Invited review Intestinal nematode parasites, cytokines and effector mechanisms

International Journal for Parasitology 17 "0887# 0034Ð0047

Invited review

Intestinal nematode parasites\ cytokines and e}ector mechanisms K[J[ Elsea\ Fred D[ Finkelmanb a

School of Biological Sciences\ University of Manchester\ 2[128\ Stopford Building\ Oxford Road\ Manchester M02 8PT\ U[K[ b Division of Immunology\ Department of Medicine\ University of Cincinnati College of Medicine\ PO Box 569452\ 120 Bethesda Avenue\ Cincinnati\ OH 34156!9452\ U[S[A[ Received 14 November 0886^ received in revised form 5 March 0887^ accepted 8 March 0887

Abstract Laboratory models of intestinal nematode infection have played an important role in developing our understanding of the immune mechanisms that operate against infectious agents[ The type of helper T cell response that develops following infection with intestinal nematode parasites is critical to the outcome of infection[ The early events that mediate polarisation of the helper T cell subsets towards either Th0 or Th1 during intestinal nematode infection are not well characterised\ but it is likely that multiple factors in~uence the induction of a Th0 or Th1 type response\ just as multiple e}ector mechanisms are involved in worm expulsion[ Costimulatory molecules have been shown to be important in driving T helper cell development down a speci_c pathway as has the immediate cytokine environment during T cell activation[ If helper T cells of the Th1 type gain ascendancy then a protective immune response ensues\ mediated by Th1 type cytokines and the e}ector mechanisms they control[ In contrast\ if an inappropriate Th0 type response predominates the ability to expel infection is compromised[ Equally important is the observation that multiple potential e}ector mechanisms are stimulated by nematode infection\ with a unique combination operating against the parasite depending on nematode species and its life cycle stage[ Despite the close association between intestinal nematode infection and the generation of eosinophilia\ mastocytosis and IgE it has been di.cult to consistently demonstrate a role for these e}ector cells:molecules in resistance to nematode parasites\ although mast cells are clearly important in some cases[ It therefore seems that\ in general\ less classical Th1 controlled e}ector mechanisms\ which remain poorly de_ned\ are probably important in resistance to nematode parasites[ Thus\ our understanding of both the induction and e}ector phases remains incomplete and will remain an intense area of interest in the coming years[ Þ 0887 Australian Society for Parasitology[ Published by Elsevier Science Ltd[ Keywords] Intestinal nematode parasites^ Th0^ Th1^ Cytokines^ E}ector mechanisms

0[ Introduction Intestinal nematodes are some of the most preva! lent infections of humans[ Estimates of the global

incidence of the major species\ Ascaris lumbricoides\ hookworm "Necator americanus and Ancylostoma duodenale# and Trichuris trichiura suggest that over 0999 million people are infected with each of these

Corresponding author[ Tel[] 9059!164!4124^ fax] 9050!164!4539^ e!mail] Kathryn[J[ElseÝman[ac[uk[ Abbreviations] Ag\ antigen^ APC\ antigen presenting cell^ B\ B cell^ Eos\ eosinophils^ M cell:baso\ mast cell:basophil^ IFN!g\ interferon gamma^ IL\ interleukin^ Mf\ macrophage^ MHC\ Major histocompatibility complex^ NK\ Natural killer cell^ Th\ T helper cell^ TCR\ T cell receptor[ S9919!6408:87 ,08[99¦9[99 Þ 0887 Australian Society for Parasitology[ Published by Elsevier Science Ltd[ Printed in Great Britain PII] S9919!6408"87#99976!2

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K[J[ Else\ F[D[ Finkelman : International Journal for Parasitolo`y 17 "0887# 0034Ð0047

parasite species ð0Ł[ Infections tend to be chronic\ have high reinfection rates and are typically over! dispersed with intense infections con_ned to the minority of the population ð1\ 2Ł[ Such intense infec! tions are associated with clinical disease but mod! erate levels of infection are also pathogenic\ having important developmental consequences\ par! ticularly for children ð3Ł[ Despite the chronic nature of many of these human nematode infections\ immunoepidemio! logical studies provide compelling evidence for the existence of protective immunity in the _eld ð4Ł[ In such studies behavioural\ nutritional and environ! mental factors represent multiple variables that compound to make _eld data complex and hard to interpret[ The development of well de_ned lab! oratory models of human infection has hence made a signi_cant contribution to our understanding of immunity to infection[ Indeed laboratory models have contributed to our understanding of immunity to infection at three levels] 0[ the types of T cell responses which control: regulate the e}ector response[ 1[ the events involved in initiating a particular type of T cell response[ 2[ the e}ector mechanisms responsible for worm expulsion[ Recent studies have concentrated on four main species of intestinal nematode parasites\ Nip! postrongylus brasiliensis\ Trichinella spiralis\ Helig! mosomoides polygyrus and Trichuris muris in the mouse[ Each parasite has its own unique life cycle characteristics] N[ brasiliensis and T[ spiralis both have tissue migratory larval stages^ adult stages of N[ brasiliensis and H[ polygyrus live in the gut lumen whilst T[ muris induces syncitium formation and lives completely or partially within the intestinal epithelial cells according to the stage of the parasite present\ and T[ muris occupies a niche within the large intestine whilst the other three parasites are small intestinal dwelling[ Not surprisingly\ there! fore\ each parasite provokes slightly di}erent immune responses in the host and requires a di}er! ent set of e}ector mechanisms to bring about expul! sion[ Important di}erences also exist in the ability of the mouse host to expel a primary infection with each of the four nematodes[ Thus\ primary infec!

tions with T[ spiralis and N[ brasiliensis are expelled from the mouse within weeks ð5Ð7Ł whereas the ability to expel a primary T[ muris infection is dependent on the strain of mouse infected ð8Ł[ In contrast primary infections with H[ polygyrus tend to be chronic\ although challenge infections are readily expelled ð09\ 00Ł[ Data on immunity to H[ polygyrus infection therefore are often based on the responses seen during a secondary infection[ 0[0[ Helper T cell subset development during intes! tinal nematode infection A central role for CD3¦ helper T cells in resist! ance to infection has been demonstrated for all four species by adoptive transfers and:or in vivo depletions of CD3¦ cells ð01Ð04Ł[ The discovery that CD3¦ T cells can be divided into at least two polarised helper T cell subsets\ Th0 and Th1\ in both humans and mice ð05\ 06Ł provided a basis for understanding the underlying cell regulatory mechanisms controlling resistance to infection[ Th0 and Th1 cell subsets are de_ned by the set of cyto! kines they secrete[ Thus Th0 type cells produce interferon!gamma "IFN!g#\ lymphotoxin\ and interleukin!1 "IL!1# whilst Th1 type cells secrete IL! 3\ IL!4\ IL!5\ IL!8\ IL!09 and IL!02[ A naive T cell can di}erentiate into either a Th0 or Th1 type cell\ passing through an intermediate stage where it has an unrestricted cytokine pro_le ð07Ð19Ł[ The di}er! entiation pathway towards either Th0 or Th1 is in~uenced by a number of factors\ the most potent of which seems to be the immediate cytokine environment a T cell experiences at the time of antigen presentation ð10\ 11Ł[ Thus\ IL!01 promotes the development of Th0 type cells whilst Th1 type cells develop in the presence of IL!3 ð12Ð15Ł[ The interaction between each cytokine and its receptor leads to the activation of signalling molecules including signal transducer and activator of tran! scription "STAT# proteins[ Two STAT proteins have been shown to be involved in helper T cell subset development] STAT!3 is activated by IL!01 and is important in the development of Th0 cells ð16Ð18Ł whilst IL!3 activates STAT!5 in Th1 cells ð29\ 20Ł[ Thus STAT!3 and STAT!5 knockout mice have reduced abilities to mount Th0 and Th1 type responses respectively ð21\ 22Ł[ Once an immune

K[J[ Else\ F[D[ Finkelman : International Journal for Parasitolo`y 17 "0887# 0034Ð0047

response starts to polarise it becomes progressively more polarised due to the cross!regulatory e}ects of each subset|s signature cytokines ð23\ 24Ł[ 0[1[ Th1 type responses are important in resistance to infection Analyses of cytokine mRNA expression during intestinal nematode infection or cytokines secreted after in vitro restimulation of draining lymph node cells reveal a dominant Th1 type response in mice resistant to intestinal nematode infection ð25Ð30Ł[ This is in contrast to the dominant Th0 type re! sponses triggered by intracellular pathogens such as Leishmania major during resolution of infection ð31Ł[ The clearest evidence for the importance of Th1 cytokines\ and speci_cally the Th1 cytokine IL!3\ in resistance to infection comes from the H[ poly! gyrus and T[ muris models[ The ability of mice to expel a challenge infection with H[ polygyrus can be blocked for at least 06 days post challenge using mAbs against IL!3 or its receptor\ which blocks the IL!02 receptor as well as the IL!3 receptor ð32Ł[ Control mice expel their challenge infection well within this time period[ Likewise\ host protective immunity to a primary T[ muris can be abrogated using mAbs against the IL!3 receptor ð33Ł[ This treatment results in the establishment of a chronic infection in a normally resistant strain of mouse and is accompanied by an upregulation of Th0 type responses "IFN!g production and IgG1a# and a downregulation of responses typically associated with Th1 cells such as IgE and IgG0 production\ eosinophilia and mastocytosis[ Data from gene!tar! geted mice support these in vivo ablation studies[ Thus\ IL!3 knockout mice\ which lack a functional IL!3 gene\ are susceptible to a primary T[ muris infection and are unable to mount a protective immune response to H[ polygyrus ð39\ 34Ł[ A central role for IL!3 in the development of resistance to these two intestinal nematode parasites has been further demonstrated by administering IL!3 as a complex with a neutralising anti!IL!3 mAb to mice with chronic infections[ IL!3 administered as an IL! 3 complex has an extended half life in vivo ð35Ł and facilitates expulsion of both T[ muris and H[ polygyrus ð33\ 36Ł[ IL!3 also appears to be important in the development of resistance to a primary infec!

0036

tion with T[ spriralis\ with mice treated with anti! IL3 receptor mAb exhibiting a prolonged adult infection and having higher muscle larval burdens ð39Ł[ The role of IL!3 in the development of protective immunity to a primary infection with N[ brasiliensis is more complex[ In dissecting out the involvement of IL!3 in resistance to this parasite\ an important and probably dominant role of another Th1 type cytokine\ IL!02\ has been revealed[ Thus\ IL!3 knockout mice expel N[ brasiliensis normally as do anti!IL!3 receptor mAb treated mice ð30\ 37Ł[ As mentioned above\ this antibody blocks both the IL! 3 and IL!02 receptor\ presumably via blocking the common IL!3 receptor alpha chain[ These obser! vations initially suggest that IL!02 is not responsible for the observed IL!3 independent worm expulsion[ However\ a series of recent experiments have shown that IL!3 receptor alpha knockout mice\ IL!3 knockout mice treated with the anti!IL!3 receptor mAb and STAT5 knockout mice all fail to expel a primary N[ brasiliensis infection ð38Ł[ Only IL!3 and IL!02 are currently known to cause STAT5 acti! vation by the IL!3 receptor alpha chain\ so taken together these data suggest that IL!02 can indeed mediate resistance to infection in the absence of IL! 3 and perhaps anti!IL!3 receptor mAb treatment does not lead to a complete blocking of the IL!02 receptor in immunocompetent mice[ Indeed\ treat! ment of N[ brasiliensis infected immunocompetent mice with a soluble IL!02 receptor alpha 1!human IgGFc fusion protein "sIL!02Ra 1!Fc# dramatically inhibits expulsion of N[ brasiliensis[ Fecund adult worms are still present 05 days p[i[ whereas control mice harbour no worms at this time point[ Impor! tantly\ IL!3 knockout mice treated in a similar man! ner with the sIL!02Ra 1!Fc\ harbour higher numbers of more fecund parasites than the immuno! competent sIL!02Ra 1!Fc!treated mice[ These data suggest that both IL!3 and IL!02 contribute to the expulsion of N[ brasiliensis\ operating through an IL!3 receptor alpha!dependent\ STAT5 dependent mechanism\ with IL!02 probably being quan! titatively the more important cytokine[ Inter! estingly\ although STAT5 knockout mice are unable to expel a primary N[ brasiliensis\ they do mount very strong anti!parasite IgG0 and IgG1 responses compared with wild type mice and

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develop a profound intestinal mastocytosis\ clearly implying that antibody and mast cells are not su.cient to expel N[ brasiliensis ð38Ł\ "see below#[ A role for IL!3 in controlling a normally redun! dant immune mechanism operating against N[ bra! siliensis has also been revealed by studies carried out in anti!CD3 treated mice and SCID mice[ Thus\ IL!3 complexes administered to these CD3¦ de_cient mouse models are su.cient to cause expul! sion of chronic N[ brasiliensis infectionsð36Ł[ IL!02 is also thought to be important in resist! ance to T[ muris[ During the generation of a pro! tective primary immune response to this parasite\ IL!02 is produced in large amounts[ Recent data have shown that mice with a targeted disruption in the IL!02 gene are fully susceptible to T[ muris infection unlike their wild type controls ð34Ł\ dem! onstrating the importance of this cytokine in the development of protective immunity[ A role for another Th1 type cytokine\ IL!8\ in resistance to both primary T[ spiralis and T[ muris infections is also evident[ Again\ this cytokine is produced in very high amounts by resistant strains of mice p[i[ and has been shown to increase resistance to these two parasites "ð49Ł\ Faulkner H\ Renauld J!C\ Van Snick J and Grencis RK\ unpublished#[ In the case of T[ spiralis\ IL!8 is probably acting via its role in enhancing Th1 type responses and\ speci_cally\ mastocytosis "see below#[ However\ although IL!8 seems to promote the loss of T[ muris\ the e}ector mechanisms operating are unknown[ Some of the di}erences and similarities in the protective immune responses which develop during infection of mice with each of the four species of intestinal nematode parasite are summarised in Table 0[

0[2[ Th0 type responses promote susceptibility to infection Arguably the best model for illustrating the del! eterious e}ects that Th0 cytokines have on host protective immunity to intestinal nematode infec! tion is T[ muris in the mouse[ Susceptible strains of mouse respond to a primary T[ muris infection by mounting an immune response characterised by high levels of IFN!g and parasite!speci_c IgG1a\ both hallmarks of a Th0 type response[ These mice go on to harbour long term chronic infections and are unable to expel the parasite ð25\ 26Ł[ If\ however\ susceptible strains are treated with anti!IFN!g mAbs during the early larval stages of infection\ they are able to expel the parasite and mount a Th1 type response ð33Ł[ Likewise treatment of sus! ceptible mice with anti!IL!01 mAbs early in infec! tion promotes resistance ðBancroft AJ pers commŁ[ Conversely\ treatment of normally resistant strains of mouse with IL!01 allows the establishment of a chronic infection\ with IL!01 having its e}ects via the induction of IFN!g ð40Ł[ IL!01 has also been shown to prolong infection with N[ brasiliensis and\ again\ the IL!01 e}ects are dependent on IFN!g ð41Ł[ 0[3[ Th1 controlled effector mechanisms The Th1 controlled e}ector mechanisms which limit intestinal nematode infection in most cases\ are unidenti_ed[ The Th1 type responses observed during intestinal nematode infection are accom! panied by an elevation in a number of parameters including eosinophilia\ intestinal mastocytosis and

Table 0 Di}erences and similarities in the protective immune responses that develop during infection of mice with the intestinal nematode parasites\ Trichinella spiralis\ Trichuris muris\ Heligmosomoides polygyrus\ and Nippostongylus brasiliensis Nematode

CD3¦Th1 mediated resistance

IL!3

IL!8

IL!02

Trichinella spiralis Trichinella muris Heligmosomoides polygyrus Nippostongylus brasiliensis

¦ ¦ ¦ ¦

¦ ¦ ¦ not essential

¦ ¦ < <

< ¦ < ¦

Th1\ T helper 1^ IL\ interleukin^ ¦\ thought to be important^ <\ involvement not known[

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IgE[ Although classical hallmarks of intestinal hel! minth infection\ a direct role for these e}ector cells:antibodies in resistance to infection has been di.cult to demonstrate[ However\ through selective ablation studies and the use of gene targeted mice\ it has been possible to address the role of speci_c components of the immune response observed in resistance to infection[ 0[4[ Eosinophils A signi_cant eosinophilia is observed during intestinal nematode infection and there is a marked increase in levels of IL!4\ the Th1 type cytokine responsible for the generation of eosinophils[ Despite this\ a protective role for eosinophils has not been identi_ed[ Thus\ treatment of mice with anti!IL!4 mAbs to ablate eosinophilia does not pre! vent the expulsion N[ brasiliensis ð42Ł\ T[ spiralis ð43Ł\ T[ muris "Betts CJ\ Else KJ\ unpublished#\ or H[ polygyrus ð32Ł\ strongly suggesting that eosino! phils are not a major e}ector mechanism against helminths that reside in the gut[ In contrast\ there is some evidence for an eosinophil mediated pro! tective immune response operating against the migratory tissue dwelling larval stages of two other nematodes\ Angiostrongylus cantonensis ð44Ł\ and Strongyloides venezuelensis ð45Ł[ 0[5[ Mast cells A prominent mastocytosis is observed during gut nematode infections and is controlled by a variety of Th1 type cytokines\ including IL!2\ IL!3\ IL!8\ IL!09 and the growth factor stem cell factor ð46Ð 54Ł[ Treatment of mice with anti!IL!2 and anti!IL! 3 mAb results in an 74) decrease in the mas! tocytosis observed during a primary N[ brasiliensis infection but does not prevent worm expulsion ð37Ł[ Likewise W:Wv mice\ which have a defect in the stem cell factor receptor c!kit\ and are thus de_cient in intestinal mast cells\ are still able to expel a N[ brasiliensis infection ð55Ł[ In addition\ and as men! tioned earlier\ STAT5 knockout mice develop a strong intestinal mastocytosis during N[ brasiliensis infection and yet are unable to expel this parasite ð38Ł[ The mast cell also seems to be non!essential in resistance to a primary infection with T[ muris[ Here

0038

treatment of mice with anti!IL!2 mAbs to partially depress the intestinal mastocytosis\ or with anti! bodies to the stem cell factor receptor\ which abro! gates mast cell development\ fails to alter the course of expulsion in resistant strains of mice "Betts CJ\ Else KJ\ unpublished#[ In contrast there is compelling evidence that the mast cell plays a major role in resistance to a pri! mary infection with T[ spiralis[ Infection of mice with T[ spiralis provokes a severe in~ammatory response in the small intestine with the mast cell representing a major component of this in~am! mation[ Measurements of mucosal mast cell speci_c proteases during infection have demonstrated that the mast cells are functionally active ð56Ł[ Early studies detected a delay in expulsion of T[ spiralis from W:Wv mice ð57Ł[ Subsequently it was dem! onstrated that antibodies to stem cell factor or its receptor\ c!kit\ inhibited the expulsion of a primary T[ spiralis infection and abrogated the mast cell response ð58Ł[ Evidence for a mast cell mediated e}ector mechanism operating against T[ spiralis is also provided by studies performed in IL!8 trans! genic mice[ These mice\ which constitutively over! express IL!8\ have heightened Th1 type responses in general and display extremely fast expulsion kin! etics[ However\ treatment of these mice with anti! c!kit mAbs dramatically delays worm expulsion\ accompanied by a severely depressed intestinal mastocytosis ð49Ł[ The mast cell may also play a role in resistance to H[ polygyrus[ A primary infection with this para! site is chronic in most strains of mouse and\ in general\ a mast cell response is absent[ Some strains however do eventually exhibit a protective immune response to a primary infection\ and expel the para! site ð28Ł[ In situations where worm expulsion is observed a mast cell response does begin to develop and\ in contrast to strains of mouse which cannot eliminate their worm burdens\ these resistant mice are able to maintain elevated levels of IL!2 and IL!8 ð28Ł[ Thus it would appear that there is an immunomodulatory e}ect of H[ polygyrus resulting in a selective down regulation of some Th1 associ! ated cytokines and the prevention of an appropriate e}ector mechanism[ In situations where mast cells appear to play an important role in resistance to infection\ the exact

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mechanism by which they do so has not been ident! i_ed[ It is likely that they contribute to a non!spec! i_c in~ammatory response within the gut through the secretion of in~ammatory mediators such as proteases and leukotrienes[ Leukotrienes and mast cell proteases are known to be produced during intestinal helminth infection ð56\ 69\ 60Ł and mast cell protease production in the rat has been shown to correlate with an increased permeability of the gut epithelium ð61Ł[ Such changes will contribute to the development of an environment that is poten! tially detrimental to worm survival[ Mast cell activation during parasitic infection represents another relatively unde_ned area[ Classi! cally\ mast cell activation involves the binding of IgE to the high a.nity IgE receptors "FcoRI# on mast cells\ and certainly an elevation in serum IgE is observed during infection[ However\ much of this IgE is non!speci_c and may even serve to promote worm survival by blocking the IgE receptors on mast cells thus preventing speci_c IgE from binding ð62Ł[ In addition\ it is clear from experiments using mice with a disruption in the g chain of the Fc receptor "FcgR knockout mice#\ which hence lack FcoRI\ that mast cell activation can occur inde! pendently of IgE[ Thus\ infection of FcgR knockout mice with T[ spiralis or T[ muris provokes an intes! tinal mast cell response accompanied by mast cell protease release and worm expulsion ðGrencis RK\ Betts CJ\ Ravetch J and Else KJ\ unpublishedŁ[ 0[6[ Antibody A Th1 controlled antibody isotype as an e}ector molecule in resistance to infection has been a fav! oured hypothesis over the years\ based on the ability to transfer protective immunity with large volumes of immune serum given early during infection ð63Ł[ As high levels of parasite!speci_c antibodies are not usually generated this early p[i[\ if antibody does play a role it may contribute more to resistance to secondary rather than primary infections[ Intestinal nematode infection is accompanied typically by elevations in IgG0 and IgE\ with both these isotypes under the control of Th1 type cytokines[ The pas! sive transfer of puri_ed IgG0 has implicated this isotype in resistance to H[ polygyrus ð64Ł and there is evidence from studies using T[ spiralis in the rat

that IgE may be important[ Here rapid expulsion can be transferred with puri_ed IgE antibody and suppression of the IgE response results in increased muscle larvae burdens ð65Ð67Ł[ However\ there are probably important di}erences in the e}ector mechanisms operating in the rat compared to the mouse[ Transfer of immunity to a primary T[ spi! ralis infection in the mouse using immune sera from infected mice has given equivocal results ð68\ 79Ł[ In contrast\ high levels of immunity can be achieved using sera from vaccinated mice ð70\ 71Ł[ This sug! gests that vaccination results in antibody responses quantitatively or qualitatively di}erent from those generated by infection and that the e}ector responses to T[ spiralis following infection and vac! cination are di}erent[ Despite these studies\ an essential role for antibody in resistance to gut para! sites has not been demonstrated[ This is typi_ed by studies conducted with T[ muris[ Here passive transfer studies have again shown that antibody can enhance resistance to infection ð72Ł[ However the adoptive transfer of highly pure immune CD3¦ T cells to SCID mice\ which lack functional B or T cells\ very readily protects these mice from a pri! mary T[ muris infection in the complete absence of an antibody response ð73Ł[ In addition some mice\ such as the IL!8 transgenic animals\ are able to mediate expulsion of T[ muris very rapidly in the absence of any detectable parasite speci_c anti! bodies "Faulkner H\ Renauld J!C\ Van Snick J\ Grencis RK\ unpublished#[ As mentioned above FcgR knockout mice are resistant to T[ muris infec! tion^ therefore a classical antibody:cell interaction is not necessary for worm expulsion[ A non!essen! tial role for antibody in protective immune responses is also seen in the context of N[ brasiliensis infection[ Here\ STAT5 knockout mice generate strong anti!parasite antibody responses yet cannot expel N[ brasiliensis ð38Ł and mice treated with anti! IgM produce little antibody but retain their ability to expel this parasite ð74Ł[ In contrast\ m chain de_cient mice\ which lack B cells\ develop more severe secondary H[ polygyrus infections than con! trol animals[ However this may be related to the importance of the B cell as an antigen presenting cell rather than re~ecting a lack of antibody ð39Ł[ Thus there are very few data to indicate that anti! body represents a principal e}ector mechanism in

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resistance to intestinal nematodes\ although rela! tively little attention has been paid to local as opposed to peripheral antibody production in the context of infection[ Thus\ antibodies secreted at mucosal surfaces may yet prove to be important in protective immunity to gut dwelling helminths[ 0[7[ Interleukin!3 As mentioned in the previous section\ CD3¦ T cells can transfer immunity to SCID mice in the absence of antibody and with no other potential classical e}ector mechanism "mastocytosis\ eosino! philia# correlating with resistance status[ This raises the question as to how the CD3¦ T cells are media! ting immunity[ One possibilty is that a Th1 cyto! kine\ and speci_cally IL!3\ could act as an e}ector molecule as opposed to simply directing and ampli! fying the helper T cell response towards Th1[ Cer! tainly there are strong data to suggest that IL!3 can mediate protection in this manner against at least some stages of some intestinal helminths[ Thus\ if mice with established H[ polygyrus infections are treated with IL!3 in the form of a complex with a neutralising anti!IL!3 mAb\ as outlined earlier\ a decrease in worm fecundity and worm numbers is observed ð36Ł[ These anti!parasite e}ects are accompanied by changes in gastrointestinal physi! ology including increased ~uid secretion and smooth muscle contractibility ð39\ 36Ł[ The e}ects of exogenous IL!3 treatment are only apparent against adult stages of the parasite and seem to involve the mast cell as they are not observed in IL!3 complex treated W:Wv mice[ IL!3 complex treatment of N[ brasiliensis!infected SCID mice is also anti!para! sitic[ Again the e}ects are directed against the adult stages of the parasite\ but in this model cure is more complete and the mast cell is not involved ð36Ł[ IL! 3 complex treatment fails to bring about expulsion of N[ brasiliensis in STAT5 knockout mice^ there! fore it is unlikely that IL!3 is operating via a direct action on the worm itself ð39Ł[ Indeed\ it is felt likely that the mechanism by which IL!3 is promoting adult worm expulsion is by inhibiting feeding through the observed changes in intestinal physi! ology ð39Ł[ In the context of T[ muris infection\ IL! 3 complex treatment brings about a decrease in the adult worm burdens of SCID mice but\ in common

0040

with the H[ polygyrus and N[ brasiliensis models\ has no e}ect against larval parasites ðElse\ Fin! kelman and Betts\ unpublishedŁ[ This raises the question of the importance of this sort of e}ector mechanism in vivo in a normally resistant host\ where worm loss occurs during the larval stages of parasite development[ Certainly in the CD3¦ to SCID adoptive transfer model\ worm loss is com! plete by the L2 stage[ In vivo tracking studies have shown that these CD3¦ T cells home to the gut epithelium of infected mice and peak in numbers at the time of worm expulsion\ raising the possibility of some form of CD3¦ mediated cytotoxicity operating in resistance to this intracellular helminth parasite ðElse and Betts\ unpublishedŁ[ 0[8[ Goblet cells and mucins Many intestinal nematode infections induce a goblet cell hyperplasia and an increase in mucin production\ with these changes thought to be at least in part under the control of a CD3¦ Th1 type response ð75\ 76Ł\ ðKhan and Grencis\ pers commŁ[ Although a feature of most intestinal nematode infections\ the role of the goblet cell in the protective immune response has not received much attention[ Possibly the strongest data for a role of the goblet cell in parasite expulsion are provided by the N[ brasiliensis model in the rat\ during both primary and challenge infections[ Here\ increases in goblet cell numbers and the quantity and quality of mucus secreted have been demonstrated ð77Ð89Ł[ Goblet cell hyperplasias are also prominent during primary infections of mice with T[ spiralis ð75\ 76Ł and T[ muris ðKhan and Grencis\ pers commŁ with a cor! relation between worm expulsion and peak mucin production observed for the latter parasite[ Table 1 summarises the possible involvement of candidate e}ector cells and molecules in resistance to T[ spir! alis\ T[ muris\ H[ polygyrus and N[ brasiliensis[ 0[09[ Factors in~uencing the polarisation of the helper T cell response The ability to divide helper T cells into de_ned subsets according to their cytokine pro_les has con! tributed signi_cantly to our understanding of the underlying cell regulatory mechanisms that control

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Table 1 The involvement of candidate e}ector cells and molecules in the protective immune response to intestinal nematode infection

Nematode

Eos

Mast cells

Antibody PT essential

Goblet cells:mucins

IL!3

Trichinella spiralis Trichinella muris Heligmosomoides polygyrus Nippostongylus[ brasiliensis

− − − −

¦ − 2 −

¦ ¦ ¦ ¦

correlate with resistance correlate with resistance correlate with resistance correlate with resistance

< 2 ¦ ¦

< no < no

eos\ eosinophils^ PT\ passive transfer of resistance^ −\ not involved^ ¦\ involved^ <\ involvement not known^ 2\ may play some role[

resistance and susceptibility to intestinal nematode infection[ It is apparent that resistance to this type of pathogen requires the development of a domi! nant Th1 type response with a Th0 dominated response being inappropriate for the generation of protective immunity[ Our knowledge of the actual Th1 controlled e}ector mechanisms that culminate in worm expulsion is less complete and varies according to the parasite species and developmental stage[ Likewise we are only just beginning to appreciate the developmental regulation of Th0 and Th1 type cells from naive precursors during infec! tion[ One of the critical in~uences in helper T cell subset polarisation has been shown to be the immediate cytokine environment at the time of anti! gen presentation\ with IL!01 promoting di}er! entiation towards Th0 cells and IL!3 promoting the development of Th1 type cells ð12Ð15Ł[ Both macrophages and dendritic cells are major IL!01 producing cells whilst the cellular source of early IL!3 production remains uncertain[ One possible candidate is the NK0[0¦ CD3¦ ab T cell[ Although there is little direct evidence implicating NK0[0¦ CD3¦ ab T cells as the early source of IL!3 during intestinal nematode infections\ they are known to produce IL!3 very quickly upon stimu! lation through CD2 ð80Ł[ These cells are thought to be stimulated by antigen presented by CD0 molecules\ rather than conventional MHC mol! ecules ð81Ł[ CD0 molecules are expressed at high levels on intestinal epithelium and thus are good candidates for presenting antigen from intestinal dwelling parasites ð82Ł[ The type of antigen presenting cell "APC# involved has also been shown to be important\ with

antigen presented by macrophages favouring Th0 development whilst antigen presentation by B cells appears to induce Th1 type responses ð83Ł[ Related to this\ the costimulatory interactions which occur between APC and T cell are also thought to be involved in helper T cell subset polarisation\ with attention centring on the interaction between B6 molecules on APCs and their counter receptors CD17 and CTLA3 on T cells ð84Ł[ It is in this area that most work on the induction of helper T cell subset during intestinal nematode infection has been conducted[ Initial studies involved the use of mice with experimental allergic encephalomyelitis ð85\ 86Ł[ Here it was demonstrated\ via the manipu! lation of the interactions between the B6 molecules on APCs and their ligands "CD17:CTLA3# on T cells\ that stimulation via B6!0 promoted a Th0 type response whilst stimulation through B6!1 resulted in a Th1 polarisation[ In the context of H[ polygyrus infection\ there is little evidence for the di}erential signalling of Th0 and Th1 type cells through B6!0 and B6!1[ Administration of CTLA3Ig "a chimeric fusion protein which binds to and blocks B6 mol! ecules# to H[ polygyrus infected mice inhibits the development of a Th1 type response ð87Ł and recent work\ using anti!B6!0 and anti!B6!1 mAbs\ has demonstrated that this Th1 type response is only blocked when mice are treated with both antibodies ð88Ł[ Thus\ either B6!0 or B6!1 is su.cient to stimu! late a Th1 response to H[ polygyrus[ In contrast\ antibodies directed against B6!1 alone prevent the generation of a Th1 type response in mice normally resistant to T[ muris and hence allows the estab! lishment of a chronic\ Th0 dominated infection ðElse KJ\ Bancroft AJ\ Abe R and Grencis RK\ unpublishedŁ[

K[J[ Else\ F[D[ Finkelman : International Journal for Parasitolo`y 17 "0887# 0034Ð0047

Other factors have also been implicated in deter! mining helper T cell subset di}erentiation[ In T[ muris infection\ antigen load has been shown to be important with a low level infection in a normally resistant\ Th1 dominated host promoting the devel! opment of a Th0 type response and susceptibility to infection ð099Ł[ Non!MHC linked genetic factors are also clearly important\ although they have not been studied in any great detail for intestinal nema! tode parasites[ It has been suggested that BALB:c mice develop a disease exacerbating Th1 type response to L[ major due\ in part\ to their inability to sustain IL!01 responsiveness[ The locus controlling this genetic e}ect maps to a region of chromosome 00 ð090\ 091Ł[ Finally\ although again not assessed for intestinal nematode parasites as yet\ it has been suggested that the binding a.nity of an antigenic determinant is crucial in the development of either Th0 or Th1\ with peptides binding with low a.nity to MHC Class II inducing a Th1 type response ð092Ł[ Thus\ there are several factors which are important in determining the developmental path! way a naive T cell takes towards either Th0 or Th1[ As the type of helper T cell response that develops has such a profound in~uence on host susceptibility or resistance to a pathogen\ the factors involved in inducing a polarised response will no doubt become an even more intensely studied area[

1[ General conclusions Whilst it is di.cult to make many gener! alisations\ two common features are apparent[ 0[ Resistance to intestinal nematode infections cor! relates with the ability to mount a CD3¦ Th1 type response[ 1[ Resistance to intestinal nematode infections is impaired by CD3¦ Th0 type responses[ The ability to expel an intestinal nematode infection clearly depends on CD3¦ T cells that can make Th1 type cytokines[ Although these cytokines typi! cally include IL!3\ IL!4\ IL!5\ IL!8\ IL!09 and IL! 02 it is likely that each species of nematode requires a unique set of Th1 type cytokines to initiate expul! sion[ IL!3 appears to be particularly important in the expulsion of H[ polygyrus\ IL!3 and IL!02 are

0042

involved in resistance to T[ muris\ whilst IL!3 inde! pendent e}ector mechanisms can operate against N[ brasiliensis\ with IL!02 being particularly important here[ Exactly how IL!3\ or indeed IL!02\ mediate resistance is unknown[ Although IL!3 can operate against adult stages of some parasites via changes in gut physiology\ it may promote resistance in a more natural situation by its role in promoting a Th1 type response in general[ Classically\ the Th1 associated hallmarks of intestinal parasitic infec! tion are eosinophilia\ mastocytosis and elevated IgE\ but it has been di.cult to demonstrate a role for these potential e}ector mechanisms in worm expulsion[ Certainly eosinophils do not appear to be important against intestinal dwelling worms and IL!4 is a non!essential cytokine in resistance to infection[ A stronger case can be made for the involvement of the mast cell in the expulsion of some parasites[ Mast cells contribute to the severe intestinal in~ammatory response that appears to result in loss of T[ spiralis[ It has been hard to show an essential role for IgE\ or indeed any of the Th1! controlled antibody isotypes\ in resistance to a pri! mary infection[ Indeed\ despite the fact that\ in general\ the passive transfer of immune sera increases resistance to a primary intestinal nema! tode infection\ there is little evidence to suggest that protection is defective in the absence of antibody[ It may be that the mechanisms employed during worm expulsion involve less well studied e}ector cells:e}ector molecules that are under the control of Th1 cytokines[ These Th1 type cytokines need not necessarily be produced by IL!3 dependent Th1 cells\ and indeed\ it has been shown that gene expression of some Th1 cytokines can occur in the absence of IL!3 ð093Ł[ In addition\ there is no evi! dence in any model of intestinal nematode infection that IL!01\ IFN!g and a Th0 dominated response can mediate protection[ A postulated sequence of events during intestinal nematode infection\ from antigen presentation through to the induction of the e}ector response\ is illustrated in Fig[ 0[ It is likely that infection with intestinal nematode parasites provokes the host into mounting a Th1 dominated response\ possibly by the recognition of some feature"s# common to all gut dwelling nema! todes[ Factors involved in driving a polarised Th1

0043

K[J[ Else\ F[D[ Finkelman : International Journal for Parasitolo`y 17 "0887# 0034Ð0047

Fig[ 0[ Postulated sequence of events during intestinal nematode infection\ from antigen presentation through to the induction of the e}ector response[ IL!3 production by naive Th cells and:or some other unidenti_ed cellular source\ polarises the Th response towards the Th1 cell subset and inhibits Th0 cell development "indicated by Ð#[ IL!8 is also thought to be a Th1 growth factor[ Costimulatory molecules "in particular the CD17!B6 axis# may also be important in this polarisation[ Th1 type responses protect the host against intestinal nematode infections and promote mastocytosis\ eosinophilia\ antibody production by B cells and probably goblet cell hyperplasia[ Some\ but not all\ of these Th1 controlled responses are implicated in the mechanisms mediating the expulsion of intestinal nematodes[ In addition\ IL!3 has been shown to be an important e}ector molecule in some systems[ Early production of IL!01 and IFN!g by APCs and NK cells respectively promote the development of Th0 cells and inhibit Th1 cell development[ Th0 type responses are associated with susceptibility to intestinal nematode infection\ induce the production of high levels of IgG1a and activate macrophages\ resulting in delayed type hypersensitivity responses[

type response may centre around the presence of IL!3 during early T cell activation and:or the loss of IL!01 responsiveness[ If the combined induction conditions in the host are conducive to the devel! opment of a Th1 type response\ the Th1 cells that develop\ control\ via the secretion of Th1 type cyto! kines\ multiple potential e}ector mechanisms[ The actual e}ector mechanisms employed against a speci_c parasite will vary from species to species and\ indeed\ may vary depending on whether larval or adult parasites are present and whether it is a primary or challenge infection[ A common theme in the development of protective immunity appears to be the creation of an environment hostile to worm survival[ Thus\ by the generation of in~am! matory responses in the gut\ by alterations in gut physiology\ by possibly antibody mediated inter! ference of feeding and by other\ as yet uncharac!

terised\ Th1 controlled e}ector responses\ parasites are damaged and ultimately forced from their niche within the host[

Acknowledgements We would like to thank our colleagues Dr Joe Urban\ Dr Bill Gause\ Dr Allison Bancroft and Dr Richard Grencis for their help over the years and for allowing us to discuss their unpublished data[ We would also like to thank Dr Waliul Khan for permission to quote unpublished work and we are grateful to Richard Grencis for his helpful dis! cussions and comments on the manuscript[ The work from our laboratories has been supported by the Wellcome Trust "Grant No[33383:Z:84:Z# and NIH grants RO0 AI24876 and RO0 AI26079[

K[J[ Else\ F[D[ Finkelman : International Journal for Parasitolo`y 17 "0887# 0034Ð0047

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immunity[ Expression of rapid expulsion of Trichinella spi! ralis in rats transfused with IgE and thoracic duct lym! phocytes[ J Immunol 0880^035]2452Ð2469[ Dessein AF\ Parker WL\ James SL\ David JR[ IgE antibody and resistance to infection[ I[ Selective suppression of IgE antibody response to Trichinells spiralis infection[ J Exp Med 0870^042]312Ð325[ McCoy OR\ Bond FF[ Attempted passive transfer to rats and mice of immunity to Trichinella spiralis[ J Parasitol 0830^16]13Ð14[ Denham DA[ Immunity to Trichinella spiralis IV Passive immunity in mice[ Folia Parasitologica 0858^05]072Ð076[ Jarvis LM\ Pritchard DI[ An evaluation of the role of carbo! hydrate epitopes in immunity to Trichinella spiralis[ Parasite Immunol 0881^03]378Ð490[ Robinson K\ Bellaby T\ Wakelin D[ Immunity to Trich! inella spiralis transferred by serum form vaccinated mice not protected by immunisation[ Parasite Immunol 0884^06]74Ð89[ Else KJ\ Wakelin D\ Wassom DL\ Hauda KMMH[ C! restricted antibody responses to Trichuris muris excretory: secretory "E:S# antigen[ Parasite Immunol 0889^ 01]498Ð406[ Else KJ\ Grencis RK[ Antibody independent e}ector mech! anisms in resistance to the intestinal nematode parasite Trichuris muris[ Infect Immunity 0885^53]1849Ð1843[ Jacobson RH\ Reed ND\ Manning DD[ Expulsion of Nippostongylus brasiliensis from mice lacking antibody pro! duction potential[ Immunology 0866^21]756Ð763[ Garside P\ Grencis RK\ Mowatt[ AMcI[ T lymphocyte dependent enteropathy in murine Trichinella spiralis infec! tion[ Parasite Immunol 0881^03]106Ð114[ Ishikawa N\ Wakelin D\ Mahida YR[ Role of T helper 1 cells in intestinal goblet cell hyperplasia in mice infected with Trichinella spiralis[ Gastroenterology 0886^002]431Ð 438[ Ishikawa N\ Horii Y\ Nawa Y[ Immune mediated alteration of the terminal sugars of goblet cell mucins in the small intestine of Nippostrongylus brasiliensis infected rats[ Immunology 0882^67]292Ð296[ Koninkx JF\ Mirck MH\ Hendriks HG\ Mouwen JM\ van Dijk JE[ Nippostrongylus brasiliensis] histochemical chan! ges in the composition of mucins in goblet cells during infection in rats[ Exp Parasitol 0877^54]73Ð89[ Miller HRP\ Huntley JF\ Wallace GR[ Immune exclusion and mucus trapping during the rapid expulsion of Nip! postrongylus brasiliensis from primed rats[ Immunology 0870^33]308Ð318[ Yoshimoto T\ Benedlac A\ Watson C\ Hu!Li J\ Paul WE[ Role of NK0[ 0¦ T cells in a Th1 response and in immu! noglobulin E production[ Science 0884^169]0734Ð0736[ Benedelac A\ Lantz O\ Quimby ME\ Yewdell JW\ Bennink JR\ Brutiewicz RR[ CD0 recognition by mouse NK0¦T lymphocytes[ Science 0884^157]752Ð754[ Porcelli S[ The CD0 family] a third lineage of antigen pre! senting molecules[ Adv Immunol 0884^48]0Ð17[ Gajewski TF\ Pinnas M\ Wong T\ Fitch FW[ Murine Th0 and Th1 clones proliferate optimally in response to distinct

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Trichuris muris signi_cantly a}ects the polarisation of the CD3 response[ Eur J Immunol 0883^13]2002Ð2007[ Guler ML\ Jacobson NG\ Gubler U\ Murphy KM[ T cell genetic background determines maintenance of IL!01 signaling[ E}ects on BALB:c and B09[ D1 T helper cell type 0 phenotype development[ J Immunol 0886^ 048]0656Ð0663[ Gorham JD\ Guler ML\ Steen RG\ et al[ Genetic mapping of a murine locus controlling development of T helper 0:T helper 1 type responses[ Proc Natl Acad Sci USA 0885^82]01356Ð01361[ Kumar V\ Bhardwaj V\ Soares L\ Alexander J\ Sette A\ Sercaz E[ Major histocompatibility complex binding a.nity of an antigenic determinant is crucial for the di}erential secretion of interleukin 3:4 or interferon!g by T cells[ Proc Natl Acad Sci USA 0884^81]8409Ð8403[ Subramanian G\ Kazura JW\ Pearlman E\ Jia X\ Malhotra I\ King CL[ B6!1 requirement for helminth!induced granu! loma formation and CD3 type 1 T helper cell cytokine expression[ J Immunol 0886^047]4803Ð4819[