메뉴 건너뛰기




Volumn 10, Issue 6, 2010, Pages 575-581

The current state of recombinant allergens for immunotherapy

Author keywords

allergen immunotherapy; hypoallergenic allergen derivatives; recombinant allergen vaccines; recombinant allergens; subcutaneous immunotherapy

Indexed keywords

POLLEN ANTIGEN; RECOMBINANT ALLERGEN; RECOMBINANT BIRCH ALLERGEN; RECOMBINANT GRASS ALLERGEN; UNCLASSIFIED DRUG;

EID: 78449257414     PISSN: 15284050     EISSN: 14736322     Source Type: Journal    
DOI: 10.1097/ACI.0b013e32833fd6c5     Document Type: Review
Times cited : (22)

References (46)
  • 1
    • 38949193498 scopus 로고    scopus 로고
    • The CREATEproject: Development of certified reference materials for allergenic products and validation of methods for their quantification
    • Van Ree R,Chapman MD, Ferreira F, et al. The CREATEproject: development of certified reference materials for allergenic products and validation of methods for their quantification. Allergy 2008; 63:310-326.
    • (2008) Allergy , vol.63 , pp. 310-326
    • Van Ree Rchapman, M.D.1    Ferreira, F.2
  • 3
    • 38949120490 scopus 로고    scopus 로고
    • Fromallergen genestonew forms of allergy diagnosis and treatment
    • Vrtala S. Fromallergen genestonew forms of allergy diagnosis and treatment. Allergy 2008; 63:299-309.
    • (2008) Allergy , vol.63 , pp. 299-309
    • Vrtala, S.1
  • 5
    • 0036069469 scopus 로고    scopus 로고
    • Genetic engineering of allergens: Future therapeutic products
    • Ferreira F, Wallner M, Breiteneder H, et al. Genetic engineering of allergens: future therapeutic products. Int Arch Allergy Immunol 2002; 128:171-178.
    • (2002) Int Arch Allergy Immunol , vol.128 , pp. 171-178
    • Ferreira, F.1    Wallner, M.2    Breiteneder, H.3
  • 6
    • 1042298988 scopus 로고    scopus 로고
    • Strategies for converting allergens into hypoallergenic vaccine candidates
    • Vrtala S, Focke-Tejkl M, Swoboda I, et al. Strategies for converting allergens into hypoallergenic vaccine candidates. Methods 2004; 32:313-320.
    • (2004) Methods , vol.32 , pp. 313-320
    • Vrtala, S.1    Focke-Tejkl, M.2    Swoboda, I.3
  • 7
    • 0027323846 scopus 로고
    • Peripheral T-cell tolerance induced in näive and primed mice by sub-cutaneous injection of peptides from the major cat allergen Feld1
    • Briner TJ, Kuo M, Keating KM, et al. Peripheral T-cell tolerance induced in näive and primed mice by sub-cutaneous injection of peptides from the major cat allergen Feld1.P Natl Acad Sci USA 1993; 90:7608-7616.
    • (1993) P Natl Acad Sci USA , vol.90 , pp. 7608-7616
    • Briner, T.J.1    Kuo, M.2    Keating, K.M.3
  • 8
    • 0027451437 scopus 로고
    • Inhibition of T cell and antibody responses to house dust mite allergen by inhalation of the dominant T cell epitope in näive and sensitized mice
    • Hoyne GFR, O'Hehir DC, Wraith WR, et al. Inhibition of T cell and antibody responses to house dust mite allergen by inhalation of the dominant T cell epitope in näive and sensitized mice. J Exp Med 1993; 178:1783-1788.
    • (1993) J Exp Med , vol.178 , pp. 1783-1788
    • Gfr, H.1    O'Hehir, D.C.2    Wraith, W.R.3
  • 9
    • 0034919459 scopus 로고    scopus 로고
    • Preclinical evaluation of an immu-notherapeutic peptide comprising 7 T-cell determinants of Cry j 1 and Cry j 2, the major Japanese cedar pollen allergens
    • Hirahara K, Tatsuta T, Takatori T, et al. Preclinical evaluation of an immu-notherapeutic peptide comprising 7 T-cell determinants of Cry j 1 and Cry j 2, the major Japanese cedar pollen allergens. J Allergy Clin Immunol 2001; 108:94-100.
    • (2001) J Allergy Clin Immunol , vol.108 , pp. 94-100
    • Hirahara, K.1    Tatsuta, T.2    Takatori, T.3
  • 11
    • 0030444839 scopus 로고    scopus 로고
    • Fed 1 peptides: Effect on skin tests and cytokine synthesis in cat-allergic subjects
    • Simons FE, Imada M, Li Y, et al. Fed 1 peptides: effect on skin tests and cytokine synthesis in cat-allergic subjects. Int Immunol 1996; 8:1937-1945.
    • (1996) Int Immunol , vol.8 , pp. 1937-1945
    • Simons, F.E.1    Imada, M.2    Li, Y.3
  • 12
    • 0037031090 scopus 로고    scopus 로고
    • Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: A randomized controlled trial
    • Oldfield WL, Larche M, Kay AB. Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomized controlled trial. Lancet 2002; 360:47-53.
    • (2002) Lancet , vol.360 , pp. 47-53
    • Oldfield, W.L.1    Larche, M.2    Kay, A.B.3
  • 13
    • 24744438448 scopus 로고    scopus 로고
    • The effect of Feld 1 derived T-cell peptides on upper and lower airway outcome measurements in cat-allergic subjects
    • Alexander C, Tarzi M, Larche M, Kay AB. The effect of Feld 1 derived T-cell peptides on upper and lower airway outcome measurements in cat-allergic subjects. Allergy 2005; 60:1269-1274.
    • (2005) Allergy , vol.60 , pp. 1269-1274
    • Alexander, C.1    Tarzi, M.2    Larche, M.3    Kay, A.B.4
  • 14
    • 33750365602 scopus 로고    scopus 로고
    • Immunoregulation bytargetingTcellsinthetreatmentofallergyand asthma
    • Larche M. Immunoregulation bytargetingTcellsinthetreatmentofallergyand asthma. Curr Opin Immunol 2006; 18:745-750.
    • (2006) Curr Opin Immunol , vol.18 , pp. 745-750
    • Larche, M.1
  • 15
    • 0031866059 scopus 로고    scopus 로고
    • Successful immunotherapy with T-cell epitope peptides of bee venum phospholipase A 2 induces specific T-cell anergy in patients allergic to bee venom
    • Mueller U, Adkis CA, Fricker M, et al. Successful immunotherapy with T-cell epitope peptides of bee venum phospholipase A 2 induces specific T-cell anergy in patients allergic to bee venom. J Allergy Clin Immunol 1998; 101:747-754.
    • (1998) J Allergy Clin Immunol , vol.101 , pp. 747-754
    • Mueller, U.1    Adkis, C.A.2    Fricker, M.3
  • 16
    • 0343953087 scopus 로고    scopus 로고
    • Conjugation of immunostimulatory DNA to the short ragweed allergen Amb a 1 enhances its immunogenecity and reduces its allergenicity
    • Tighe H, Takabayashi K, Schwartz D, et al. Conjugation of immunostimulatory DNA to the short ragweed allergen Amb a 1 enhances its immunogenecity and reduces its allergenicity. J Allergy Immunol 2000; 106:124-134.
    • (2000) J Allergy Immunol , vol.106 , pp. 124-134
    • Tighe, H.1    Takabayashi, K.2    Schwartz, D.3
  • 17
    • 2442681742 scopus 로고    scopus 로고
    • A novel approach to specific allergy treatment: The recombinant fusion protein of a bacterial surface (S-layer) proteinand the majorbirch allergen Betv1 (rSbcC-Betv1) combines reduced allergenicity with immunomodulating capacity
    • Bohle B, Breitwieser A, Zwolfer B, et al. A novel approach to specific allergy treatment: the recombinant fusion protein of a bacterial surface (S-layer) proteinand the majorbirch allergen Betv1 (rSbcC-Betv1) combines reduced allergenicity with immunomodulating capacity. J Immunol 2004; 172:6642-6648.
    • (2004) J Immunol , vol.172 , pp. 6642-6648
    • Bohle, B.1    Breitwieser, A.2    Zwolfer, B.3
  • 18
    • 33749436870 scopus 로고    scopus 로고
    • Immunotherapy with a rag-weed-toll-like receptoragonistvaccineforallergic rhinitis
    • Creticos PS, Schroeder JT, Hamilton RG, et al. Immunotherapy with a rag-weed-toll-like receptoragonistvaccineforallergic rhinitis. N Engl J Med 2006; 355:1445-1455.
    • (2006) N Engl J Med , vol.355 , pp. 1445-1455
    • Creticos, P.S.1    Schroeder, J.T.2    Hamilton, R.G.3
  • 19
    • 0030854098 scopus 로고    scopus 로고
    • Engineering of the major house dust mite allergen Derf2forallergen- specific immunotherapy
    • Takai T, Yokota T, Yasue N, et al. Engineering of the major house dust mite allergen Derf2forallergen-specificimmunotherapy. Nature Biotechnol1997; 15:754-758.
    • (1997) Nature Biotechnol , vol.15 , pp. 754-758
    • Takai, T.1    Yokota, T.2    Yasue, N.3
  • 20
    • 0031952580 scopus 로고    scopus 로고
    • Modulation of IgE reactivityofallergens by site-directed mutagenesis: Potential use of hypoallergenic variants for im-munotherapy
    • Ferreira F, Ebner C, Kramer B, et al. Modulation of IgE reactivityofallergens by site-directed mutagenesis: potential use of hypoallergenic variants for im-munotherapy. FASEB J 1998; 12:231-242.
    • (1998) FASEB J , vol.12 , pp. 231-242
    • Ferreira, F.1    Ebner, C.2    Kramer, B.3
  • 21
    • 6344222889 scopus 로고    scopus 로고
    • Allergy vaccine engineering: Epitope modulation of recombinant Bet v 1 reduces IgE-binding but retains protein folding pattern for induction of protective blocking-antibody responses
    • Holm J, Gajhede M, Ferreras M, et al. Allergy vaccine engineering: epitope modulation of recombinant Bet v 1 reduces IgE-binding but retains protein folding pattern for induction of protective blocking-antibody responses. J Immunol 2004; 173:5258-5267.
    • (2004) J Immunol , vol.173 , pp. 5258-5267
    • Holm, J.1    Gajhede, M.2    Ferreras, M.3
  • 22
    • 78449260577 scopus 로고    scopus 로고
    • Mutantsof the majorryegrass pollen allergen Lol p 5, with reduced IgE binding capacity: Candidates for grass pollen-specific immunotherapy
    • Swoboda I, deWeerd N, Bhalla PL, et al. Mutantsof the majorryegrass pollen allergen, Lol p 5, with reduced IgE binding capacity: candidates for grass pollen-specific immunotherapy. Eur J Biochem 2002; 32:295-302.
    • (2002) Eur J Biochem , vol.32 , pp. 295-302
    • Swoboda, I.1    Deweerd, N.2    Bhalla, P.L.3
  • 23
    • 6344225313 scopus 로고    scopus 로고
    • Hypoallergenic variants of the major latex allergen Hev b 6.01 retaining human T lymphocyte reactivity
    • Drew AC, Eusebius NP, Kenins L, et al. Hypoallergenic variants of the major latex allergen Hev b 6.01 retaining human T lymphocyte reactivity. J Immunol 2004; 173:5872-5889.
    • (2004) J Immunol , vol.173 , pp. 5872-5889
    • Drew, A.C.1    Eusebius, N.P.2    Kenins, L.3
  • 24
    • 1642344674 scopus 로고    scopus 로고
    • The recombinant major allergen of Parietaria judaica and its hypoallergenic variant: In vivo evaluation in a murine model of allergic sensitization
    • Orlandi A, Grasso F, Corinti S, et al. The recombinant major allergen of Parietaria judaica and its hypoallergenic variant: in vivo evaluation in a murine model of allergic sensitization. Clin Exp Allergy 2004; 34:470-477.
    • (2004) Clin Exp Allergy , vol.34 , pp. 470-477
    • Orlandi, A.1    Grasso, F.2    Corinti, S.3
  • 25
    • 33846439330 scopus 로고    scopus 로고
    • Hypoallergenic mutants of Ole e 1, the major olive pollen allergen, as candidates for allergy vaccines
    • Mazaruela EG, Rodriguez R, Barber D, et al. Hypoallergenic mutants of Ole e 1, the major olive pollen allergen, as candidates for allergy vaccines. Clin Exp Allergy 2006; 37:251-260.
    • (2006) Clin Exp Allergy , vol.37 , pp. 251-260
    • Mazaruela, E.G.1    Rodriguez, R.2    Barber, D.3
  • 26
    • 27144547578 scopus 로고    scopus 로고
    • Molecular design of allergy vaccines
    • Linhart B, Valenta R. Molecular design of allergy vaccines. Curr Opin Immunol 2005; 17:646-655.
    • (2005) Curr Opin Immunol , vol.17 , pp. 646-655
    • Linhart, B.1    Valenta, R.2
  • 27
    • 0013687727 scopus 로고    scopus 로고
    • Comparison of genetically engineered hypoallergenic rBet v1 derivatives with rBet v 1 wild-type by skin prick and intradermal testing: Results obtained in a French population
    • Pauli G, Purohit A, Oster JP, et al. Comparison of genetically engineered hypoallergenic rBet v1 derivatives with rBet v 1 wild-type by skin prick and intradermal testing: results obtained in a French population. Clin Exp Allergy 2000; 30:1076-1084.
    • (2000) Clin Exp Allergy , vol.30 , pp. 1076-1084
    • Pauli, G.1    Purohit, A.2    Oster, J.P.3
  • 28
    • 0032739068 scopus 로고    scopus 로고
    • Skin test evaluation of genetically engineered hypoallergenic derivatives of the major birch pollen allergen Bet v 1: Results obtained with a mix of two recombinant Bet v 1 fragments and recombinant Bet v 1 trimer in a Swedish population before the birch pollen season
    • van Hage-Hamsten M, Kronqvist M, Zetterstrom O, et al. Skin test evaluation of genetically engineered hypoallergenic derivatives of the major birch pollen allergen Bet v 1: results obtained with a mix of two recombinant Bet v 1 fragments and recombinant Bet v 1 trimer in a Swedish population before the birch pollen season. J Allergy Clin Immunol 1999; 104:969-977.
    • (1999) J Allergy Clin Immunol , vol.104 , pp. 969-977
    • Van Hage-Hamsten, M.1    Kronqvist, M.2    Zetterstrom, O.3
  • 29
    • 34548267677 scopus 로고    scopus 로고
    • Genetically engineered hybrid proteins from Parietera judaica pollen for allergen-specific immunotherapy
    • Gonzales-Rioja R, Ibarrola I, Arilla MC, et al. Genetically engineered hybrid proteins from Parietera judaica pollen for allergen-specific immunotherapy. J Allergy Clin Immunol 2007; 120:602-609.
    • (2007) J Allergy Clin Immunol , vol.120 , pp. 602-609
    • Gonzales-Rioja, R.1    Ibarrola, I.2    Arilla, M.C.3
  • 30
    • 24644509434 scopus 로고    scopus 로고
    • Allergen specific immunotherapywith recombi-nantgrasspollenallergens
    • Jutel M, Jaeger L, Suck R, et al. Allergen specific immunotherapywith recombi-nantgrasspollenallergens. J Allergy Clin Immunol 2005; 116:608-613.
    • (2005) J Allergy Clin Immunol , vol.116 , pp. 608-613
    • Jutel, M.1    Jaeger, L.2    Suck, R.3
  • 31
    • 49149107253 scopus 로고    scopus 로고
    • Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis
    • Pauli G, Larsen TH, Rak S, et al. Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis. J Allergy Clin Immunol 2008; 122:951-960.
    • (2008) J Allergy Clin Immunol , vol.122 , pp. 951-960
    • Pauli, G.1    Larsen, T.H.2    Rak, S.3
  • 32
    • 46849121475 scopus 로고    scopus 로고
    • Clinical effects of immunotherapy with genetically modified recombinant birch pollen Bet v 1 derivatives
    • Purohit A, Niederberger V, Kronqvist M, et al. Clinical effects of immunotherapy with genetically modified recombinant birch pollen Bet v 1 derivatives. Clin Exp Allergy 2008; 38:1514-1525.
    • (2008) Clin Exp Allergy , vol.38 , pp. 1514-1525
    • Purohit, A.1    Niederberger, V.2    Kronqvist, M.3
  • 33
    • 27144509153 scopus 로고    scopus 로고
    • Specific immunotherapy with recom-binant birch pollen allergen rBet v 1-FV is clinically efficacious
    • Klimek L, Bachert C, Doemer C, et al. Specific immunotherapy with recom-binant birch pollen allergen rBet v 1-FV is clinically efficacious. Allergy Clin Immunol Int 2005; (Suppl N1):15.
    • (2005) Allergy Clin Immunol Int , vol.15 , Issue.SUPPL. N1
    • Klimek, L.1    Bachert, C.2    Doemer, C.3
  • 34
    • 33846964159 scopus 로고    scopus 로고
    • Recommendations for standardization of clinical trials with allergen specific immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce
    • Canonica GW, Baena-Cagnani, Bousquet J, et al. Recommendations for standardization of clinical trials with allergen specific immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce. Allergy 2007; 62:317-324.
    • (2007) Allergy , vol.62 , pp. 317-324
    • Canonica, G.W.1    Baena-Cagnani Bousquet, J.2
  • 35
    • 0026028924 scopus 로고
    • Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis
    • Juniper EF, Guyatt GH. Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis. Clin Exp Allergy 1991; 21:77-83.
    • (1991) Clin Exp Allergy , vol.21 , pp. 77-83
    • Juniper, E.F.1    Guyatt, G.H.2
  • 36
    • 0031838266 scopus 로고    scopus 로고
    • Immunotherapy as an effective tool in allergy treatment
    • Malling HJ. Immunotherapy as an effective tool in allergy treatment. Allergy 1998; 53:461-472.
    • (1998) Allergy , vol.53 , pp. 461-472
    • Malling, H.J.1
  • 37
    • 0031817107 scopus 로고    scopus 로고
    • Allergen immunotherapy: Therapeutical vaccines for allergic diseases
    • World Health Organization Position Paper
    • Bousquet J, Malling HJ, Locket RF, World Health Organization Position Paper. Allergen immunotherapy: therapeutical vaccines for allergic diseases. Allergy 1998; 53 (Suppl 54):1-15.
    • (1998) Allergy , vol.53 , Issue.SUPPL. 54 , pp. 1-15
    • Bousquet, J.1    Malling, H.J.2    Locket, R.F.3
  • 38
    • 54449098165 scopus 로고    scopus 로고
    • Update on mechanisms of allergen injection immu-notherapy
    • James LK, Durham SR. Update on mechanisms of allergen injection immu-notherapy. Clin Exp Allergy 2008; 38:1074-1088.
    • (2008) Clin Exp Allergy , vol.38 , pp. 1074-1088
    • James, L.K.1    Durham, S.R.2
  • 39
    • 0036413238 scopus 로고    scopus 로고
    • Nasal challenges with recombinant derivatives of the major birch pollen allergen Bet v 1 induce fewer symptoms and lower mediator release than rBet v 1 wild-type in patients with allergic rhinitis
    • van Hage-Hamsten M, Johansson E, Roquet A, et al. Nasal challenges with recombinant derivatives of the major birch pollen allergen Bet v 1 induce fewer symptoms and lower mediator release than rBet v 1 wild-type in patients with allergic rhinitis. Clin Exp allergy 2002; 32:1448-1453.
    • (2002) Clin Exp Allergy , vol.32 , pp. 1448-1453
    • Van Hage-Hamsten, M.1    Johansson, E.2    Roquet, A.3
  • 40
    • 76949102610 scopus 로고    scopus 로고
    • Specific immunotherapy with recom-binant birch pollen allergen rBet v1-FV is clinically efficacious-results of a phase III study
    • Abst.81
    • Kettner J, Bachert C, Doemer C, et al. Specific immunotherapy with recom-binant birch pollen allergen rBet v1-FV is clinically efficacious-results of a phase III study. Allergy 2007; 62 (Suppl83):33. (Abst.81).
    • (2007) Allergy , vol.62 , Issue.SUPPL.83 , pp. 33
    • Kettner, J.1    Bachert, C.2    Doemer, C.3
  • 41
    • 0031794759 scopus 로고    scopus 로고
    • Recombinant birch pollen allergens (rBet v 1 and rBet v 2) contain most of the IgE epitopes present in birch, alder, hornbeam, hazel, and oak pollen: A quantitative IgE inhibition study with sera fromdifferentpopulations
    • Niederberger V, Pauli G, Grönlund, et al. Recombinant birch pollen allergens (rBet v 1 and rBet v 2) contain most of the IgE epitopes present in birch, alder, hornbeam, hazel, and oak pollen: a quantitative IgE inhibition study with sera fromdifferentpopulations. J Allergy Clin Immunol 1998; 102:579-591.
    • (1998) J Allergy Clin Immunol , vol.102 , pp. 579-591
    • Niederberger, V.1    Grönlund, P.G.2
  • 42
    • 33646949257 scopus 로고    scopus 로고
    • Der p 1 peptide onvirus-like particles is safe and highly immunogenic in healthy adults
    • Kündig TM, Senti G, Schnetzler G, et al. Der p 1 peptide onvirus-like particles is safe and highly immunogenic in healthy adults. J Allergy Clin Immunol 2006; 117:1470-1476.
    • (2006) J Allergy Clin Immunol , vol.117 , pp. 1470-1476
    • Kündig, T.M.1    Senti, G.2    Schnetzler, G.3
  • 43
    • 69549130776 scopus 로고    scopus 로고
    • Displaying Feld 1 onvirus-like particles prevents reactogenicity despite greatly enhanced immunogenicity: A novel therapy for cat allergy
    • Schmitz N, Dietmeier K, Bauer M, et al. Displaying Feld 1 onvirus-like particles prevents reactogenicity despite greatly enhanced immunogenicity: a novel therapy for cat allergy. J Exp Med 2009; 206:1941-1955.
    • (2009) J Exp Med , vol.206 , pp. 1941-1955
    • Schmitz, N.1    Dietmeier, K.2    Bauer, M.3
  • 44
    • 6344278432 scopus 로고    scopus 로고
    • Non anaphylactic surface-exposed peptides of the major birch pollen allergen, Bet v1, for preventive vaccination
    • Focke M, Linhart B, Hartl A, et al. Non anaphylactic surface-exposed peptides of the major birch pollen allergen, Bet v1, for preventive vaccination. Clin Exp Allergy 2004; 34:1525-1533.
    • (2004) Clin Exp Allergy , vol.34 , pp. 1525-1533
    • Focke, M.1    Linhart, B.2    Hartl, A.3
  • 45
    • 76349094087 scopus 로고    scopus 로고
    • Developments in allergen-specific immunotherapy: From allergen extracts to allergy vaccines bypassing allergen-specificimmunoglobulin e and Tcell reactivity
    • Focke M, Swoboda I, Marth K, Valenta R. Developments in allergen-specific immunotherapy: from allergen extracts to allergy vaccines bypassing allergen-specificimmunoglobulin E and Tcell reactivity.Clin Exp Allergy 2010;40:385-397.
    • (2010) Clin Exp Allergy , vol.40 , pp. 385-397
    • Focke, M.1    Swoboda, I.2    Marth, K.3    Valenta, R.4
  • 46
    • 76349083910 scopus 로고    scopus 로고
    • Acombination vaccineforallergy and rhinovirus infections based on rhino-virus-derived protein VP1 and a nonallergenic peptide of the major timothy grass pollen allergen, Phl p1
    • Edlmayer J, Niespodziana K, Linhart B, et al. Acombination vaccineforallergy and rhinovirus infections based on rhino-virus-derived protein VP1 and a nonallergenic peptide of the major timothy grass pollen allergen, Phl p1. J Immunol 2009; 182:6298-6306.
    • (2009) J Immunol , vol.182 , pp. 6298-6306
    • Edlmayer, J.1    Niespodziana, K.2    Linhart, B.3


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.