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A retrospective evaluation of the role of T cells in the development of malaria vaccine

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A retrospective evaluation of the role of T cells in the development of malaria vaccine
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  A retrospective evaluation of the role of T cells in the developmentof malaria vaccine Moriya Tsuji * HIV and Malaria Vaccine Program, Aaron Diamond AIDS Research Center, New York, NY 10016, USA a r t i c l e i n f o  Article history: Received 19 October 2009Received in revised form 18 November 2009Accepted 22 November 2009Available online 26 November 2009 Keywords: MalariaCD8+ T cellsCD4+ T cellsHepatic stagesImmunityVaccine a b s t r a c t Due to the fact that the life cycle of malaria parasites is complex, undergoing both an extracellular andintracellular phases in its host, the human immune system has to mobilize both the humoral and cellulararms of immune responses to fight against this parasitic infection. Whereas humoral immunity is direc-ted toward the extracellular stages which include sporozoites and merozoites, cell-mediated immunity(CMI), in which T cells play a major role, targets hepatic stages – liver stages – of the parasites. In thisreview, the role of T cells in protective immunity against liver stages of the malaria infection is beingre-evaluated. Furthermore, this review intends to address how to translate the findings regarding the roleof T cells obtained in experimental systems to actual development of malaria vaccine for humans.   2009 Elsevier Inc. All rights reserved. 1. Role of CD8+ T cells against murine malaria The first observation of a successful induction of sterileimmunity against malaria infection, i.e. protective immunity thatcan totally protect against subsequent infection, was made byNussenzweig and Vanderberg in mice immunized with radiation-attenuated sporozoites (IrSp) of rodent malaria parasites, Plasmodium berghei (Nussenzweig et al., 1967). Initiallythis power-ful protectiveimmunityinduced by IrSp was shown to be primarilymediated by humoral immunity – neutralizing antibodies againstsporozoites (Potocnjak et al., 1980; Yoshida et al., 1980). More re-cently, however, two independent studies involving the depletionof CD8+ T cells from immunized mice  in vivo , demonstrated thatthe immunity induced by IrSp was also, in part, contributed byCD8+ T cells (Schofield et al., 1987; Weiss et al., 1988). In thesestudies, a group of IrSp-immunized mice were depleted of CD8+T cell population just prior to malarial challenge, and it was foundthat CD8+ T cell-depleted mice, unlike untreated mice, failed tomount protective immunity against malaria. This observation pre-sents strong evidence of the significant role performed by CD8+ Tcells in protective immunity against pre-erythrocytic stages of ro-dent malaria, consisting of the sporozoite and liver stages. Soonafterwards, the protective role of CD8+ T cells was further definedby adoptive transfer studies (Rodrigues et al., 1991; Romero et al.,1989). In these studies, CD8+ T cell clones against an immunodom-inant CD8+ T cell epitope of the circumsporozoite (CS) protein,a major sporozoite antigen, were generated and then transferredinto naïve mice followed by infection with live malarial sporozo-ites. Adoptive transfer of CS antigen-specific CD8+ T cell clonescould confer protection against subsequent malarial challenge,indicating that CD8+ T cells play a key role in conferring protectionagainst rodent malaria, including  P. berghei  and  Plasmodium yoelii .In the latter study, the parasite load in the liver was measured bydetermining the amount of parasite-specific ribosomal RNA(rRNA), and it was found that CD8+ T cell clones displayed theirprotective effect by inhibiting the parasite development in the liver(Rodrigues et al., 1991). This indicates that CD8+ T cells are indeedcapable of attacking the hepatic stages of malaria parasites. It isnoteworthy that the subsequent study by Rodrigues et al. foundthat adoptive transfer of only CD44 high , but not CD44 low , CD8+ Tcell clone specific for the CS protein could confer protection. Thisstudy also found that the protective capacity of the CD44 high CD8+ T cell clone is associated with their ability to home in onthe proximity of malaria-infected hepatocytes upon adoptivetransfer  in vivo  (Rodrigues et al., 1992). Interestingly, there wasno clear correlation between the ability of the CD8+ T cell clonesto confer protection and their ability to secrete IFN- c , TNF- a , serineesterase or perforin, nor was there any link to their ability to lysethe target cells.The protective role of CD8+ T cells was also shown in micehaving received immunization of other forms of malaria vaccines.The first group to show that recombinant vaccine induces CD8+ Tcell-mediated protection against malaria was the group led by 0014-4894/$ - see front matter    2009 Elsevier Inc. All rights reserved.doi:10.1016/j.exppara.2009.11.009 *  Fax: +1 212 725 1126. E-mail address:  mtsuji@adarc.org.Experimental Parasitology 126 (2010) 421–425 Contents lists available at ScienceDirect Experimental Parasitology journal homepage: www.elsevier.com/locate/yexpr  Sadoff et al. (1988). This group showed that oral immunizationwith a recombinant  Salmonella typhimurium  expressing  P. berghei CS protein induces protective immunity against a  P. berghei  sporo-zoite challenge and that this immunity is mediated by CD8+ T cells,since depleting the CD8+ T cells  in vivo  abrogated the protection(Sadoff et al., 1988). Later, the same group showed that immuniza-tion of mice with a recombinant vaccinia virus expressing  P. berg-hei  CS protein could elicit a high level of protection, which did notcorrelate with CS repeat-specific antibody responses and was abro-gated by  in vivo  CD8+ T cell depletion (Lanar et al., 1996). We haveshown that immunization with a single immunizing dose of a re-combinant adenovirus expressing the CS protein of   P. yoelii  couldinduce a very potent protective immunity against the liver stagesof malaria and that the level of protective immunity was dimin-ished to a large degree, i.e. 60%, upon depleting the CD8+ T cellpopulation, whereas CD4+ T cell depletion reversed the level of protective immunity to a lesser degree, <20% (Rodrigues et al.,1997). More recently, Jobe et al. have found that three doses of vac-cination with genetically attenuated  P. berghei  sporozoites induceda sterile immunity in mice and that the sterile immunity observedin wild-type mice was abolished in mice lacking  b 2-microglobulin( b 2m) ( Jobe et al., 2007). And most recently, Schmidt et al. wereable to elicit a very high frequency of CS antigen-specific CD8+ Tcells that last more than a year. This was achieved by priming micewith dendritic cells (DCs) pulsed with a peptide corresponding tothe CD8+ T cell epitope of the CS protein followed by boosting witha recombinant  Listeria monocytogenes  expressing the same CS anti-gen-derived CD8+ T cell epitope. The CS antigen-specific memoryCD8+ T cells mediated a life-long protection in mice (Schmidtet al., 2008). Subsequently, Schmidt et al. have also shown thatthe induction of a high level of CS antigen-specific CD8+ T cell re-sponse by this immunization regimen permitted mice to developsterilizing sporozoite-specific antibodies after repeated asymp-tomatic challenges with physiologic numbers of viable sporozoites(Schmidt et al., 2009). Altogether these studies further confirm thekey role of CD8+ T cells in protective anti-malaria immunity,regardless of immunogens used under different experimentalsettings.A groupled by Zavalagenerated T cell receptor (TCR)-transgenicmice expressing a T cell receptor (TCR), based on the TCR sequenceof CS antigen-specific CD8+ T cell clone recognizing the immuno-dominant CD8+ T cell epitope of the  P. yoelii  CS antigen as usedin the study described above (Sano et al., 2001). Using the TCR-transgenic mice, this group yielded several key findings. First, theyshowed that the  in vivo  presentation of the CD8+ T cell epitope of the CS protein occurs within a relatively short period of time, i.e.<48 h (Hafalla et al., 2002). Second, the proper development of CSantigen-specific, protective CD8+ T cell response requires IL-4 se-creted by CD4+ T cells (Carvalho et al., 2002). Lastly, after an infec-tious mosquito bite, CS antigen-specific, protective CD8+ T cellresponse induced are primed by dendritic cells (DCs) that residein skin-draining lymph nodes (Chakravarty et al., 2007).Besides the CS protein, thrombospondin-related anonymousprotein (TRAP), or sporozoite surfaceprotein 2 (SSP2), is the secondT cell antigen that has been well characterized (Rogers et al.,1992b). Antibodies to extracellular domains of TRAP have no effecton sporozoite infectivity, because TRAP is localized in micronemes(Muller et al., 1993; Rogers et al., 1992a). Therefore TRAP vaccinescan only be effective by generating T cell responses. In fact, TRAPhas been shown to induce a specific CD8+ T cell response, andcloned TRAP-specific CD8+ T cells were shown to contribute to pro-tection against malaria challenge, upon their adoptive transfer(Khusmith et al., 1991). The last pre-erythrocytic antigen thatcan induce ‘‘protective” CD8+ T cell response is called PyHep17.This was supported by the study in which immunization of micewith a naked DNA encoding PyHep17 could induce protectiveimmunity that is mediated by CD8+ T cells (Doolan et al., 1996).Most recently, using CS-transgenic JHT mice, in which immune re-sponse to the CS antigen is tolerated and, in addition, generation of antibodies is impaired, Kumar et al. have found that hyper-immu-nizing these mice with IrSp of   P. yoelii  could induce a very strongprotective anti-malaria immunity. This protection is mainly medi-ated by CD8+ T cells, since the depletion of CD8+ T cells abolishedthe protection (Kumar et al., 2006). This finding underscores thepresence of protective CD8+ T cell responses against sub-dominantnon-CS antigens in IrSp.As for the questions regarding how CD8+ T cells exert theirinhibitory activity against the liver stages, it was earlier believedthat IFN- c  might be one of the key players that mediate the anti-plasmodial effects of CD8+ T cells againstthe liver stages of malariabased on the following three sets of studies. A first study showedthat the inoculation of a recombinant IFN- c  into malaria-infectedmice resulted in a strong inhibition of the liver stage developmentin their liver (Ferreira et al., 1986). The second study showed thatthe administration of neutralizing anti-IFN- c  antibody tosporozoite-immunized mice abrogated the protection against spo-rozoite-induced malaria (Schofield et al., 1987), and in the laststudy, a single immunizing dose of IrSp, which could mount a pro-tective immunity in wild-type mice, had failed to do so in IFN- c receptor-deficient mice (Tsuji et al., 1995). Collectively, these stud-ies highlighted the role of IFN- c  in mediating protective immunityagainst pre-erythrocytic stages. More recently, however, our grouphas shown that, in contrast to sporozoite-induced immunity that ismediated by IFN- c , a single immunizing dose of a recombinantadenovirus expressing the CS protein was able to induce CD8+ Tcell-mediated protective immunity against the liver stages, whichis independent of IFN- c  (Rodrigues et al., 2000). These findingswere later corroborated by the study, in which CS-specific trans-genic CD8+ T cells derived from IFN- c -deficient mice immunizedwith a recombinant vaccinia virus expressing the CS protein wereable to display anti-liver stages activity upon adoptive transfer(Chakravarty et al., 2008). I would liketo emphasize that,therefore,at present it is still not clear whether IFN- c  plays a vital role inmediating anti-liver stages effects of CD8+ T cells.Although the role of nitric oxide, which is induced intracellu-larly by IFN- c , in protective immunity against the liver stageshad been investigated using its antagonists, the conclusions re-main inconclusive (Doolan et al., 1996; Mellouk et al., 1991,1994; Seguin et al., 1994). In addition, mice lacking perforin orFas were still able to induce protective immunity against sporozo-ite-induced malaria, thereby suggesting that these molecules donot mediate anti-parasitic activity of CD8+ T cells (Renggli et al.,1997). However, it is important to be cautious in interpreting theresults whenever genetically engineered knock-out mice are usedin the experiments, because of the presence of a compensatorymechanism in these mice. In fact, the study by Doolan and Hoff-man indicated the complexity of protective immunity against li-ver-stage malaria, by showing that distinct mechanisms of protection are induced in different strains of inbred mice by a sin-gle immunizing dose of IrSp, and in the same strain by differentmethods of immunization, such as sporozoites and DNA (Doolanand Hoffman, 2000). In conclusion, the effector mechanisms bywhich CD8+ T cells attack the liver stages remain uncovered, andfurther studies are required to identify the key molecule that med-iated anti-liver stages activity of CD8+ T cells.Another key issue on the effector mechanisms of anti-malarialCD8+ T cells is how CD8+ T cells is able to recognize or identify ma-laria-infected hepatocytes among so many uninfected hepatocytesin order to exert their anti-parasite activity. In early studies, CSantigen-specific CD8+ T cells were isolated from mice receivingimmunization with IrSp. When these isolated CS antigen-specificCD8+ T cells were co-cultured  in vitro  with MHC-matched primary 422  M. Tsuji/Experimental Parasitology 126 (2010) 421–425  hepatocytes infected with live sporozoites, they could inhibit theliver stage development only in the presence of a peptide corre-sponding to the CD8+ T cell epitope of the CS protein (Weisset al., 1990). This was the first demonstration uncovering themechanisms underlying how malaria-immune CD8+ T cells displaytheir anti-parasitic activity. The essential role of MHC class I mol-ecules in mediating CD8+ T cell-dependent anti-malaria immunitywas shown by the study in which adoptively transfer of malaria-immune splenocytes into  b 2m-deficient mice failed to conferprotection (White et al., 1996). A most recent study using TCR-transgenic mice showed that CS protein-specific CD8+ T cells candisplay anti-parasitic activity in the absence of MHC-matchedhematopoietic cells in the recipient bone marrow chimeric mice(Chakravarty et al., 2007). This indicates that malaria-specificCD8+ T cells do not require bone marrow-derived antigen-present-ing cells for protection, but instead, they recognize antigen onparenchymal cells – presumably parasitized hepatocytes. Futurestudies will hopefully yield compelling evidence for the indispens-able role of MHC class I molecules expressed by hepatocytes forCD8+ T cells to recognize the parasites and exert their anti-plasmo-dial activity  in vivo .The final question with regards to the role of CD8+ T cells inprotective anti-malaria immunity is how malaria antigen-specificCD8+ T cells get elicited  in vivo . One group has shown that DCs,particularly those reside in cutaneous lymph nodes, are responsi-ble for priming malaria antigen-specific CD8+ T cells after an infec-tious mosquito bite (Chakravarty et al., 2007). This was shown bythe fact that the ablation of the skin-draining lymphoid sites im-pairs subsequent development of protective immunity. However,another group has shown that liver DCs, particularly those expressCD8 a , present malarial antigen to hepatic CD8+ T cells ( Jobe et al.,2009). It is interesting to note that this group immunized micethrough intravenous inoculation of IrSp. Lastly, there are a coupleof studies presenting evidence that hepatocytes are the ones thatpresent malarial antigens to CD8+ T cells. In one study, livers wereisolated from mice immunized with IrSp, followed by being adop-tively transferred to intrasplenically to mice (Renia et al., 1994).These mice could mount a protective immunity that preventedsome of the mice from malaria infection. In a more recent study,primary hepatocytes were infected with live sporozoites  in vitro ,and then their ability to process and present the CS antigen toCD8+ T cells had been investigated (Bongfen et al., 2007). Theyshowed that infected primary hepatocytes are able to processand present the CS antigen to specific CD8+ T cells, which is largelydependent on proteasomes. Although these studies together dem-onstrated the capability of hepatocytes as an antigen-presentingcell (APC) to process and present exo-erythrocytic antigens, it isunclear to which extent hepatocytes contribute as APCs  in vivo after malaria-infected mosquito bites. Overall, the major cell typesthat process and present exo-erythrocytic antigens remain un-known and further studies are required to solve this importantissue. 2. Role of CD8+ T cells against human malaria In contrast to the amassed experimental proof of the protectiverole of CD8+ T cells in anti-malaria immunity in a mouse model,there are only a few circumstantial evidence for their role in hu-man malaria. One of the first studies to demonstrate the protectiverole of CD8+ T cells against humanmalaria was done by a groupledby Hill, who showed that HLA-B53 MHC class I allele was associ-ated with protection from severe forms of   Plasmodium falciparum malariainfection inAfrican children (Hill et al., 1992). In this study,HLA-B53-restricted CD8+ T cells were found to recognize aconserved nonamer peptide from LSA-1 antigen among malaria-immune Africans. The same group later identified HLA-B53-re-stricted CD8+ T cell responses against several epitopes present inLSA-3 antigen, as well as in Exp-1, the homolog of PyHEP17 that in-duces a CD8+ T cell-mediated protection in a rodent malaria modelas described above (Aidoo et al., 2000). In the same year, a CD8+ Tcell clone specific for HLA-A2-restricted CD8+ T cell epitope of the P. falciparum  CS protein was establishedfrom an adult living in ma-laria endemic area in Africa (Bonelo et al., 2000), and it was shownthat the CD8+ T cell clone could efficiently get activated upon rec-ognizing human hepatocytes infected with a recombinant vacciniavirus expressing the  P. falciparum  CS protein (Bonelo et al., 2000).More recently, taking advantage of newly available genomic infor-mation, HLA-supertype considerations, and  in vitro  IFN- c  Elispotassay, one study elegantly identified several novel antigens thatcan induce a significant CD8+ T cell response in people immunizedwith IrSp and protected from malaria challenge (Doolan et al.,2003). Surprisingly, although CD8+ T cell responses were detectedagainst well known pre-erythrocytic antigens including CS protein,TRAP, LSA-1 and Exp-1, these responses did not seem to be associ-ated with protection, since the CD8+ T cell responses against theseantigens were higher in sporozoite-immunized individuals whowere not protected from malaria challenge. This is most likelydue to the widely diversified nature of HLAs in humans, which pre-vents against skewing toward a few immunodominant antigens. Inanycases, the use of cutting-edgebioinformaticsand othermodernimmunological tools may lead us to identify key antigens that canelicit protective CD8+ T cell responses in humans, thereby ulti-mately providing us the evidence to support the protective roleof CD8+ T cells against human malaria. 3. Role of CD4+ T cells against murine malaria The role of CD4+ T cells as anti-malarial effector CD4+ T cellswas first shown by our study in which a CD4+ T cell clone wasestablished that recognizes an antigen shared by both the sporozo-ite and blood stages of rodent malaria parasites and adoptivelytransferred into mice for the purpose of determining the protectiveeffect of the CD4+ T cell clone (Tsuji et al., 1990). Upon its adoptivetransfer, mice were protected from subsequent malarial sporozoitechallenge and did not develop parasitemia. This protection is stagespecific, since an adoptive transfer of this CD4+ T cell clone failedto confer protection against blood stages of malaria infection (Tsujiet al., 1990). Taken together, this study indicates that this CD4+ Tcell clone specific for yet unidentified antigen plays a definite rolein mediating protective immunity against pre-erythrocytic stages,but not blood stages of malaria. Soon after, CD4+ T cell clonesagainst either immunodominant or cryptic epitopes of the CS pro-tein were established and adoptively transferred to naïve miceprior to sporozoite challenge (Renia et al., 1993; Takita-Sonodaet al., 1996). Interestingly, regardless of Th1 or Th2 profile of theCD4+ T cell clones, they were able to confer protection againstmalaria.The protective role of CD4+ T cells against rodent malaria wasalso shown in other antigens besides the CS antigen. It was demon-strated that protective anti-malaria immunity induced by immuni-zation with synthetic peptides corresponding to either TRAP orHep17 protein of   P. yoelii  was abolished by way of depletingCD4+ T cell population (Wang et al., 1996).The relative contribution of CD4+ T cells in protective immunityagainst pre-erythrocytic stages of malaria was first shown byWeiss et al, who depleted CD4+ T cells from a group of mice priorto sporozoite immunization (Weiss et al., 1993). The CD4+ T celldepletion treatment caused loss of protection in sporozoite-immu- M. Tsuji/Experimental Parasitology 126 (2010) 421–425  423  nized mice against malaria challenge. Because this CD4+ T celldepletion had also abolish the ability of B cells to produce neutral-izing antibodies against sporozoites, they infused hyperimmunesera but had no effect on restoring immunity in CD4+ T cell-de-pleted mice. It still remains possible that the absence of CD4+ Tcells might have some influence on the competent function of CD8+ T cells. Nevertheless, this study demonstrated the overallcontribution of CD4+ T cells as helper CD4+ T cells, as well as cyto-toxic CD4+ T cells, in protective immunity against pre-erythrocyticstages of rodent malaria. For the purpose of determining the rela-tive contribution of CD4+ and CD8+ T cells in mediating protectiveanti-malaria immunity, Rodrigues et al. depleted B cells from B10mice, carrying H-2 b haplotype, before giving a single immunizingdose of IrSp, and then, a few days prior to challenging the micewith live sporozoites, they further depleted CD4+ T cells or CD8+T cells (Rodrigues et al., 1993). They found that the depletion of either CD4+ T cells or CD8+ T cells inhibited partially – 30% – theprotective immunity induced by IrSp, indicating that CD4+ T cellsand CD8+ T cells equally contributed to the protective immunityin B10 mice. Since H-2 b mice do not have an immunodominantCD8+ T cell epitope, this mice model may resemble more closelyto humans rather than H-2 d mice. This finding was latercorroborated by the study in which  b 2 m-deficient mice were used(Oliveira et al., 2008). In this study, the depletion of CD4+ T cellsfrom sporozoite-immunized,  b 2 m-deficient mice with C57BL/6background that also carries H-2 b haplotype, prior to malaria chal-lenge, abolished the protective anti-malaria immunity, indicatingthatin the absence of CD8+ T cells, CD4+ T cells play a predominantrole in mediating protective immunity against pre-erythrocyticstages. 4. Role of CD4+ T cells against human malaria In early studies, human volunteers, who received a vaccinationwith IrSp of   P. falciparum  and protected from malaria infection,were shown to raise CS antigen-specific CD4+ T cells having acytolytic activity in a peptide-specific fashion  in vitro  (Morenoet al., 1991). When CD4+ T cell clones were isolated from the vol-unteers immunized with a synthetic peptide containing a univer-sal CD4+ T cell epitope of the CS protein, they were shown to bepredominantly Th1-type CD4+ T cell clones that produce high lev-els of IFN- c  (Calvo-Calle et al., 2005). In fact, in a recent study, inwhich peripheral blood mononuclear cells (PBMCs) were usedfrom volunteers immunized with a RTS,S vaccine, a virus-like par-ticle consisting of a portion of the CS protein fused to the hepati-tis B virus surface antigen, the presence of IFN- c -producing CD4+T cells specific for a conserved epitope of the CS protein was de-tected by a cultured Elispot assay, and this CD4+ T cell responsehas been shown to be correlated with protection of humans inWest Africa against natural  P. falciparum  infection and disease(Reece et al., 2004). One study demonstrated the presence of CSantigen-specific opsonizing antibodies in the sera of RTS,S-immu-nized volunteers correlates with protection against  P. falciparum challenge, indicating that these antibodies may facilitate the pro-cessing/presenting via exogenous pathway, thereby inducing CSantigen-specific CD4+ T cells that inhibit the development of liverstages of malaria parasites in immunized people (Schwenk et al.,2003). Overall, similarly to CD8+ T cells, the definitive role of CD4+ T cells in protective immunity against human malaria hasyet to be determined. I hope that with recent technological ad-vances and the growing amount of key information relate to bio-informatics would be able to facilitate research and reveal therole that CD4+ T cell plays in mediating and/or contributinganti-malaria immunity in humans. 5. Future prospect toward a T cell-based malaria vaccine Althoughthe role of CD8+T cells inprotective immunityagainstmalaria is well established in an experimental mouse model, thereis still no compelling evidence showing that is the case for humanmalaria as well. In this regard, it is rather urgent that the role of CD8+ T cells in protective immunity against hepatic stages of hu-man malaria be established. Once the protective role of CD8+ Tcells against human malaria is established, then it would becomemore logical to take an approach to design a vaccine that can elicita potent malaria-specific CD8+ T cell response in humans. Themost advanced clinical trials are based on RTS,S vaccine that seemsto elicit primarily humoral response and, to a lesser extent, CD4+ Tcell responses specific for the CS protein (Kester et al., 2009). Thisindicates that, (1) without eliciting CD8+ T cell response and (2)without having any responses against other antigens than the CSprotein, RTS,S is still able to mount some degree of protectiveimmunity in young children living in an endemic area. This is in-deed very promising news, because these RTS,S trials indicate tous that there is certainly room for improvement to the RTS,S; mak-ing it more potent by adding more ‘‘protective” antigens and/ordesigning the vaccine to elicit a stronger CD8+ T cell response.Any of these strategies would make the RTS,S vaccine more power-ful and hopefully increase the efficacy of the vaccine, another steptowards the successful eradication of malaria.  Acknowledgments The author thanks Chui Ng for reviewing the manuscript. Thiswork was supported in part by NIH Grants AI070258, AI073658and AI081510, and by support from Otsuka Pharmaceutical Co.,GlaxoSmithKline and the Irene Diamond Foundation. 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