key: cord-0042446-v6xjc17i
authors: Renegar, Kathryn B.; Small, Parker A.
title: Passive Immunization: Systemic and Mucosal
date: 2012-12-02
journal: Handbook of Mucosal Immunology
DOI: 10.1016/b978-0-12-524730-6.50035-x
sha: 8598dadfbc1ab716f1359b8278556172cd9ea516
doc_id: 42446
cord_uid: v6xjc17i

nan

Kothryn B. Renegar · Parker A Small, Jr.

The passive transfer of maternal immunity is responsible for keeping all mammalian species alive. The process of evolution developed effective mechanisms for the passive transfer of both systemic and mucosal immunity from the mother to her offspirng. Experimental passive transfer of systemic immunity via serum antibody is well established, but the experimental passive transfer of mucosal immunity has been accomplished only recently. This chapter addresses the contributions of both natural and experimental mechanisms to the study of passive immunization.

The transfer of systemic immunity (IgG) from mother to offspring occurs prenatally via the placenta or yolk sac and after birth via the colostrum. Species vary in the contribution each route makes to the transfer of immunity (Waldman and Strober, 1969) and can be grouped into three categories (Table  I) based on this variation.

The first group, using prenatal transfer only, includes primates, rabbits, and guinea pigs. Transport of IgG in primates occurs almost exclusively through the placenta. IgG transfer occurs via receptor-mediated transcytosis across the syncytiotrophoblast and transcellular transport through the fetal endothelium (Leach et al., 1990) . Human placental transfer of protective IgG antibodies against a number of pathogens including rotavirus (Hjelt et al., 1985) , hepatitis B (Hockel and Kaufman, 1986) , measles (Lennon and Black, 1986) , and group B streptococcus (Baker et al., 1988) has been reported. Prenatal transfer of IgG in the rabbit occurs via the yolk sac and in the guinea pig via both the yolk sac and the fetal gut (Waldman and Strober, 1969) .

The group using combined prenatal and postnatal transfer includes rats, mice, cats, and dogs. Prenatal transmission occurs via the yolk sac/placenta and the fetal gut in the rat (Waldman and Strober, 1969) . IgG is bound rapidly to receptors on the surface of the yolk sac membrane (Mucchielli et al., 1983) , endocytosed in clathrin-coated vesicles, and, early in gestation, is stored in subapical vacuoles. By late gestation, the antibody has been hydrolyzed or transferred to fetal capillaries (Jollie, 1985) . Prenatal transmission in mice occurs by a similar mechanism (Gardner, 1976) .

Although placental transfer occurs, studies in rodents have shown that most transport of antibody occurs postnatally from colostrum or milk (Nejamkis et al., 1975; Oda et al., 1983; Kohl and Loo, 1984; Arango-Jaramillo et al., 1988; Barthold et al., 1988; Heiman and Weisman, 1989) . Postnatal transmission of systemic immunity from colostrum and milk occurs over a period of 10-21 days, depending on the species, with a gradual decrease in transmission over the last 3 days of the period (Waldman and Strober, 1969) , and is limited to antibodies of the IgG class (Hammerberg et al., 1977; Appleby and Catty, 1983) . Transport is a receptor-mediated process (Simister and Rees, 1983) . In rats, the receptor is found in enterocytes of the proximal intestine during the early postnatal period but is absent after weaning (Jakoi et al., 1985) . The receptor is specific for IgG and its Fc fragment and consists of two similar polypeptides of 48,000-52,000 daltons (p51) in association with ß 2 -microglobulin (Jakoi et al., 1985; Simister and Mostov, 1989) . The Fc binding subunit (p51) has three extracellular domains and a transmembane region, all of which are homologous to the corresponding domains of Class I major histocompatibility complex (MHC) antigens (Simister and Mostov, 1989) .

Ruminants (cattle, sheep, goats), horses, and pigs (reviewed by Tizzard, 1987) use only postnatal transfer. Transport of colostral proteins from the lumen of the ileum in ruminants is largely nonspecific but, in the horse and pig, IgG and IgM are absorbed preferentially. Proteins are taken up actively by epithelial cells through pinocytosis and passed through these cells into the lacteals and intestinal capillaries (Tizzard, 1987) . Intestinal absorption occurs for only the first 24-48 hours after birth, then the "open gut" closes down and no further transfer from milk or colostrum occurs (Waldman and Strober, 1969; Francis and Black, 1984; Ellis etal., 1986; Tizzard, 1987) . Newborn piglets have also been shown to absorb colostral lymphoid cells during this time period (Tubolyitftf/.,1988) .

Absorption of colostral immunoglobulin is normally extremely effective, supplying the newborn with serum immunoglobulin (particularly IgG) at a level approaching that found in adults (Tizzard, 1987) ; however, failure of passive transfer -Guire et al., 1975; Tizzard, 1987) . In the McGuire study (1975) , 2 of 9 FPT foals died of infections within a few days of birth and 5 of the remaining 7 developed nonfatal respiratory infections between 2 and 5 weeks of age. McGuire et al. (1976) also reported FPT in calves, finding that 85% of calves less than 3 weeks old dying from infectious diseases had significant hypogammaglobulinemia. Although adequate methods to diagnose and treat FPT are available (Tizzard, 1987; Bertone et al., 1988) , the phenomenon remains a significant veterinary problem.

Mother's milk provides passive protection of the mucosal surfaces it contacts. This protection may be mediated by nonspecific factors found in milk, for example, lactoferrin, lysozyme, fatty acids, and complement, or by specific antibody (reviewed by Goldman et al., 1985) . The antibody composition of milk differs from that of colostrum (Tizzard, 1987) and the class of protective antibody in milk varies with the species and the route of immunization of the mother. With the exception of IgG in rodents, these protective antibodies are not absorbed systemically by the suckling offspring but exert their protective effect locally by neutralizing viruses or virulence factors and by binding to microbial pathogens to prevent their attachment to the mucosal surface (Goldman et al., 1985) . Secretory IgA is especially suited to this protective role since secretory component enhances its resistance to proteolytic enzymes and gastric acid (Kenny et al., 1967; Tomasi, 1970; Zikan*?/a/., 1972; Lindh, 1975) providing extra antibody stability in mucosal secretions.

Rodents have been a popular model for the study of passive transfer of maternal immunity via milk; however, this group of animals has a major drawback as a model for passive mucosal immunity. Rats and mice can actively transport IgG from the gut into the serum for approximately 2 weeks (Sec-Kathryn B. Renegar · Parker A. Small, Jr. tion I,A,2). Thus, observed protection could be the result of antibody in the milk bathing the mucosal surfaces or of maternal antibody being transported into the serum and secretions of the offspring. This caveat should be kept in mind during the evaluation of the many reports of milk-borne protection in these species. Three rodent models in which protection of mucosal surfaces is due to milk-borne, not serumderived, antibody are described here.

The predominant immunoglobulin in mouse milk is IgG, although significant levels of IgA can also be present (Ijaz et al., 1987) . Protection of infant mice from colonization with Campylobacter jejuni can be achieved by the consumption of immune milk at and after the time of bacterial challenge. The milk in this study contained high concentrations of specific IgG antibodies and very little specific IgA antibody; infant mice were not protected by prior consumption of colostrum. Milk antibody was required in the gut lumen for protection to be observed (Abimiku and Dolby, 1987) . A similar requirement for antibodies active at the intestinal cell surface in murine immunity to primate rotavirus SA-11 was reported by Offit et al. (1984) .

In rats, protection against dental caries by milk can be due to IgG or SIgA antibodies, depending on the route of maternal immunization. Rat dams immunized intravenously with heatkilled Streptococcus mutans developed IgG antibodies in their colostrum, milk, and serum. Their offspring demonstrated significant protection against S. mutans-maxxcea caries formation. Rat dams locally injected in the region of the mammary gland with heat-killed S. mutans or fed formalinkilled S. mutans developed SIgA antibodies in their colostrum and milk. Their offspring were also protected against caries formation (Michalek and McGhee, 1977) . Caries protection in suckling rats theoretically could be due to either bathing mucosal surfaces or antibody leakage into the saliva from the serum. Nonimmune adult rats can be protected from S. mwtans-induced caries by feeding on lyophilized immune bovine milk or on immune bovine whey containing specific IgG (Michalek et al, 1978a (Michalek et al, , 1987 . Since adult rats are unable to transport orally administered IgG into their serum, protection is from milk-derived antibodies bathing the oral cavity.

In ruminants (sheep, cattle, goats), the predominant antibody in both colostrum and milk is IgG,. The predominant antibody in the colostrum of pigs and horses is also IgG but, as lactation progresses and colostrum becomes milk, IgA predominates (Tizzard, 1987) . Protection can be mediated by either antibody class. Whereas bathing of the mucosal surfaces by milk-derived antibodies can provide passive immunity to some pathogens, the high rate of infections in FPT foals and calves shows that milk (mucosal immunity) alone cannot provide complete protection to neonates.

In cattle and pigs, passive immunity against enteric infections with viruses such as rotaviruses and coronaviruses [transmissible gastroenteritis (TGE)] is dependent on the continual presence in the gut lumen of a protective level of specific antibodies (Crouch, 1985) . In swine, passive immunity against intestinal infection with the TGE virus is generally more complete in piglets ingesting IgA antibodies than in those ingesting IgG antibodies, although both classes of antibody are protective. The class of antibody present in sow milk depends on the route of immunization (Bohl and Saif, 1975) . In cattle, passive immunity in calf scours (neonatal bovine colibacillosis caused by Escherichia coli) correlates with the level of specific IgA antibody in milk (Wilson and Jutila, 1976) .

In primates, IgA is the predominant immunoglobulin in both colostrum and milk (Tizzard, 1987) . Both lysozyme and SIgA in human milk remain bioavailable in the digestive tract of the early infant (Eschenburg et al, 1990) . Human milk has been shown to contain SIgA antibodies against at least five viruses and nine bacterial pathogens, as well as against fungi, parasites, and food antigens (Goldman et al., 1985) . Mucosal immunity to rotavirus, for example, was shown to be transferred to the infant by the SIgA in milk. A positive correlation was found between titers of secretory component in mother's milk and infant feces, and virus-specific IgA was found in infant fecal samples (Rahman et al., 1987) . In addition to providing passive mucosal immunity, human breast milk also stimulates the early local production of SIgA in the urinary and gastrointestinal tracts, thus accelerating the development of an active local host defense system in the infant (Prentice, 1987; Koutras and Vigorita, 1989) .

Since the first transfer of immunity by the injection of serum (von Behring and Kitasato, 1890), passive transfer of humoral immunity has been investigated intensively. The use of specific serum antibody (IgG) to transfer protection to nonimmune individuals has become so routine that it is now common medical practice in, for example, the postexposure prophylaxis of rabies and tetanus and the treatment of snakebite (Arnold, 1982; Centers for Disease Control, 1991a,b) .

Local immunity has been correlated with the level of IgA in various secretions (Table II) . However, direct demonstration of the mediation of local immunity by injected IgA could not occur until specific transport of passively administered IgA had been confirmed.

Mucosal Surfaces

In rabbits, rats, and mice, polymeric IgA can be and is transported efficiently from the circulation into the bile via the liver (Orlans et al., 1978 (Orlans et al., ,1983 Delacroix et al., 1982; Koertge and Butler, 1986a; Mestecky and McGhee, 1987) . These species express secretory component on their hepatocytes (Socken et al., 1979) and, in addition, have polymeric IgA as the primary molecular form in their serum (Vaerman, 1973; Heremans, 1974) . Serum IgA is also transported effi- ciently into bile in cattle (Butler et al., 1986) . In fact, most IgA in ruminant bile may be of serum origin.

Transport of serum IgA into bile in humans has been reported (Delacroix et al, 1982; Dooley et al, 1982) , although IgA transport is about 50-fold less efficient than in rats and rabbits. The human biliary IgA level is approximately 20% of the human serum IgA level and, under physiologic conditions, only 50% of human biliary IgA is derived from the serum (Vaerman and Delacroix, 1984) . Although transport is possible, passively administered IgA does not reach high levels in human bile. In one study, less than 3% of intravenously injected radiolabeled polymeric IgA was found in human bile after 24 hr (Vaerman and Delacroix, 1984) . This subject is reviewed in Chapter 10.

Serum polymeric IgA can be transported into saliva in dogs (Montgomery et al., 1977) , monkeys (Challacombe et al., 1978) , and humans (Delacroix et al., 1982; Kubagawa et al., 1987) . In humans, the amount of IgA acquired from the serum is low (only 2% from the serum) compared with the amount acquired from local production (Delacroix et al., 1982) . Transfer of polymeric IgA from serum into canine saliva is a selective process requiring secretory component (Montgomery et al., 1977) , whereas transport into oral fluids in monkeys appears to be by leakage from the plasma into the crevicular spaces surrounding the deciduous molars (Challacombe et al., 1978) .

In sheep, active transport of IgA from the circulation into milk seems likely (Sheldrake et al., 1984) ; however, studies on the transport of IgA into murine milk have produced conflicting results. Using radiolabeled IgA, Halsey et al. (1983) demonstrated in the mouse that IgA can be transported from the circulation into milk during early lactation. Other investigators (Russell et al., 1982; Koertge and Butler, 1986b) , using assays based on antibody-binding activity, were unable to show transport of IgA into murine milk. Using radiolabeled IgA, Koertge and Butler (1986b) were able to show that the IgA present in milk was degraded and suggested that the previous study (Halsey et al., 1983) detected only IgA fragments that had been transudated into the milk from the serum and not specifically transported IgA. Passively administered IgA is not transported into the milk of rats (Dahlgren et al., 1981; Koertge and Butler, 1986b) .

Only a limited number of studies on the transport of antibodies into respiratory secretions have been reported, but the results have shown that selective transport of passively administered serum IgA into the respiratory tract is possible in sheep and mice. Because of their importance as background information for the experiments demonstrating the passive transfer of local immunity by IgA, these respiratory transport studies will be addressed in more detail. a. Sheep. Using the intravenous (iv) injection of radioiodinated ovine immunoglobulin, Scicchitano et al. (1984) showed that 35% of the IgA in the mediastinal lymph of sheep is plasma derived. These investigators further demonstrated (Scicchitano et al., 1986) , by the simultaneous injection of Kathryn B. Renegar · Parker A. Small, Jr.

radiolabeled IgA and radiolabeled IgG, or IgG 2 , that IgA is transported selectively into ovine respiratory secretions. Transport of IgA, calculated 24 hr postinjection, was approximately 4.5 times greater than transport of IgG, and the transported IgA was intact in the secretions. Biologic activity of transported IgA was not determined. b. Mice. Mazanec et al. (1989) found that, 4-5 hr after the iv injection of radiolabeled monomeric or polymeric IgA anti-Sendai virus monoclonal antibodies into mice, transport of polymeric IgA into nasal secretions was 3-7 times more efficient than transport of monomeric IgA whereas polymeric IgA transport into bronchioalveolar la vages was only 1-3 times more efficient. This difference probably reflects an increased contribution of serum antibody to bronchioalveolar secretions because of the transudation of IgG into alevolar fluids. Transport of polymeric IgA into the gut was 4-5 times more efficient than the transport of monomeric IgA, as expected. The agreement of the nasal secretion and gut transport indices suggests that transport could occur by a similar mechanism. The investigators were unable to demonstrate the presence of functionally intact polymeric IgA in the upper respiratory tract.

The polymeric IgA transported into murine nasal secretions in the studies reported by Renegar and Small (1991a) was, in contrast, functionally intact. To avoid problems associated with the quantitation of intact compared with degraded radiolabeled IgA in secretions (described by Koertge and Butler, 1986b) , this study used an anti-influenza enzymelinked immunosorbent assay (ELISA) to evaluate the transport of monomeric or polymeric IgA or IgG! monoclonal antiinfluenza antibodies into the nasal secretions of mice. Any antibodies detected by this assay were, of necessity, functional. Nonimmune mice were injected intravenously with influenza-specific monomeric or polymeric IgA or IgG, and sacrificed at varying times between 2 and 24 hr postinjection. Nasal wash, serum, and bile samples were collected and assayed by ELISA for anti-influenza antibody. The peak nasal wash polymeric IgA titer was reached 4 hr after antibody injection and was approximately 35 times greater than the nasal wash titer of either monomeric immunoglobulin.

To determine whether polymeric IgA was transported selectively relative to IgG l5 the investigators injected a mixture of the two monoclonal antibodies intravenously into nonimmune mice and calculated a selective transport index (STI) for nasal antibody for each mouse. An STI greater than 1 indicates that polymeric IgA was transported specifically relative to IgGj whereas a value of 1 indicates that the same extent of transport, leakage, or transudation of both polymeric IgA and IgG, occurred in that animal. Of the 31 mice studied, 29 showed an STI greater than 1 (average STI at 4 hr was 36 ± 19) demonstrating the selective transport of polymeric IgA relative to IgGj. Selective transport of polymeric IgA relative to monomeric IgA was also demonstrated.

Thus, transport of serum IgA into nasal secretions is possible in some species. The relevance of this transport to the passive transfer of local immunity will be addressed in Section II,B,2,a.

Studies on the passive transfer of local immunity can be classified into two categories. In the first category are studies in which the antibody is introduced into the local secretions exogenously or mixed with the target pathogen prior to host challenge. The second category includes those studies in which systemically administered polymeric IgA must be transported physiologically (i.e., by secretory componentmediated mechanisms) to its site of activity.

The studies in this category have investigated the role of IgA in mucosal immunity by feeding antibody or instilling it intranasally, then challenging, or by administering antibody-pathogen mixtures intranasally.

a. Oral antibody. Offit et al. (1984) demonstrated the ability of milk-derived IgG and IgA to protect the murine intestine from infection with primate rotavirus SA-11. Suckling mice were protected by milk from dams that had been immunized orally with SA-11 virus. This protective activity was detected in both the IgG and IgA fractions, but the IgA fraction was more potent in vivo than the IgG fraction. In newborn mice from immune dams foster-nursed on seronegative dams, the presence of circulating systemic antirotavirus antibodies in high titer did not protect against SA-11 viral infection. Thus, the specific antibody had to be present in the gut lumen to protect the intestinal cell surface from viral infection, and SIgA could mediate this protection.

b. Intranasal antibody. Three studies have shown that exogenously administered IgA can protect against intranasal challenge with a pathogen. Bessen and Fischetti (1988) showed that SIgA given by the intranasal route protected mice against streptococcal infection. Live streptococci were mixed with affinity-purified human salivary SIgA or serum IgG antibodies directed toward the streptococcal M6 protein.

The mixture was administered intranasally to mice. The SIgA antibody protected against streptococcal infection whereas the serum antibody had no effect. This study suggested that SIgA alone is capable of protecting the mucosa against bacterial invasion. Mazanec et al. (1987) demonstrated that IgA can protect mucosal surfaces against viral infection. Ascites fluid containing IgA anti-Sendai virus monoclonal antibody was administered intranasally to lightly anesthetized mice before and after the mice were challenged intranasally with live virus. Mice were sacrificed 3 days later and lung viral titers were determined. Animals treated with the specific monoclonal antibody were protected against viral infection. Additional work from the same laboratory showed that local immunity to Sendai virus also can be mediated by intranasal IgG (Mazanec et al. (1992) . Tamura et al. (1991) purified anti-influenza SIgA antibodies from the respiratory tracts of mice immunized with influenza hemagglutinin molecules. This IgA, when given intranasally, protected nonimmune mice from influenza infection. Protection, which was observed up to 3 days after antibody administration, was proportional to the amount of IgA administered and was observed at IgA doses equivalent to naturally occurring antibody titers.

These studies show that local IgA or IgG can protect against viral or bacterial infection of the mucosa. They do not show that physiologically transported (secretory) IgA or serum-derived IgG actually does so. For that demonstration, antibody must be administered parenterally and transported into the mucosal secretions by a physiologic mechanism. The studies presented in the next section satisfy that criterion.

The definitive studies in this category have involved the respiratory and gastrointestinal tracts, although passive transfer of uterine immunity by polymeric IgA also has been observed (K. B. Renegar, A. C. Menge, P. A. Small, Jr., and J. Mestecky, unpublished results) . Work with the respiratory and gastrointestinal tracts will be presented in more detail.

a. Respiratory tract. Numerous studies have shown that passively administered serum anti-influenza antibody (IgG) can prevent lethal viral pneumonia (Loosli et al., 1953; Barber and Small, 1978; Ramphai et al, 1979; Kris et al., 1988) . Serum antibody, however, does not prevent influenza infection of the upper respiratory tract (Barber and Small, 1978; Ramphai et al. y 1979; Kris et al., 1988) . Protection of the nose correlates with an increased nasal secretion IgA antibody level (Table II) , making influenza an excellent model in which to investigate the hypothesis that nasal immunity is mediated by SIgA.

The first demonstration of the passive transfer of local immunity by physiologically transported SIgA was reported by Renegar and Small (1991a) in the murine influenza model. These researchers showed, as described in Section II,A,4,b, that intravenously administered polymeric IgA is transported into nasal secretions in a physiologic manner. To determine whether intravenously administered polymeric IgA anti-influenza monoclonal antibody could mediate protection against local influenza virus challenge, passively immunized mice were challenged intranasally while awake with influenza virus. The mice were sacrificed 24 hr later and the amount of virus shed in their nasal secretions was determined. Of the 24 saline-injected control mice, 23 shed virus into the nasal secretions whereas only 5 of the 25 polymeric IgAinjected mice shed virus; those 5 that did shed virus had a low viral titer. The observed protection was significant (p <0.001). Passive immunization with influenza-specific polymeric IgA, therefore, conferred complete protection against viral infection in 80% of the mice and partial protection in the remaining 20%.

To determine whether serum IgG! also could confer local protection to influenza challenge, the relative abilities of equivalent virus-neutralizing doses of influenza-specific polymeric IgA or IgG! to protect against influenza challenge were compared. Intravenous polymeric IgA significantly reduced viral shedding compared with either intravenous saline or intravenous IgGj. Intravenous IgG, also reduced viral shedding (p <0.02); however, the protection against infection was not significant (p = 0.5), since viral shedding was prevented in only 1 of 8 mice injected. Additional studies (K. B. Renegar and P. A. Small, Jr., unpublished results) have shown that IgG, can also mediate local protection against influenza infection, but 10 times the polymeric IgA protective dose is required to produce this protection.

The passive protection studies showed that IgA can mediate local immunity. To confirm that IgA is the mediator of local immunity, a method to abolish IgA-mediated protection was needed. Mice passively immunized with polymeric IgA were given nose drops of anti-IgA antibody 10 min before and 6 hr after they were challenged intranasally with influenza virus suspended in anti-IgA antiserum. Anti-IgA treatment abrogated IgA-mediated protection in the passively immunized mice (Renegar and Small, 1991a) . To show that passive transfer of local immunity by IgA was a reflection of the natural situation, the abrogation technique was extended to mice convalescent from influenza infection (Renegar and Small, 1991b) . Nonimmune mice and convalescent mice, that is, mice that had recovered from an influenza virus infection 4-6 weeks earlier and were therefore naturally immune, were treated intranasally with antiserum to IgA or IgG or with a mixture of antisera to IgG and IgM, then challenged while awake with influenza virus mixed with antiserum. Intranasal administration of antiserum was continued at intervals for 24 hr. Mice were killed 1 day after viral challenge, and their nasal washes were assayed for virus shedding (Figure 1 ). Nonimmune mice all became infected, regardless of whether the virus was administered in saline, normal rabbit serum, or anti-immunoglobulin antiserum. Convalescent mice, as expected, were protected from viral infection. Administration of influenza virus in either anti-IgG or a mixture of anti-IgG and anti-IgM antisera did not affect protection, that is, the convalescent mice were still immune. Administration of virus in anti-IgA antiserum, however, abrogated convalescent immunity. These results show that IgA is the major (if not the sole) mediator of mucosal immunity to influenza virus in the murine nose and suggest that passive immunization mimics the role SIgA plays in natural immunity.

b. Gastrointestinal tract. Additional evidence that secretory IgA is the mediator of local immunity comes from studies of the gastrointestinal tract. Polymeric IgA hybridomas against Vibrio cholerae were generated and the resulting monoclonal antibodies used to determine whether IgA can mediate immunity toward a bacterial pathogen in the gut (Winner et al., 1991) . The investigators selected a clone that produced dimeric monoclonal IgA antibodies directed against an Ogawa-specific lipopolysaccharide carbohydrate antigen exposed on the bacterial surface. These antibodies were able to cross-link bacterial organisms in vitro, suggesting that they might be effective in preventing mucosal colonization by the pathogen in vivo. To provide continuous physiologic (i.e., : nonimmune and convalescent mice were treated with 20 μ\ anti-IgG (anti-γ). Convalescent control mice were treated with saline. Experiment 5 (Δ): nonimmune and convalescent mice were treated with 20 μ\ anti-IgG and anti-IgM (anti-γ + μ). Convalescent control mice were treated with saline. EID 50 , 50% egg infective dose. Reprinted with permission from Renegar and Small (1991b) .

secretory component-mediated) transport of specific antibody into the gut, hybridoma cells were injected subcutaneously into the backs of adult BALB/c mice. These "backpack" tumors released monoclonal IgA into the circulation and the serum IgA was transported into the gut lumen. Neonatal mice bearing these backpack tumors survived challenge with V. cholerae whereas neonatal mice bearing backpack tumors of unrelated IgA hybridomas and non-tumor-bearing neonatal mice died. This ingenious model provides the first evidence that secretory IgA alone can mediate mucosal immunity to a bacterial pathogen and serves as the second example of the passive transfer of local immunity by IgA.

The general approach of passive parenteral transfer of mucosal immunity should be a useful research tool for determining the role of SIgA in protection against other pathogens and at other mucosal surfaces. The possibility of therapy by passively administered Ig A antibody is more problematic. Generation of gastrointestinal protection by feeding specific antibodies is certainly possible and already has been reported in cattle (Tsunemitsu et al. y 1989) . Passive protection by injection is, however, highly speculative because of the questionable efficiency of transport to the targeted mucosal surface and the potential adverse effects of intravenous IgA antibody. Serum IgA has been associated with both decreased complement activation (Russell et al., 1989) and decreased immune lysis (Griffiss and Goroff, 1983) . Systemically administered polymeric IgA may also be highly suppressive of both specific humoral and cellular responses (K. B. Renegar, S. Taylor, and P. A. Small, Jr., unpublished observations) . A more thorough knowledge of the role IgA can play in regulating the immune response is needed before passive mucosal immunization via parenteral antibody administration can become an acceptable means of therapy in humans.

The mechanism of protection of infant mice from intestinal colonisation with Campylobacter jejuni

Transmission of immunoglobulin to foetal and neonatal mice

Newborn rats in the murine typhus enzootic infection cycle: Studies on transplacental infection and passively acquired maternal antirickettsial antibodies

Rattlesnake Venoms; Their Actions and Treatment

Immunization of pregnant women with a polysaccharide vaccine of group B streptococcus

Local and systemic immunity to influenza infections in ferrets

Mouse hepatitis virus and host determinants of vertical transmission and maternally-derived passive immunity in mice

Enhanced murine respiratory tract IgA antibody respone to oral influenza vaccine when combined with a lipoidal amine (avridine)

Evaluation of a test kit for determination of serum immunoglobulin G concentration in foals

Passive acquired mucosal immunity to group A streptococci by secretory immunoglobulin A

Passive immunity in transmissible gastroenteritis of swine: Immunoglobulin characteristics of antibodies in milk after inoculationg virus by different routes

Subclass distribution and molecular form of immunoglobulin A hemagglutinin antibodies in sera and nasal secretions after experimental secondary infection with influenza A virus in humans

Correlation of host immune response with quantitative recovery of Chlamydia trachomatis from the human endocervix

Mucosal and systemic immunity to Campylobacter jejuni in rabbits after gastric inoculation

Rabies prevention-United States: Recommendations of the Immunization Practices Advisory Committee (ACIP)

Diptheria, tetanus, and pertussis: Recommendations for vaccine use and other preventative measures: recommendations of the Immunization Practices Advisory Committee (ACIP)

Passage of immunoglobulins from plasma to the oral cavity in rhesus monkeys

Intestinal defense of the neonatal pig; Interrelationship of gut and mammary function providing surface immunity against colibacillosis

Specific immune response in the respiratory tract after administration of an oral polyvalent bacterial vaccine. Infect. Immun

Vaccination against enteric rota and coronaviruses in cattle and pigs: Enhancement of lactogenic immunity

Dimeric IgA in the rat is transferred from serum into bile but not into milk

Secretory immune response in intestinal mucosa and salivary gland after experimental infection of pigs with transmissible gastroenteritis virus

Selective transport of polymeric immunoglobulin A in bile. Quantitative relationships of monomeric and polymeric immunoglobulin A, immunoglobulin M, and other proteins in serum, bile, and saliva

Hepatobiliary transport of plasma IgA in the mouse: contribution to the clearance of intravascular IgA

A comparative study of the biliary secretion of human dimeric and monomeric IgA in the rat and in man

The effect of colostrum-derived antibody on neonatal transmission of caprine arthritis-encephalitis virus infection

Fecal SIgA and lysozyme excretion in breast feeding and formula feeding

Nonreplicating oral whole cell vaccine protective against enterotoxigenic Escherichia coli (ETEC) diarrhea: Stimulation of anit-CFA (CFA/I) and anti-enterotoxin (anti-LT) intestinal IgA and protection against challenge with ETEC belonging to heterologous serotypes

Modes of action of poliovirus vaccines and relation to resulting immunity

The effect of vaccination regimen on the transfer of foot and mouth disease antibodies from the sow to her piglets

Localization of rabbit gamma globulins in the mouse visceral yolk sac placenta

Host defenses: Development and maternal contributions

IgA blocks IgM and IgGinitiated immune lysis by separate molecular mechanism

The origin of secretory IgA in milk: A shift during lactation from a serum origin to local synthesis in the mammary gland

Uptake of colostral immunoglobulins by the suckling rat

Transplacental or enteral transfer of maternal immunization-induced antibody protects suckling rats from type III group B streptococcal infection. Pediatr

Immunoglobulin A

Comparison of intranasal inoculation of influenza HA vaccine combined with cholera toxin B subunit with oral or parenteral vaccination

Rotavirus antibodies in the mother and her breast-fed infant

Placental transfer of class G immunoglobulins treated with beta-propiolactone (beta-PL) for intravenous application-A case report

Role of intestinal immunization in urinary tract defense

Effect of different routes of immunization with bovine rotavirus on lactogenic antibody response in mice

Transepithelial transport of maternal antibody: Purification of IgG receptor from newborn rat intestine

Saliva, breast milk, and serum antibody responses as indirect measures of intestinal immunity after oral cholera vaccination or natural disease

Immunocytochemical localization of antibody during placental transmission of immunity in rats

Effector mechanism of host resistance in murine giardiasis: Specific IgG and IgA cell-mediated toxicity

Antibodies in blood and secretions of chickens immunized parenterally and locally with killed Newcastle disease virus vaccine

Bacterial and viral coproantibodies in breast-fed infants

Combined parenteral and oral immunization results in an enhanced mucosal immunoglobulin A response to Shigellaflexneri

The enteric immune response to Shigella antigens

Dimeric mouse IgA is transported into rat bile five times more rapidly than into mouse bile

Dimeric M315 is transported into mouse and rat milk in a degraded form

The relative role of transplacental and milk immune transfer in protection against lethal neonatal herpes simplex virus infection in mice

Fecal secretory immunoglobulin A in breast milk versus formula feeding in early infancy

Passive serum antibody causes temporary recovery from influenza virus infection of the nose, trachea, and lung of nude mice

Analysis of paraprotein transport into the saliva by using anti-idiotype antibodies

Secretory IgA and serum type IgA in nasal secretions and antibody activity against the M protein

Immunity to vaginal reinfection in female guinea pigs infected sexually with Chylamydia of guinea pig inclusion conjunctivitis

The effects of oral and combined parenteral/oral immunization against an experimental Escherichia coli urinary tract infection in mice

Uptake and intracellular routing of peroxidase-conjugated immunoglobulin-G by the perfused human placenta

Maternally derived measles immunity in era of vaccine-protected mothers

Parenteral immunization with Shigella ribosomal vaccine elicits local IgA

Increased resistance of immunoglobulin dimers to proteolytic degradation after binding of secretory component

Airborne influenza virus A infection in immunized animals

Systemic immunization with pneumoccocal polysaccharide vaccine induces predominantly IgA 2 response of peripheral blood lymphocytes and increases both serum and secretory antipneumococcal antibodies

Hypogammaglobulinemia predisposing to infection in foals

Failure of colostral immunoglobulin transfer in calves dying from infectious disease

Immunoglobulin A monoclonal antibodies protect against Sendai virus

Transport of serum IgA into murine respiratory secretions and its implications for immunization strategies

Comparison of IgA versus IgG monoclonal antibodies for passive immunization of the murine respiratory tract

Influenza immunization: Intranasal live vaccinia recombinant contrasted with parenteral inactivated vaccine

Immunoglobulin A (IgA): Molecular and cellular interactions involved in IgA biosynthesis and immune response

Immunoglobulins coat microorganisms of skin surface: a comparative immunohistochemical and ultrastructural study of cutaneous and oral microbial symbionts

Effective immunity to dental caries: passive transfer to rats of antibodies to Streptococcus mutans elicits protection

Effective immunity to dental caries: Selective induction of secretory immunity by oral administration of Streptococcus mutans in rodents

Effective immunity to dental caries: Dose-dependent studies of secretory immunity by oral administration of Streptococcus mutans to rats

Oral adjuvants enhance IgA responses to Streptococcus mutans

Effective immunity to dental caries: Gastric intubation of Streptococcus mutans whole cells or cell walls induces protective immunity in gnotobiotic rats

Protection of gnotobiotic rats against dental caries by passive immunization with bovine milk antibodies to Streptococcus mutans

Ocular immunity to Staphylococcus aureus

Selective transport of an oligomeric IgA into canine saliva

Effective immunity to dental caries: enhancement of salivary anti-Streptococcus mutans antibody responses with oral adjuvants

A new experimental method for the dynamic study of the antibody transfer mechanism from mother to fetus in the rat

Systemic and local intestinal antibody response in dogs given both infective and inactivated canine parvovirus

Combined oral/nasal immunization protects mice from Sendai virus infection

Passive immunity against Junin virus in mice

Transplacental and transcolostral immunity to pertussis in a mouse model using acellular pertussis vaccine

A murine model of oral infection with a primate rotavirus (simian SA-11)

Immunization of the gastrointestinal tract with bacterial and viral antigens: Implications in mucosal immunity

Rapid active transport of immunoglobulin A from blood to bile

Comparative aspects of the hepatobiliary transport of IgA

Protective immunity evoked by oral administration of attenuated aroA Salmonella typhimurium expressing cloned streptococcal M protein

Significance of immune mechanisms in relation to enteric infections of the gastrointestinal tract in animals

Breast feeding increases concentrations of IgA in infants' urine

Local production of rotavirus specific IgA in breast tissue and transfer to neonates

Serum antibody prevents lethal murine influenza penumonitis but not tracheitis

Passive transfer of local immunity to influenza virus infection by IgA antibody

Immunoglobulin A mediation of murine nasal anti-influenza virus immunity

Potential for immunological intervention against dental caries

Preferential transport of IgA and IgA-immune complexes into bile compared with other external secretions

Anti-inflammatory activity of human IgA antibodies and their Fab'alpha fragments: Inhibition of IgG-mediated complement activation

Immunoglobulin-containing cells and the origin of immunoglobulins in the respiratory tract of sheep

Origin of immunoglobulins in respiratory tract secretion and saliva of sheep

Selective transport of serum-derived Ig A into mucosal secretions

An Fc receptor structurally related to MHC class I antigens

Properties of immunoglobulin G-Fc receptors from neonatal rat intestinal brush borders

Protective effect of antibody to parainfluenza type 1 virus

Identification of secretory component as an Ig A receptor on rat hepatocytes

Correlation between intestinal synthesis of specific immunoglobulin A and protection against experimental cholera in mice

Cross-protection against influenza A virus infection by passively transferred respiratory tract IgA antibodies to different hemagglutinin molecules

Veterinary Immunology-An Introduction

The structure and function of mucosal antibodies

Protection against bovine rotaviruses in newborn calves by continuous feeding of immune colostrum

Intestinal absorption of colostral lymphoid cells in newborn piglets

Role of the liver in the immunobiology of IgA in animals and humans

On the acquisition of immunity against diphtheria and tetanus in animals

Metabolism of immunoglobulins

Experimental neonatal colibacillosis in cows: Immunoglobulin classes involved in protection

New model for analysis of mucosal immunity: Intestinal secretion of specific monoclonal immunoglobulin A from hybridoma tumors protects against Vibrio cholerae infection

Studies on human secretory immunoglobulin A. V. Trypsin hydrolysis at elevated temperatures