, called M cells, appears to be a part of the
`antigen-sampling process resulting in the development
`of gut-associated lymphoid tissue [5). The term bacte(cid:173)
`rial translocation has been used to describe the pas(cid:173)
`sage of bacteria from the gut lumen through the mu(cid:173)
`cosa to the MLNs and other organs. The main factors
`promoting bacterial translocation include virulence and
`pathogenicity of the bacterial strain, increased numbers
`of the bacterial strain in the gut because of disturbances
`in the indigenous intestinal microflora, permeability of
`the intestinal mucosa, and a lowered immune status of
`the host.
`
`Translocation has not been shown directly in healthy
`individuals. However, tf"anslocation enables contact of
`bacteria or bacterial fragments with the immune system
`and consequently leads to the production of systemic
`antibacterial antibodies. Indeed such antibodies have
`been detected in healthy individuals directed against
`their own anaerobic fecal bacteria [6) and a facultatively
`anaerobic E. coli strain that colonized the gastrointest(cid:173)
`inal tract after oral ingestion [7]. Apperloo-Renkema
`et a/. [8••) demonstrate a decrease in the coloniza(cid:173)
`tion resistance of intestinal microflora in patients with
`the autoimmune disease systemic lupus el)'thematosus.
`A lower colonization resistance theoretically increases
`the risk of translocation of more bacterial species,
`which may trigger the polyclonal and antigen-specific
`B-cell activation that leads to the production of multi(cid:173)
`ple autoantibodies in systemic lupus erythematosus.
`
`Bacterial translocation has been identified as a possible
`mechanism for the development of sepsis in various
`experimental conditions and in surgery, obstructive
`jaundice, acute pancreatitis, and burn patients. Runkel
`et al. [9-l examined the hypothesis that prolonged in(cid:173)
`testinal transit time may disrupt the luminal microflora
`of the gut and thereby promote bacterial translocation
`in an animal model. Following administration of mor(cid:173)
`phine, which is known to inhibit bowel transit, sam(cid:173)
`ples were obtained from the MLNs, blood, spleen, liver,
`duodenum, jejunum, ileum, and cecum for standard
`bacteriology. The bacterial counts increased signifi(cid:173)
`cantly in each intestinal segment following morphine
`treatment. Bacteria translocated to the MLNs in five,
`and to distant sites in four of eight morphine-tested
`
`animals. The authors concluded that the morphine-in(cid:173)
`duced prolongation in bowel transit promotes bacte(cid:173)
`rial translocation secondary to an overgrowth of en(cid:173)
`teric bacteria in the intestinal lumen. Thus, bacterial
`overpopulation of the bowel is an important promoter
`of translocation. Further studies are needed to deter(cid:173)
`mine whether therapeutic stimulation of motility might
`be a possible means of managing sepsis and whether
`the use of drugs that slow bowel motility are clinically
`important in the pathogenesis of sepsis. Price et a/.
`[lo••J assessed the effects of rejection, graft-versus-host
`disease (GVHD) and immunosuppression after hetero(cid:173)
`topic small bowel transplantation in rats. Isografts, al(cid:173)
`lografts with and without immunosuppression, and the
`semiallogenic parent to the Fl hybrid GVHD model
`were studied. Intestinal microflora in graft and host
`loops and bacterial translocation to host organs and
`the graft MLNs were determined. Bacterial tr.ansloca(cid:173)
`tion was not detected in isografted animals, but was
`observed in all other animal groups. These data show
`that bacterial translocation from the intestine occurs in
`the presence of acute rejection and GVHD and that
`immunosuppression to prevent rejection does not pre(cid:173)
`vent translocation.
`
`Bacterial lipopolysaccharide has been speculated to fa(cid:173)
`ciLitate bacterial translocation by a mechanism involv(cid:173)
`ing physical disruption of the gut mucosal barrier. Wells
`eta/. [II••) used polarized, cultured intestinal epithelial
`cells (Caco2 cells) to study the effect of lipopolysaccha(cid:173)
`ride on emerocyte structure, viability, and susceptibility
`to bacterial invasion and found no discernible effect.
`Thus, lipopolysaccharide-induced bacterial transloca(cid:173)
`tion might not involve loss of epithelial viability or fa(cid:173)
`cilitated entry of bacteria into intestinal epithelial cells.
`
`Nord [I2] has reviewed the ecologic effects of peni(cid:173)
`cillins, cephalosporins, macrolides, tetracyclines, ni(cid:173)
`troimidazoles, and quinolines on the human intestinal
`microflor.a. The disturbances in normal intestinal mi(cid:173)
`c roflora can cause bacterial overgrowth and emergence
`of resistant microorganisms, which may lead to serious
`infections and also encourage transfer of resistance fac(cid:173)
`tors among bacteria.
`
`Intestinal immune system
`
`The intestine is the largest immune organ in the body.
`It has been estimated that gut-associated lymphoid tis(cid:173)
`sue contains 400/0 of the immune effector cells in the
`body, possibly representing up to 25% of the intesti(cid:173)
`nal mucosal mass. Intestinal immune cells are found
`in one of three compartments: as aggregates in folli(cid:173)
`cles and Peyer's patches, distributed within the mu(cid:173)
`cosa as diffuse elements of the lymphoid network, and
`in the epithelium [I3l. Various interleukins and other
`cytokines that contribute to interactions among cellu(cid:173)
`Ear components of the immune system are produced
`by cells within the lamina propria. Conversely, cellu(cid:173)
`Ear constituents of the lamina propria mucosae have
`been found to respond to various cytokines. Pang et al.
`
`

`

`Bacteria and gut immunity Char and Farthing
`
`661
`
`(14•] reported the presence of interleukin-2-activated
`large granular lymphocytes in the lamina propria of
`human duodenal mucosa that secrete an array of cy(cid:173)
`tokines and may thus regulate cells of myeloid and
`monocytic lineages. The intestinal epithelium is where
`the host encounters a myriad of different environmen(cid:173)
`tal antigens and pathogens. A number of recent re(cid:173)
`ports demonstrate that intestinal epithelial cells are a
`potentially important source of a number of cytokines
`that may modulate the immune response at the in(cid:173)
`testinal mucosa. Intestinal epithelial cell populations
`have been found to express or respond to interleukin-
`1, interleukin-2 (15•), interleukin-6 (16•], tumor necro(cid:173)
`sis factor (TNF), interferon-"( , and transforming growth
`factor-PU5•]. Nicholls et al. [17•] have shown that there
`is a constant low-grade production of TNF-o. in the in(cid:173)
`testines of healthy people and attribute this produc(cid:173)
`tion to the possible leaking of antigenic products of
`the normal flora across normal epithelium, leading to
`continual stimulation of the intestinal immune system.
`Using immunohistochemistry, they have documented
`cells containing TNF-o. the subepithelial lamina pro(cid:173)
`pria mucosae of colonic biopsy specimens from chil(cid:173)
`dren with no detectable gut disease [18•].
`
`The use of cytokines in nonspecific therapy of bacte(cid:173)
`rial infections has been reviewed by Vogels and van der
`Meer (19). Administrc:ltion ofTNF-o. or interleukin-1 and
`interleukin-6 to mice before infection with Salmonella
`typhimurium and Listeria monocytogenes, respec(cid:173)
`tively, protected them from an otherwise lethal infec(cid:173)
`tion. Interferon-"( inhibits the replication of L. mono(cid:173)
`cytogerws in hepatocytes [20•]. Baqar et a/. [21•] have
`shown that orally administered cytokines interleukin-
`2, interleukin-5, or interleukin-6 offered protection in
`mice challenged with Campylobacter jejuni. Although
`the mechanism involved in developing such immuniry
`is not yet known, the oral administration of cytokines
`could minimize many of the problems associated with
`the systemic administration of these molecules.
`
`Mucosal vaccines
`
`Secretory lgA represents the primary immune bar(cid:173)
`rier against pathogens. Gut-associated lymphoid tis(cid:173)
`sue secretes 40 mg/kg body weight of IgA daily, com(cid:173)
`pared with 30 mg/kg of IgG produced by the to(cid:173)
`taJ immune system. Intestinal B cell activation, al(cid:173)
`though quite variable after oral cholera vaccination,
`is in the rank order IgA, IgG, and IgM. Nilssen
`et al. [22•) report that in IgA-deficient individuals,
`IgG antibodies are elicited as compensation for the
`impaired IgA response following oral cholera vac(cid:173)
`cination. Although
`the vaccine might be of im(cid:173)
`portance for enhancing mucosal immunity in IgA(cid:173)
`deficient individuals, the authors caution that in pa(cid:173)
`tients with chronic gut disease it could enhance IgG(cid:173)
`mediated immunopathology in the absence of anti(cid:173)
`inflammatory IgA antibodies.
`
`Many groups are currently working on the develop(cid:173)
`ment of enteric vaccines for the prevention of both
`
`intestinal and systemic infections. McGhee et at. [23•]
`have reviewed areas that are currently receiving ex(cid:173)
`tensive research attention and will be of major impor(cid:173)
`tance for development of mucosal and systemic immu(cid:173)
`nity following oral vaccination. The use of delivery sys(cid:173)
`tems such as biodegradable microspheres incorporat(cid:173)
`ing an array of antigens is reviewed by Elridge et a/.
`[24•]. Orr eta/. [25•) evaluated an acellular approach to
`induce type-specific anti-Shigella immunity using the
`proteosome delivery system. Proteosomes are prepa(cid:173)
`rations of neissarial outer membrane protein vesicles
`that have previously been shown to enhance the par(cid:173)
`enteral immunogenicity of peptides. Their new candi(cid:173)
`date vaccine for shigellosis was composed of Shigella
`lipopolysaccharide complexed with proteosome. Their
`data demonstrate that proteosomes can be used as
`an effective mucosal vaccine delivery system and that
`orally or intranasally administered acellular vaccines
`can protect against Shigella infections. Hornquist and
`Lycke [26•] demonstf"c:~te that cholera toxin given orally
`as an adjuvant with antigen-promoted antigen priming
`of both the helper T-cell subsets Thl and Th2 of CD4+
`T precursor cells. Further information will no doubt
`be forthcoming in the next few years regarding opti(cid:173)
`mal mucosal vaccine delivery systems and protocols for
`mucosal immunization.
`
`References and recommended reading
`
`Papers of particular interest, published within the annual period of
`review, have been highlighted as:
`Of special interest
`Of outstanding interest
`
`••
`
`1.
`
`Fried M, Siegrist H, Feci R. Froehlich F. Duroux P, Thorens
`), Blum A, Bille G. Convers n. Cyr K: Duodenal Bacterial
`Overgrowth During Treatment With Omeprazote. Gut 1994.
`35:23-26.
`The extent of bacterial overgrowth during the profound inhibition of acid
`secretion that occurs with omeprazole treatment is unknown. This con(cid:173)
`trolled prospective study examined the bacterial content of duodenal as(cid:173)
`pirates of patients treated with omeprazole. The results indicate that duo(cid:173)
`denal bacteria l overgrowth of both fecal and oral type bacteria occurs
`often in ambulatory patient~ treated with omeprazole.
`2.
`Shindo K. Machida M. Miyakawa K, f'ukumura M: A Syndrome
`of Cirrhosis, Achlorhydria. Small Intestinal Bacterial Overgrowth,
`amd Fat Malabsorption. Am} Gastroemero/ 1993, 88:2084-2091.
`Twenry-s.:ven patients with liver cirrhosis, tested by a breath analysis
`technique using glycine-J-14C- Iabeled glycocholate. showed a marked
`increase of t·1C02-specific activity. Bacterial overgrowth was found in the
`jejunal fluid of these patients. The majority of the bacterial species that
`were identified deconjugated bile acids. There was a good correlation
`between t1COz a~;ivity and gastric pH. The authors conclude that some
`patients with liver cirrhosis have bacterial overgrowth in the proxima l
`small imestine. which is probably associated with the shift to alkaline pH
`in gastriC' juice.
`3.
`Lidbeck A, Nord CE: l..actobacilli and the: Normal Human Anaer-
`obic Microflora. Clir1 Infect Dis 1993, 16:Sl8J-s187.
`The normal human micronora is a complex and usually stable ecosystem.
`Administrntion of antimicrobial agents may disrupt the normal microflora,
`leading to a decrease in colonization resistance. lactobacilli are part or
`the normal gram-positive anaerobic microflora. Several studies have in(cid:173)
`dicated the protective effect of lactobacilli against potential pathogens in
`the gastrointestinal tract. Thus, it is considered important to maintain or
`increase their levels in the intestinal micronora.
`4.
`Lim SG, Condez A, Poulter LW: Mucosal Macrophage Subsets
`of the Gut in Hrv: Decrease in Anligen·Presenting l'hcnorype.
`Clfn F.xp Immunol 1993, 92:442-447.
`
`

`

`662
`
`Immunology
`
`6.
`
`7.
`
`8.
`
`The aim of this study was to investigate alterations in macrophage sub(cid:173)
`populations in patients at different stages of HIV disease and their rele(cid:173)
`vance to the associated decrease in mucosal immunity. The result sug(cid:173)
`gests that the antigen-presenting arm of mucosal immune defenses may
`be seriously compromised in HIV infection.
`5.
`Wells CL, Maddaus MA, Simmons RL: Proposed Mechanisms for
`the Translocation of Intestinal Bacteria. Rev Infect Dis 1988,
`10:958-978.
`Apperloo-Renkema HZ, Wilkinson MFH, van der Waaij 0 :
`Circulating Antibodies Against Faecal Bacteria Assessed by
`lmmunomorphometry: Combining Quanlltuive lmmunolluores(cid:173)
`cen~ and Image Analysis. Epidemiollnfect 1992, 109:497-506.
`Apperloo-Renkema HZ, van der Waaij 0 : Study of Coloniza(cid:173)
`tion Resistance for Enterobacterlauae in Man by Experimental
`Contamination and Biocyping as WeU as the Possible Role of An(cid:173)
`tibodies in the Clearance of These Bacteria From the Intestines.
`Epidemiol Infect 1991, 107:619-626.
`Apperloo-Renkema HZ, Bootsma H. Mulder AI, Kallenberg CG,
`van der Waaij D: Host-Microllora Interaction in Systemic Lupus
`Erythematosus (systemic lupus erythematosus): Colonizallon Re(cid:173)
`sistance of the Indigenous Bacteria of the Jnt~-stinal Tract. Epi(cid:173)
`demiol Infect 1994, 112:367-373.
`There is increasing evidence that in autoimmune disease-prone animals,
`the composition of the indigenous intestinal micronora might play an im(cid:173)
`portant role in the expression of autoimmune disorders. In this study, col(cid:173)
`onization resistance (the defense capacity of the indigenous micronora
`against colonization of the intestines by foreign bacteria) was measured
`in healthy individuals and patients with the autoimmune disease systemic
`lupus erythematosus by a comprehensive biotyping technique. coloniza(cid:173)
`tion resistance tended to be lower in patients with active systemic lupus
`erythematosus than in healthy individuals. The authors suggest that this
`difference could indicate that, in systemic lupus erythematosus, more and
`different bacteria translocate across the gut wall, some of which could
`serve as polydonal B-cell activators or as antigens cross reacting with
`DNA.
`9.
`
`Runkel NSf, Moody fG, Smith GS, Rodriguez Lf, Chen Y,
`Larocco MT, Miller TA: Alterations in Rat Intestinal Transit by
`Morphine Promote Bacterial Translocation. Dig Dis Sci 1993.
`38:1530-1536.
`This study examined the role of altered bowel transit in influencing in(cid:173)
`testinal bacteriostasis and bacterial translocation using morphine as a
`pharmacologic inhibitor of transit and concluded that the morphine-in(cid:173)
`duced prolongation in bowel transit promotes baCterial translocation sec(cid:173)
`ondary to an overgrowth of enteric bacteria in the intestina l lumen.
`10.
`Price BA, Cumberland NS, Ingham Clark CL. Pockley AG, Lear
`••
`PA, Wood RFM: The EffeCt of Rejection and Graft-Versus-Host
`Disease on SmaU Intestinal Mlcroflora and Bacterial Translo(cid:173)
`cation After Rat SmaU Bowel Transplantation. Transplantation
`1993. 56:1072--1076.
`The effects of rejection, GVHD, and immunosuppression on intestinal
`microflora and bacterial translocation after heterOtropic rat small bowel
`transplantation were assessed in this study. The results demonstr-Jte that
`rejection and G VHD are associated with shifts in intestinal micro nora to(cid:173)
`ward potentially pathogenic organisms and that bacterial translocation
`into recipient tissues poses a major threat for the development of sep(cid:173)
`sis.
`
`11. .. Wells CL, jechorek RP, Olmsted SB. Erlandsen SL: Eff~'<:t of
`
`LPS on EpitheUal Integrity and BaCterial Uplalce in the Polar·
`ized Human Enterocyte·Uke Cell Une Caco2. Ctrc Shock 1993.
`40:276-288.
`Bacterial lipopolysaccharide has been speculated to facilitate bacterial
`translocation by a mechanism involving physic-dl disruption of the gut
`mucosal barrier. Using a polarized. cultured intestinal epithelial cell line
`(Caco2), this study demonstrated that lipopolysaccharide-induced bacte(cid:173)
`rial translocation might not involve loss of epithelial viability or facilitated
`entry of bacteria into intestinal epithelial cells.
`Nord C: The Effect of Antinticrobial Agents on the Ecology of
`12.
`the Human Intestinal Microflora. Vet Mtcrobfol1993, 35:193-197.
`Kagnoff MF: Immunology of the Intestinal Tract. Gastroenterol(cid:173)
`ogy 1993. 105:1275-1280.
`Pang G, Buret A, Batey RT, Chen QY, Couch L. Cripps A, Clancy
`R: Morphological, Phenotypic and Functional Characteristics of a
`Pure Population of CDS6+ CD16-CD3- Large Granular Lympho(cid:173)
`cytes Generated From Human Duodenal Mucosa. Jmmur1ology
`19')3, 79:498-505.
`
`13.
`
`14.
`
`This study has shown for the first time that CD56+ CDI6-CD3-large gran(cid:173)
`ular lymphocytes can be generated from histologically normal duodenal
`mucosa by culturing the biopsy-obtained tissue in the presence of recom·
`binant interleukin-2. These cells may be related to classic NK cells and
`rna y produce an array of cytokines and direct cytotoxJcity against rumor
`cells. The results provide evidence for an important role of gut mucosal
`large granular lymphocytes in the induction and regulation of inflamma·
`lion and immunity in the gut.
`15.
`Ciacci C, Mahida YR, Koizumi M, Podolsky DK: Functional
`lmer!eu.kln-2 Receptors on Intestinal EpltheUal CeUs. 1 Gin In·
`vest 1993, 92:527-532.
`This paper repons the presence of intermediate- and low-affinity func(cid:173)
`tional receptors for the cytokine interleukin·2 in the JEC-6 cell line es(cid:173)
`tablished from normal crypt epithelium. The relevance of observations
`in the IEC-6 cell line to intestinal mucosa In vivo was supported by the
`demonstration of a gradient of expression of the interleukin-2 receptor
`in primary rat intestinal epithelial cells. These results suggest that the
`range of cellular targets of interleukin·2 is broader than appreciated, and
`interleukin-2 may serve to integrate epithelial and lymphocyte responses
`in the intestinal mucosa.
`16. McGee OW, Beagley KW, Aicher WK, McGhee JR: lfansfonnlng
`Growth Facto~ and JL.Ij} Act in Synergy to Enhance IL6 Se(cid:173)
`<.:n:tion by the Intestinal Epithelial Cell Une, IEC-6. 1 Jmmunol
`1993. 151:970-978.
`The regulation of interleukin-6 secretion by intestinal epithelial cells was
`studied using the IEC-6 cell line as a model. lnterleukin·l was found to be
`a potent inducer of interleukin-6 secretion by the IEC-6 cell line. Trans(cid:173)
`forming growth factor-P and interleukin-11} aCt in synergy to enhance
`interleukin-6 secretion by the IEC-6 cell line. These results suggest that
`the intestinal epithelial cell may be an important interleukin-6 producing
`cell in mucosal immune responses.
`Nicholls S, Stephens S, Braegger CP, Walker-smith J, Macdonald
`17.
`•
`TT: Cytokines in Stools of ChUdren with Inflammatory Bowel
`Disease or Infective Diarrhoea. 1 Clln Pathol 1993, 46:757-760.
`l11e concentrations of interleukin-6 and TNF-« were measured in feces
`from 14 healthy children, 32 children with inflammatory bowel disease,
`and 2~ 9lildren with ac;vt\! diarrhea. TNF-a was detected in the stools of
`aU healthy children. Raised values of TNF-a were indicative of mucosal
`inflammation, but were not specific. Stool interleukin-6 was of little use
`in assessing mucosal inflammation because immunoreactivity is rapidly
`lost in stool samples.
`18. Murch SH, Braegger CP, Walker-Smith JA, MacDonald TT: Loca·
`lion of TNF<t Immunohistochemistry in Cluonic Inflammatory
`Bowel Disease. Gut 1993, 34:1705-1709.
`The location and tissue density of cells immunoreactive for TNF-« in in(cid:173)
`testinal specimens from 24 patients with chronic inflammatory bowel dis(cid:173)
`ease was studied. There was increased density of TNF-a immunoreactive
`cells in the lamina propria mucosae of both ulcerative colitis and Crohn's
`disease specimens that might contribute to the pathogenesis of these dis(cid:173)
`eases.
`19.
`
`Vogels MTI;, van der Meer JWM: Use of Immune Modulators in
`Nonspecific Therapy of Bacterial Infections. Anlimtcrob Agents
`Cbemother 1992, 36:1-5.
`IFN-r Inhibits
`the Replication of
`Gregory SH. Wing EJ:
`Listeria monocytogenes in Hepatocytes. 1 lmmunol 1993,
`151:1401-1409.
`Hepatocytes constitute the principal site of listerial replication in the liv(cid:173)
`ers of nonimmune mice whereas in immune mice the bacteria are rapidly
`eliminated. This paper repons that interferon gamma produced during
`primary infection-5 exens a significant inhibitory effect on the replication
`of Listeria within the parenchymal cells of the liver. In vitro experiments
`indicate that interferon gamma-stimulated hepatocytes possess the ele·
`vated capacity to kill intracellular Listeria organisms.
`21.
`Baqar S, Pacheco NO, Rollwagen FM: Modulation of Mucosal
`Immunity Against Campylobacter jejunt by Orally Administered
`Cytoltines. Anlimlcrob Agents Cbemother 1993, 37:2688-2692.
`l11is is the first report of a study in which animals were given oral cy-
`tokines and challenged with an enteric pathogen. Using a murine model
`of infeCtion, the authors found enhanced clearance of bacteria and in(cid:173)
`creased C. jejuni-speciftc serum and secretory immunoglobulin levels af·
`ter oral cytokine feeding. The data presented suggest that interleukin-2,
`interleukin-5, and interleukin-6 may each have different roles or func(cid:173)
`tions in the induction and subsequent regulation of protective immune
`responses.
`Nilssen DE, Friman v, Theman K, Bjorkander J, Kilander A,
`22.
`Holmgren J, Hanson LA, Brandtzaeg P: 8-Cc:U Activation in Duo(cid:173)
`denal Mucosa After Oral Cholera Vaccination in lgA Defident
`
`20.
`•
`
`

`

`Bacteria and gut immunity Char and Farthing
`
`663
`
`Sub~ctS With or Without lgG Subclass lkficlcncy. Scand j Jm(cid:173)
`munol 1993. 38:201-208.
`Aher:uions in duodenal immunoglobulin·producing cells induced by IWO
`cholera 112ccines were 51\Jdied in mucosal tissue sec~ ions from adultS with
`selective lgA deficiency. The results showed that oral cholera 112ccination
`preferentially aCtivates imestinallgG·produdng cells in these subjects and
`that lgG rather than lgM antibodies are elicited as compensation for a
`lacking lgA response.
`McGhee JR, fujihashi K, Xu-Amano J, jackson RJ, Elson CO,
`23.
`•
`Beagley KW, Kiyono H: New Perspectives in Mucosal Immunity
`With Emphasis on Vaccine lkvelopment. Semitl Hematol 1993.
`30:~15.
`111e focus in this review is on five areas that arc currently receiving exten(cid:173)
`sive research anention and will be of major importance for development
`of mucosal and systemic immunity to oral vaccines. These five areas in(cid:173)
`clude the following: helper T cell subsets (Th) and cytokines for mucosal
`lgA responses, Thl· and Th2-type subsets in regulation of mucosal lgA
`responses, antigen uptake and presentation in the mucosal immune sys(cid:173)
`tem, the importanCe of memory in mucosal immunity to vaccines, and
`the determination of whether oral immuni:z:~tion alone induces immunity
`In all mucosal effector tissues.
`Elridge JH, Staas JK, Chen 0 , Marx PA. Tice TR. Gilley RM:
`24.
`New Advances in Vaccine lkUvery Systems. Semin HetMto/
`1993, 30:16-24.
`This review focuses on the usc of microspheres composed of the
`biodegradable and biocompatiblc copolymer poly DL-Iactide-co-glycol(cid:173)
`lde as a promising approach to the delivery of vaccines, combining ad(cid:173)
`juvant activity with controlled release and effective presentation to mu(cid:173)
`cosally associated lymphoid tissues.
`2S. Orr N. Robin G. Cohen D. Arnon R, Lowell GH: lmmunogenlc-
`lty and Efficacy of Oral or Intranasal Sblgelkl jlexnerl 2a and
`•
`
`SblgeUa sonnel Proteosome-Upopolysaccharide Vaccines In An·
`imal Modef5. Infect Immun 1993. 6 1:239(}-2395.
`A new acellular candidate vaccine for shigellosis composed of purified
`Shigella flexneri 2a and Sbi[Jelkl sonnei lipopolysaccharide hydrophobi·
`cally complexed with group C type 2b Neisseria meningitidEs outer mem(cid:173)
`brane protein proceosomes has been tested. Immunization of mice either
`orally or intranasally with this complex Induced specific homologous anti(cid:173)
`lipopolysaccharide antibodies in both inteslinal and respiratory secretions
`as well as in sera. These data demoru.trdtc: that proleosomes can be used
`as an effective mucosal vaccine: delivery system.
`
`26.
`
`Hornquist E, t.ycke N: Cholera Toxin Adjuvant Greatly Promotes
`Antigen Priming ofT C-c:Us. Eur j lmmutw/1993, 23:2136-2143.
`11liS study was undertaken to investigate If cholera toxi.n administered
`together with keyhole limpet hemocyanin would aet to promote or in(cid:173)
`hibit priming of keyhole limpet hemocyanin-specific T cells and whether
`1hc adjuvant effect of cholera toxin is strictly an effect on intestinal anti(cid:173)
`gen processing or is a generalized phenomenon. The results clearly show
`that cholera toxin adjuvant SIIQngly promotes antigen-specific priming of
`C04• T lymphocytes. The adjuvant effect of cholera toxin was not re(cid:173)
`striCted to mucosal immune responses but was also evident following
`a single parenteral immuniZation with keyhole limpet hemocyanin and
`cholera toxin.
`
`Shobha Char, PhD, and Michaci].G. Fanhing, MD, FRCP, The Medical
`College of St. Banholomew's Hospital, Digestive Diseases Research
`Centre, Charterhouse Square, London ECIM 6BQ, UK.
`
`