Retinoid Signals and Th17 Mediated Pathology
20 Jpn. J. Clin. Immunol., 32 (1) 20～28 (2009) 2009 The Japan Society for Clinical Immunology
The Memorial Thesis of the Best Poster Award (Recommended article) Recommender: Chairman of The 36th Annual Meeting of The Japan Society for Clinical Immunology, Prof. Nobuyuki MIYASAKA Retinoid signals and Th17mediated pathology
Christian KLEMANN,BenjaminJE RAVENEY,ShinjiOKI and Takashi YAMAMURA
Department of Immunology, National Institute of Neuroscience, NCNP, Tokyo, Japan
(Received January 21, 2009)
summary
For many years, CD4＋ eŠector T cells were categorized into two subsets: T helper type 1 (Th1) and type 2 (Th2) cells. More recent research has reˆned this model, delineating further subsets; in particular, Th17 cells, activated CD4＋ T cells characterised by the production of the cytokine IL17. Autoantigenspeciˆc Th17 cells are associated with pathology in a number of animal models of organspeciˆc autoimmune disease and evidence is mounting that Th17 cells are also critical in human autoimmunity. Retinoids, a family of compounds that bind to and activate retinoic acid receptors (RARs and RXRs),areableto alter CD4＋ T cell diŠerentiation in vitro though agonism and antagonism of a range of retinoid receptors. For example, alltrans retinoic acid (ATRA) inhibits Th17 diŠerentiation and instead promotes the upregulation of Foxp3, a key transcription factor in regulatory T cells. Importantly, treatment with retinoids can modulate Th17mediated autoim- munity: experimental autoimmune encephalomyelitis (EAE), the murine model of multiple sclerosis (MS),isamelio- rated by ATRA administration due to suppression of both the diŠerentiation and the function of Th17 cells. In this review, we discuss the unveiled molecular mechanism and the possible clinical application of retinoids for the treatment of human Th17mediated autoimmune diseases.
Key words―Retinoids; AM80; ATRA; EAE; Th17; IL17; RORgt;Treg;Foxp3;IL10
Introduction Discovery of Th17 cells
During an immune response, CD4＋ T cells can The dichotomous classiˆcation of eŠector CD4＋ T become activated in an antigenspeciˆc manner and cells based on their function, into Th1 and Th2 cells direct the nature of the response by activating and was ˆrst reported in 19861). It was demonstrated that counterregulating other leukocyte populations. naäƒve Th cells diŠerentiate to two functional classes of Upon activation, naive CD4＋ T cells can diŠerentiate cell during an immune response, Th1 cells, which into a range of cell types, which elaborate a tailored produce interferon(IFN)g and are involved in cell response depending on the nature of the immune in- mediated immunity and organspeciˆc autoimmuni- sult. These diŠerentiated cell types can be eŠector ty, and Th2 cells, which secrete interleukin(IL)4and CD4＋ T cells, including Th1, Th2, and Th17 types, or are involved in extracellular immunity and pathogen- CD4＋ regulatory T cells (Treg) that deviate the esis of asthma and allergy. Furthermore, a key ˆnding function of other immune cells, including Tr3, Th10, was that these Th subsets were able to negatively regu- iTreg types. Many factors in the microenvironment late each other, explaining how a single Thtype during CD4＋ T cell activation tune these diŠerentia- response is established following a particular immune tion processes, including signals from the antigen insult. This pioneering work fuelled the understand- presenting cell and the cytokine milieu. In addition, ing of the immune system for many years and retinoids can act to drive the generation of Treg and remained largely unchallenged. inhibit the diŠerentiation of proin‰ammatory Th17 Multiple sclerosis (MS), the human autoimmune cells. In this review, we will discuss the potential of in‰ammatory disease of the central nervous system retinoids to in‰uence Treg and Th17 responses, in (CNS), is characterised by perivascular inˆltrates in order to treat autoimmune diseases. the brain that display hallmarks of delayedtype hypersensitivity (DTH). This DTH response was ascribed to Th1 cells2) and, following this research, MS and other autoimmune diseases were thus thought 国立精神・神経センター神経研究所免疫研究部 to be mediated by Th1 cells3). Experimental autoim- KLEMANN・Retinoid signals and Th17mediated pathology 21 mune encephalomyelitis (EAE),awellestablished also been shown to be Th17mediated, such as rheu- model of cellmediated autoimmunity4,5),isalso matoid arthritis18), and in animal models of this dis- thought to be generated by the action of Th1 cells, ease severity is reduced in IL17deˆcient mice and which was supported by the fact that autoreactive by blockade of IL17 signalling19,20). Th1 cells are able to transfer the disease. Further- Earlier work demonstrated that addition of IL23 more, IL12p40deˆcient mice, which are unable to to CD4＋ T cell cultures led to IL17 production by T mount Th1 responses, were resistant to induction of cells that were initially referred to as ThIL17 EAE, supporting the hypothesis that the disease is a cells21), but later this became abbreviated to Th17 Th1mediated disorder. Thus, it was predicted that cells22).Atˆrst,IL23 was assumed to be a factor the administratration of IFNg, the key eŠector important for the de novo generation of Th17 cells. It cytokine produced by Th1 cells, should generate more soon became clear that this was not the case, since severe EAE and conversely the inhibition of the eŠect naive T cells do not express the IL23 receptor13,23). of IFNg should reduce EAE. In fact, the opposite is Instead, a combination of the immune suppressive the case: IFNg administration ameliorates disease, cytokine TGFb and proin‰ammatory IL6has whilst neutralization of IFNg with blocking antibo- been identiˆed as the diŠerentiating factors of Th17 dies leads to worsen clinical outcome6,7).Further- cells in mice13,23,24). Additionally, there may be a re- more, mice deˆcient in either IFNg,orIFNg recep- quirement for IL1b in the diŠerentiation of human tor, which lack Th1 responses are also susceptible to Th17 cells. Interestingly, the diŠerentiation of naäƒve more severe EAE8). Similar observations have also CD4＋ T cells activated in the presence of TGFb been made in other models of autoimmunity such as alone induces the generation of induced Tregs, which adjuvantinduced arthritis9). express the transcription factor Foxp325).Atthis Despite such contradicting data, the Th1/Th2 point of time, IL23 is believed to play a crucial role paradigm was upheld for more than two decades until in the expansion and maintenance of Th17 cells. new data regarding the role of IL23 allowed the for- Th17 cells are characterized by the expression of mulation of a improved hypothesis of Th diŠerentia- the transcription factor retinoid acidrelated orphan tion. IL12 and IL23 are both heterodimeric nuclear receptorgt (RORgt)26),RORa 27),andsignal cytokines consisting of a shared p40 subunit, but transducer and activator of transcription3 unlike in IL12 where this molecule combines with a (STAT3)28,29). When EAE is induced in RORgt p35 subunit, IL23 possesses a unique p19 subunit10). deˆcient mice, disease has a delayed onset and is of a The related structure of these cytokines was able to milder form than in wildtype mice26). solve a longstanding puzzle: why mice deˆcient for In humans, there is a growing body of evidence that p40, part of both IL12 and IL23, were protected implicates Th17 cells in autoimmune processes. There from EAE induction, whilst IL12p35 deˆcient mice are increased levels of transcripts for IL17 and IL6 develop worse disease. Thus, when IL23 p19 in the CNS lesions of patients with MS30),andinsuch deˆcient mice were generated, and were found to be lesions, as well as in cerebrospinal ‰uid from MS protected from EAE induction, it was concluded that patients, IL17secreting lymphocytes have been the protective eŠect in p40 mice was unrelated to detected31,32). Th17 responses have also been associat- IL1211).Furthermore,antiIL23 treatment also ed with the human autoimmune disorders such as leads to protection from EAE12). Despite this similar psoriasis33,34), rheumatoid arthritis35), and Crohn's structural make up of these two cytokines, their disease and ulcerative colitis36). biological activities diŠer greatly: IL12 controls the Vitamin A and its metabolites diŠerentiation of Th1 cells, whilst IL23 does not. In- stead, IL23 was found to be associated with eŠector Vitamin A (retinyl ester) plays essential roles in a T cells that produced large amounts of IL17A, IL number of physiological functions throughout the 17F, IL21, and IL2210,13). The pivotal roles of IL body, including vision, embryonic development, bone 23associate T cells were unveiled by a series of ex- and blood metabolism, gene transcription, and periments that showed that the adoptive transfer of immune functions37～39). The recommended daily these T cells caused severe EAE14,15), neutralization of allowances of vitamin A range from 300 mg/day in IL17 via mAb treatment ameliorated EAE, and IL childrento1200mg/day for lactating women40).Itis 17deˆcient mice developed less severe EAE with a important to note that vitamin A uptake deˆciency delayed onset16,17). Other autoimmune diseases have compromises normal immune responses. Retinol, the 22 日本臨床免疫学会会誌 (Vol. 32 No. 1) most common metabolite of dietary vitamin A, can generation retinoids confer a higher stability and be either absorbed by the gut following ingestion, resistance to heat/oxidation, increased halflives, a or generated from provitamins such as higher potency, and improved spectrum of action betacarotene37～39). Retinol is then processed into reti- with receptor speciˆcities. nal and retinoic acid (RA)41).Alltransretinoic acid The most common clinical use of retinoids to date (ATRA),9cis RA, and 11cis retinal are the most is in the treatment of acute promyelocytic leukemia active metabolites found in the body38,42).11cis reti- (APL) and Kaposi's sarcoma45,46). APL results from nal is required for the synthesis of rhodopsin and thus an abnormal fusion protein PMLRARa, formed due is essential for vision. ATRA and 9cis RA bind to to a t(15; 17)(q22; q12) chromosomal translocation, retinoic acid receptors (RARs) and retinoid X recep- inducing abnormal promyelocytic cell proliferation. tors (RXRs) and via these interactions control tran- The e‹cacy of retinoid treatment of APL has been scription of a variety of genes, both activation and reported to be due to the promotion of granulocytic repression37～39,43). ATRA preferably binds to the diŠerentiation and maturation. Importantly, the syn- RARs, whilst 9cis RA can bind to both receptor thetic retinoids exhibit greater potency in APL treat- classes37,38). As RARs and RXRs both have three iso- ment compared with their natural occurring counter- types, a, b,andg, which can combine to a form many parts: for example the third generation retinoid diŠerent heterodimers and homodimers, the range of Tamibarotene (AM80) is eŠective in ATRAun- retionid a‹nity for this range of receptors can lead to responsive APL patients47). Further studies have also a great number of possible eŠects. suggested that autoimmune disease are eŠectively tar- geted with these new generation of retinoids, such of Natural and synthetic retinoids in the clinic44 the skin disease psoriasis48). The term retinoids is applied to a family of com- Retinoidshavebeenstudiedforover20yearsas pounds that bind to and activate retinoic acid recep- potential therapeutic agents in a variety of autoim- tors (RARs and RXRs), resulting in a range of possi- mune models, including multiple sclerosis, rheuma- ble biological responses. Some natural retinoids, such toid arthritis, in‰ammatory bowel diseases, type I di- as ATRA (Tretinoin),9cis RA (Alitretinoin),and abetes, and lupus49～53). However, many clinical trials 13cis RA (Isotretinoin), are currently already used examining the potential for retionids in treating such in the clinic. As the clinical use of natural retinoids is diseases have indicated a e‹cacy and intolerable side limited by their pharmacological proˆle, including in- eŠects54). Previously, as ATRA was shown to eŠect T stability, poor bioavailability, and possible side eŠect cell diŠerentiation, both suppressing Th1 develop- due to the nonspeciˆc receptor binding of those ment and enhancing Th2 development55), the amelio- natural retinoids, a number synthetic retinoids have ration of autoimmune disease by retinoid treatment been generated. These include monoaromatic syn- was attributed to a deviation of immune from Th1 to thetic retinoids (second generation), such as Acitretin Th2. More recently, with an enhanced understanding and Etretinate, and polyaromatic synthetic retinoids of Th diŠerentiation outcomes, the eŠect of retinoid (third generation), such as Tamibarotene (AM80), treatment on Th17 and Treg cell development and Tazarotene, and Targretin (LGD1069)(See Table function has reawakened interested in use of retinoids 1). The aromatic rings found in the second and third to treat immune disorders. Furthermore, this research
Table 1. Retinoids in clinical use
Name Receptors Clinical use ATRA (Tretinoin) panRAR APL, Acne 9cis RA (Alitretinoin) panRAR, panRXR Kaposi sarcoma 13cis RA (Isotretinoin) ― Acne Etretinate ― Psoriasis Acitretin panRAR Psoriasis Tamibarotene (AM80) RARa/b≫g APL Tazarotene RARb/g≫a Acne Targretin (LGD1069) panRXR Cutaneous T lymphoma KLEMANN・Retinoid signals and Th17mediated pathology 23 has been facilitated with the availability of a new desirable panimmunosuppression. Xiao et al. range of enhanced, synthetic, receptorspeciˆc reti- demonstrated the potential application of ATRA to noid compounds. the treatment of EAE, however, in this report ATRA administration also generated signiˆcant anti Retinoids and Th17 cells proliferative eŠects61). We have determined that the It is now well established that Th17 cells constitute therapeutic eŠect of the synthetic retinoid AM80 on a distinct subset of in‰ammatory T cells, which are EAE occurs at much lower doses than ATRA. This is characterized by the production of IL17 and the achievable as the pharmacological proˆle of AM80 expression of the transcription factors RORgtand allows its administration via the oral route, which RORa56). Th17 diŠerentiation is enhanced in CD4＋ T may also be desirable in treatment of human disease. cells that are induced to overexpress RORgtorRORa Critically, we were able to demonstrate that although and overexpression of both these genes has an even these doses strongly downregulated Th17 mediated greater eŠect27). Interference with either of these pathology, no general immunosuppression was ob- genes reduces the propensity of CD4＋ T cells to served. diŠerentiate into Th17 cells and if both RORgtand An interesting observation is that retinoid treat- RORa are knocked out, Th17 diŠerentiation is ment may actually already be in current use for Th17 prevented27). Retinoids strongly suppress the in vitro mediated diseases. For some time, retinoids have production of IL17 by polyclonal TCR stimulation been utilised as a standard treatment for psoriasis62). of naäƒve CD4＋ T cells in the presence of IL6and More recently, psoriasis has been linked with Th17 TGFb57～59). This inhibition of Th17 cell function is responses33,34), thus it is likely that retinoids can be accompanied by downregulation of RORgt and up- applied to treat a wider range of immune pathologies, regulation of Foxp357～59). The suppressive eŠect of in particular those associated with Th17 dysfunction. retinoids on Th17 cell diŠerentiation has been shown Retinoids and Foxp3＋ regulatory T cells to be mediated via RARa57,59). Therefore, it is highly conceivable that retinoids, particularly those with The majority of Treg cells, CD4＋ T cells that are high a‹nity for RARa, may be of use in the clinic to able to countersuppress populations of T cells, ex- treat Th17mediated pathology. However, the ability press the transcription factor Foxp3. The function of of retinoids to inhibit Th17 diŠerenition may be of these cells is critical in the maintenance of self toler- limited use in alleviating in human autoimmune dis- ance and defects in Foxp3 lead to widespread autoim- ease, as when patients present, T cell activation and munity. This is observed in both mice (Scurfy mice) diŠerentiation is likely to be at an advance stage. It is and men, (e.g. Xlinked (IPEX) syndrome)63～65). therefore essential to consider the eŠect of retinoid on Foxp3＋ CD4＋ Treg can be generated in the thymus terminally diŠerentiated T cells. (natural Treg) or be generated in the periphery fol- We have observed that the restimulation of in vitro lowing activation (induced Treg). In vitro,naäƒveT diŠerentiated Th17 cells and activated CD4＋ spleno- cells can also be induce to diŠerentiate into Foxp3＋ cytes from mice with active Th17mediated autoim- Treg by activation in a particular cytokine environ- mune disease results in the production of highlevels ment. One such stimulus for Treg diŠerentiation is of IL17 secretion, which is reduced by the addition TGFb, a cytokine that is also required for Th17 of the synthetic retinoid AM80. Additionally, AM80 diŠerentiation. Interestingly, it has been reported that treatment of these cells also downregulates RORgt retinoids, including ATRA and AM80, are also able expression. We demonstrated inhibition of Th17 cell to alter T cell diŠerentiation, inducing Foxp3＋ CD4＋ function at AM80 doses as low as 0.110 nM, T cells (5759,6669) and unpublished data). Such however maximal suppression was achieved with con- diŠerentiation occurs in the presence of TGFb1 centrations in the order of 10100 nM (unpublished despite the addition of IL6, conditions that would observation). It is important to note that higher doses normally promote Th17 diŠerentiation. It has been of retinoid treatment have been shown to have a suggested that retinoids mediate this eŠect by disrupt- wideranging antiproliferative and immunosuppres- ing the signalling of IL6andIL23 through receptor sive eŠect on T cells (unpublished data and60)). downregulation and by Smad3dependent ampliˆca- Therefore, for translation to the clinic at the applica- tion of the TGFb signalling61). ble human dose of retinoid must be determined to Intriguingly, a subset of CD103＋ dendritic cells ensure e‹cacy of retinoid treatment without un- found in the lamina propria, and mesenteric lymph 24 日本臨床免疫学会会誌 (Vol. 32 No. 1) nodes have the ability to supply ATRA to T cells Acknowledgements during antigenpriming69,70), conversely splenic den- dritic cells do not produce signiˆcant amounts of The authors would like to thank all the contribu- ATRA67～69). The upregualtion of Foxp3 induced by tors to this work. ATRA is dependent on both TGFb andretinoidsig- References nalling. Neutralizing antibody against TGFb blocks the induction of Foxp3＋ CD4＋ T cells69) and inhibi- 1) Mosmann TR, CoŠman RL : TH1 and TH2 tion of the enzyme required for ATRA synthesis or cells : diŠerent patterns of lymphokine secre- blocking retinoid receptor signalling also prevents tion lead to diŠerent functional properties, Foxp3 induction58,68,69). Annu Rev Immunol 7 :145173, 1989. Despite the upregulation of Foxp3 generated by 2) Cher DJ, Mosmann TR : Two types of murine retinoids in vitro, treatment of EAE with retinoids helper T cell clone. II. Delayedtype hypersen- suppresses Th17 cell function without promoting sitivity is mediated by TH1 clones, J Immunol. Foxp3 expression58,61).Ithasbeensuggestedthata 138 :36883694, 1987. lack of TGFb may be the limiting factor58) or that 3) Lassmann H, RansohoŠ RM : The CD4Th1 the adjuvantinduced proin‰ammatory cytokine model for multiple sclerosis : a critical [correc- milieu, including IL1, TNFa and IL6, may active- tion of crucial] reappraisal, Trends Immunol. ly suppress Treg conversion61). Nevertheless, retinoid 25 :132137, 2004. treatment is eŠective in suppressing the de novo 4) Gold R, Linington C, Lassmann H : Under- diŠerentiation of Th17 cells in vivo as well as in vitro. standing pathogenesis and therapy of multiple Therefore, we suggest reevaluation of previous ˆnd- sclerosis via animal models : 70 years of merits ings showing the beneˆcial eŠects of retinoid treat- and culprits in experimental autoimmune en- ment in autoimmune diseases. cephalomyelitis research, Brain 129 :1953 1971, 2006. Conclusion 5) Kuchroo VK, Anderson AC, Waldner H, Mun- We have summarized the recent ˆndings that Th17 der M, Bettelli E, Nicholson LB : T cell cells are a major component in the pathology of many response in experimental autoimmune en- autoimmune diseases and that retinoids, especially cephalomyelitis (EAE) : role of self and cross synthetic one such as AM80 with a higher stability, in- reactive antigens in shaping, tuning, and creased halflife, a higher potency, and improved regulating the autopathogenic T cell repertoire, spectrum of actions with receptor speciˆcities, are po- Annu Rev Immunol 20 :101123, 2002. tent candidates for disease intervention. Recent study 6) Billiau A, Heremans H, Vandekerckhove F, has pointed out the existence of Foxp3/RORgt dou- Dijkmans R, Sobis H, Meulepas E, Carton H : ble positive T cell subset, which produces IL10 in- Enhancement of experimental allergic en- stead of IL1771). In addition, treatment of activated cephalomyelitis in mice by antibodies against T cells with TGFb and IL6 in the absence of termi- IFNgamma, J Immunol. 140 :15061510, nal diŠerentiation by IL23 rendered them to produce 1988. IL10, which are protective for EAE when trans- 7) Voorthuis JA, Uitdehaag BM, De Groot CJ, ferred adoptively72).IL10 has been shown to be Goede PH, van der Meide PH, Dijkstra CD : another important regulatory component for autoim- Suppression of experimental allergic en- mune responses. Interestingly, our recent work sug- cephalomyelitis by intraventricular administra- gested that longterm treatment with retinoids such as tion of interferongamma in Lewis rats, Clin AM80 might cause downregulation of IL10 produc- Exp Immunol. 81 :183188, 1990. tion. Therefore, retinoids have multifunctional target 8) Ferber IA, Brocke S, TaylorEdwards C, Ridg- on immune systems (downregulation of IL6/IL23 way W, Dinisco C, Steinman L, Dalton D, signals, Th17 function, and IL10 production and up- Fathman CG : Mice with a disrupted IFNgam- regulation of Foxp3, Treg function and TGFb sig- ma gene are susceptible to the induction of ex- nals) and thus, clinical application of retinoids perimental autoimmune encephalomyelitis should be determined by the evaluation of each com- (EAE), J Immunol 156 :57, 1996. ponent to achieve the maximum eŠect of retinoids. 9) Jacob CO, Holoshitz J, Van der Meide P, Strober S, McDevitt HO : Heterogeneous KLEMANN・Retinoid signals and Th17mediated pathology 25
eŠects of IFNgamma in adjuvant arthritis, J per T cell subset that links T cell activation and Immunol. 142 :15001505, 1989. bone destruction, JExpMed203 :26732682, 10) McGeachy MJ, Cua DJ : The link between IL 2006. 23 and Th17 cellmediated immune pathol- 19) Bush KA, Farmer KM, Walker JS, Kirkham ogies, Semin Immunol 19 :372376, 2007. BW : Reduction of joint in‰ammation and 11) Cua DJ, Sherlock J, Chen Y, Murphy CA, bone erosion in rat adjuvant arthritis by treat- Joyce B, Seymour B, Lucian L, To W, Kwan S, ment with interleukin17 receptor IgG1 Fc Churakova T, Zurawski S, Wiekowski M, Lira fusion protein, Arthritis Rheum 46 :802805, SA,GormanD,KasteleinRA,SedgwickJD: 2002. Interleukin23 rather than interleukin12 is the 20) Nakae S, Nambu A, Sudo K, Iwakura Y : Sup- critical cytokine for autoimmune in‰ammation pression of immune induction of collagenin- of the brain, Nature 421 :744748, 2003. duced arthritis in IL17deˆcient mice, JIm- 12) Chen Y, Langrish CL, McKenzie B, Joyce munol 171 :61736177, 2003. Shaikh B, Stumhofer JS, McClanahan T, 21) Bettelli E, Kuchroo VK : IL12and IL23in- Blumenschein W, Churakovsa T, Low J, Presta duced T helper cell subsets : birds of the same L, Hunter CA, Kastelein RA, Cua DJ : Anti feather ‰ock together, JExpMed. 201 :169 IL23 therapy inhibits multiple in‰ammatory 171, 2005. pathways and ameliorates autoimmune en- 22) Aggarwal S, Ghilardi N, Xie MH, de Sauvage cephalomyelitis, JClinInvest116 :13171326, FJ, Gurney AL : Interleukin23 promotes a dis- 2006. tinct CD4 T cell activation state characterized 13) Bettelli E, Carrier Y, Gao W, Korn T, Strom by the production of interleukin17, JBiol TB, Oukka M, Weiner HL, Kuchroo VK : Chem 278 :19101914, 2003. Reciprocal developmental pathways for the 23) Veldhoen M, Hocking RJ, Atkins CJ, Locksley generation of pathogenic eŠector TH17 and RM, Stockinger B : TGFbeta in the context of regulatory T cells, Nature 441 :235238, 2006. an in‰ammatory cytokine milieu supports de 14) Hofstetter HH, Ibrahim SM, Koczan D, Kruse novo diŠerentiation of IL17producing T N, Weishaupt A, Toyka KV, Gold R : Ther- cells, Immunity 24 :179189, 2006. apeutic e‹cacy of IL17 neutralization in mu- 24) Mangan PR, Harrington LE, O'Quinn DB, rine experimental autoimmune encephalomyeli- Helms WS, Bullard DC, Elson CO, Hatton RD, tis, Cell Immunol 237 :123130, 2005. Wahl SM, Schoeb TR, Weaver CT : Trans- 15) Langrish CL, Chen Y, Blumenschein WM, forming growth factorbeta induces develop- Mattson J, Basham B, Sedgwick JD, McClana- ment of the T(H)17 lineage, Nature 441 :231 han T, Kastelein RA, Cua DJ : IL23 drives a 234, 2006. pathogenic T cell population that induces au- 25) Ziegler SF : FOXP3 : of mice and men, Annu toimmune in‰ammation, JExpMed201 :233 Rev Immunol. 24 :209226, 2006. 240, 2005. 26) Ivanov, II, McKenzie BS, Zhou L, Tadokoro 16) Komiyama Y, Nakae S, Matsuki T, Nambu A, CE, Lepelley A, Lafaille JJ, Cua DJ, Littman Ishigame H, Kakuta S, Sudo K, Iwakura Y : DR : The orphan nuclear receptor RORgammat IL17 plays an important role in the develop- directs the diŠerentiation program of proin- ment of experimental autoimmune en- ‰ammatory IL17＋ T helper cells, Cell 126 : cephalomyelitis, J Immunol 177 :566573, 11211133, 2006. 2006. 27) Yang XO, Pappu BP, Nurieva R, Akimzhanov 17) Park H, Li Z, Yang XO, Chang SH, Nurieva R, A, Kang HS, Chung Y, Ma L, Shah B, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Panopoulos AD, Schluns KS, Watowich SS, Dong C : A distinct lineage of CD4 T cells regu- Tian Q, Jetten AM, Dong C : T helper 17 line- lates tissue in‰ammation by producing interleu- age diŠerentiation is programmed by orphan kin 17, Nat Immunol 6 :11331141, 2005. nuclear receptors ROR alpha and ROR gamma, 18) Sato K, Suematsu A, Okamoto K, Yamaguchi Immunity 28 :2939, 2008. A, Morishita Y, Kadono Y, Tanaka S, Kodama 28) Laurence A, Tato CM, Davidson TS, Kanno Y, T,AkiraS,IwakuraY,CuaDJ,Takayanagi Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, H : Th17 functions as an osteoclastogenic hel- Hennighausen L, Shevach EM, O'Shea J J : In- 26 日本臨床免疫学会会誌 (Vol. 32 No. 1)
terleukin2 signaling via STAT5 constrains T retinoic acid receptors, Faseb J 10 :940954, helper 17 cell generation, Immunity 26 :371 1996. 381, 2007. 38) Mark M, Ghyselinck NB, Chambon P : Func- 29) Yang XO, Panopoulos AD, Nurieva R, Chang tion of retinoid nuclear receptors : lessons from SH, Wang D, Watowich SS, Dong C : STAT3 genetic and pharmacological dissections of the regulates cytokinemediated generation of in- retinoic acid signaling pathway during mouse ‰ammatory helper T cells, JBiolChem282 : embryogenesis, Annu Rev Pharmacol Toxicol 93589363, 2007. 46 :451480, 2006. 30) Lock C, Hermans G, Pedotti R, Brendolan A, 39) Stephensen CB : Vitamin A, infection, and im- Schadt E, Garren H, LangerGould A, Strober mune function, Annu Rev Nutr 21 :167192, S, Cannella B, Allard J, Klonowski P, Austin 2001. A,LadN,KaminskiN,GalliSJ,Oksenberg 40) USDA : Composition of Foods Raw, JR,RaineCS,HellerR,SteinmanL:Gene Processed, Prepared USDA National Nutrient microarray analysis of multiple sclerosis lesions Database for Standard Reference, 2008. yields new targets validated in autoimmune en- 41) Napoli JL : Retinoic acid : its biosynthesis and cephalomyelitis, Nat Med 8 :500508, 2002. metabolism, Prog Nucleic Acid Res Mol Biol 31) Matusevicius D, Kivisakk P, He B, Kostulas N, 63 :139188, 1999. Ozenci V, Fredrikson S, Link H : Interleukin 42) Duester G : Families of retinoid dehydro- 17 mRNA expression in blood and CSF genases regulating vitamin A function : produc- mononuclear cells is augmented in multiple scle- tion of visual pigment and retinoic acid, Eur J rosis, Mult Scler 5 :101104, 1999. Biochem 267 :43154324, 2000. 32) Tzartos JS, Friese MA, Craner MJ, Palace J, 43) Bourguet W, Germain P, Gronemeyer H : Newcombe J, Esiri MM, Fugger L : Interleu- Nuclear receptor ligandbinding domains : kin17 production in central nervous systemin- threedimensional structures, molecular inter- ˆltrating T cells and glial cells is associated with actions and pharmacological implications, active disease in multiple sclerosis, Am J Pathol Trends Pharmacol Sci 21 :381388, 2000. 172 :146155, 2008. 44) Fukasawa H, Kagechika H, Shudo K : [Reti- 33) Teunissen MB, Koomen CW, de Waal Malefyt noid therapy for autoimmune diseases], Nihon R, Wierenga EA, Bos JD : Interleukin17 and Rinsho Meneki Gakkai Kaishi. 29 :114126, interferongamma synergize in the enhance- 2006. ment of proin‰ammatory cytokine production 45) Fenaux P, Chomienne C, Degos L : Treatment by human keratinocytes, J Invest Dermatol of acute promyelocytic leukaemia, Best Pract 111 :645649, 1998. Res Clin Haematol 14 :153174, 2001. 34) van Beelen AJ, Teunissen MB, Kapsenberg 46) Krown SE : Therapy of AIDSassociated Kapo- ML, de Jong EC : Interleukin17 in in‰amma- si ' s sarcoma : targeting pathogenetic mechan- tory skin disorders, Curr Opin Allergy Clin Im- isms, Hematol Oncol Clin North Am 17 :763 munol 7 :374381, 2007. 783, 2003. 35) Aarvak T, Chabaud M, Miossec P, Natvig JB : 47) Tobita T, Takeshita A, Kitamura K, Ohnishi K, IL17 is produced by some proin‰ammatory Yanagi M, Hiraoka A, Karasuno T, Takeuchi Th1/Th0 cells but not by Th2 cells, J Immunol M, Miyawaki S, Ueda R, Naoe T, Ohno R : 162 :12461251, 1999. Treatment with a new synthetic retinoid, Am80, 36) Duerr RH, Taylor KD, Brant SR, Rioux JD, of acute promyelocytic leukemia relapsed from Silverberg MS, Daly MJ, Steinhart AH, Abrah- complete remission induced by alltrans am C, Regueiro M, Gri‹ths A, Dassopoulos T, retinoic acid, Blood. 90 :967973, 1997. Bitton A, Yang H, Targan S, Datta LW, 48) Kuenzli S, Saurat JH : Retinoids for the treat- Kistner EO, Schumm LP, Lee AT, Gregersen ment of psoriasis : outlook for the future, Curr PK,BarmadaMM,RotterJI,NicolaeDL,Cho Opin Investig Drugs 2 :625630, 2001. JH : A genomewide association study identi- 49) Massacesi L, Abbamondi AL, Giorgi C, Sarlo ˆes IL23R as an in‰ammatory bowel disease F, Lolli F, Amaducci L : Suppression of gene, Science 314 :14611463, 2006. experimental allergic encephalomyelitis by 37) Chambon P : A decade of molecular biology of retinoic acid, J Neurol Sci 80 :5564, 1987. KLEMANN・Retinoid signals and Th17mediated pathology 27
50) Nozaki Y, Yamagata T, Sugiyama M, Ikoma S, DE : Retinoid treatment of experimental aller- Kinoshita K, Funauchi M : Antiin‰ammatory gic encephalomyelitis. IL4 production corre- eŠect of alltransretinoic acid in in‰ammatory lateswithimproveddiseasecourse,J Immunol arthritis, Clin Immunol 119 :272279, 2006. 154 :450458, 1995. 51) Osanai M, Nishikiori N, Murata M, Chiba H, 61) Xiao S, Jin H, Korn T, Liu SM, Oukka M, Lim Kojima T, Sawada N : Cellular retinoic acid B, Kuchroo VK : Retinoic acid increases bioavailability determines epithelial integrity : Foxp3＋ regulatory T cells and inhibits develop- Role of retinoic acid receptor alpha agonists in ment of Th17 cells by enhancing TGFbeta colitis, Mol Pharmacol 71 :250258, 2007. driven Smad3 signaling and inhibiting IL6and 52) Perez de Lema G, LucioCazana FJ, Molina A, IL23 receptor expression, J Immunol 181 : Luckow B, Schmid H, de Wit C, MorenoMan- 22772284, 2008. zano V, Banas B, Mampaso F, SchlondorŠ D : 62) Thaci D : Longterm data in the treatment of Retinoic acid treatment protects MRL/lpr lupus psoriasis, Br J Dermatol 159 Suppl 2 : 1824, mice from the development of glomerular dis- 2008. ease, Kidney Int 66 :10181028, 2004. 63) Bennett CL, Christie J, Ramsdell F, Brunkow 53) Zunino SJ, Storms DH, Stephensen CB : Diets ME, Ferguson PJ, Whitesell L, Kelly TE, rich in polyphenols and vitamin A inhibit the Saulsbury FT, Chance PF, Ochs HD : The development of type I autoimmune diabetes in immune dysregulation, polyendocrinopathy, nonobese diabetic mice, JNutr137 :1216 enteropathy, Xlinked syndrome (IPEX) is 1221, 2007. caused by mutations of FOXP3, Nat Genet 27 : 54) Beehler BC, BrinckerhoŠ CE, Ostrowski J : 2021, 2001. Selective retinoic acid receptor ligands for rheu- 64) Brunkow ME, JeŠery EW, Hjerrild KA, Paeper matoid arthritis, Curr Opin Investig Drugs 5 : B, Clark LB, Yasayko SA, Wilkinson JE, Galas 11531157, 2004. D, Ziegler SF, Ramsdell F : Disruption of a new 55) IwataM,EshimaY,KagechikaH:Retinoic forkhead/wingedhelix protein, scurˆn, results acids exert direct eŠects on T cells to suppress in the fatal lymphoproliferative disorder of the Th1 development and enhance Th2 develop- scurfy mouse, Nat Genet 27 :6873, 2001. ment via retinoic acid receptors, Int Immunol 65) Wildin RS, Ramsdell F, Peake J, Faravelli F, 15 :10171025, 2003. Casanova JL, Buist N, LevyLahad E, Mazzel- 56) Steinman L : A brief history of T(H)17, the la M, Goulet O, Perroni L, Bricarelli FD, Byrne ˆrst major revision in the T(H)1/T(H)2 G, McEuen M, Proll S, Appleby M, Brunkow hypothesis of T cellmediated tissue damage, ME : Xlinked neonatal diabetes mellitus, en- Nat Med 13 :139145, 2007. teropathy and endocrinopathy syndrome is the 57) Elias KM, Laurence A, Davidson TS, Stephens human equivalent of mouse scurfy, Nat Genet G, Kanno Y, Shevach EM, O ' Shea JJ : 27 :1820, 2001. Retinoic acid inhibits Th17 polarization and en- 66) Benson MJ, PinoLagos K, Rosemblatt M, hances FoxP3 expression through a Stat3/ Noelle RJ : Alltrans retinoic acid mediates en- Stat5 independent signaling pathway, Blood hanced T reg cell growth, diŠerentiation, and 111 :10131020, 2008. gut homing in the face of high levels of co 58) Mucida D, Park Y, Kim G, Turovskaya O, stimulation, JExpMed204 :17651774, 2007. Scott I, Kronenberg M, Cheroutre H : Recipro- 67) Coombes JL, Siddiqui KR, Arancibia cal TH17 and regulatory T cell diŠerentiation Carcamo CV, Hall J, Sun CM, Belkaid Y, mediated by retinoic acid, Science 317 :256 Powrie F : A functionally specialized popula- 260, 2007. tion of mucosal CD103＋ DCs induces Foxp3＋ 59) Schambach F, Schupp M, Lazar MA, Reiner regulatory T cells via a TGFbeta and retinoic SL : Activation of retinoic acid receptoralpha aciddependent mechanism, JExpMed204 : favours regulatory T cell induction at the ex- 17571764, 2007. pense of IL17secreting T helper cell diŠerenti- 68) Kang SG, Lim HW, Andrisani OM, Broxmeyer ation, Eur J Immunol 37 :23962399, 2007. HE, Kim CH : Vitamin A metabolites induce 60) RackeMK,BurnettD,PakSH,AlbertPS, guthoming FoxP3＋ regulatory T cells, JIm- Cannella B, Raine CS, McFarlin DE, Scott munol 179 :37243733, 2007. 28 日本臨床免疫学会会誌 (Vol. 32 No. 1)
69) Sun CM, Hall JA, Blank RB, Bouladoux N, M, Di Santo JP, Eberl G : In vivo equilibrium Oukka M, Mora JR, Belkaid Y : Small intestine of proin‰ammatory IL17＋ and regulatory IL lamina propria dendritic cells promote de novo 10＋ Foxp3＋ RORgamma t＋ T cells, JExpMed generation of Foxp3 T reg cells via retinoic acid, 205 :13811393, 2008. JExpMed204 :17751785, 2007. 72) McGeachy MJ, BakJensen KS, Chen Y, Tato 70) Iwata M, Hirakiyama A, Eshima Y, Kagechika CM, Blumenschein W, McClanahan T, Cua H, Kato C, Song SY : Retinoic acid imprints DJ : TGFbeta and IL6 drive the production guthoming speciˆcity on T cells, Immunity of IL17 and IL10 by T cells and restrain T 21 :527538, 2004. (H)17 cellmediated pathology, Nat Immunol 71) Lochner M, Peduto L, Cherrier M, Sawa S, 8 :13901397, 2007. Langa F, Varona R, Riethmacher D, SiTahar