diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/2072-0351-5669diaendo-5669Research ArticleСтатьиArticlesМеханизмы адаптивного иммунитета (на модели сахарного диабета 1 типа)Mechanisms of adaptive immunity (exemplified by type 1 diabetes mellitus)РепинаЕкатерина АлександровнаRepinaEkaterina Alexandrovnae_repina@mail.ruФГУ Эндокринологический научный центр, МоскваEndocrinology Research Centre, Moscow201015062010132№2 (2010)2127Copyright © Репина Е.А., 20102010Репина Е.А.Repina E.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.dia-endojournals.ru/jour/article/view/5669

В обзоре представлены механизмы адаптивного иммунитета при сахарном диабете 1 типа (СД1). Особое внимание уделено таким им-мунологическим понятиям, как антиген, долгосрочная иммунологическая память, центральная и периферическая толерантность. Даносовременное представление о роли интерлейкинов при СД1.

This review was designed to evaluate mechanisms of adaptive immunity in DM1. Special attention is devoted to such immunological concepts as antigen,long-term immunological memory, central and peripheral tolerance. Current views of the role of interleukins in DM1 are discussed.

сахарный диабет 1 типаадаптивный иммунитетиммунологическая памятьантигеныtype 1 diabetes mellitusadaptive immunityimmunological memoryantigensReferencesVeillette A., Soussou D., Latour S., Davidson D., Gervais F.G. Interaction of CD45-associated protein with the antigen receptor signaling machinery in T-lymphocytes // J. Biol. Chem. - 1999. - 274. - Р. 14392-14399.Veillette A., Soussou D., Latour S., Davidson D., Gervais F.G. Interaction of CD45-associated protein with the antigen receptor signaling machinery in T-lymphocytes // J. Biol. Chem. - 1999. - 274. - Р. 14392-14399.Todd J.A., Walker N.M., Cooper J.D., Smyth D.J., Downes K., Plagnol V., Bailey R., Nejentsev S., Field S.F., Payne F., Lowe C.E., Szeszko J.S., Hafler J.P., Zeitels L., Yang J.H., Vella A., Nutland S., Stevens H.E., Schuilenburg H., Coleman G., Maisuria M., Meadows W., Smink L.J., Healy B., Burren O.S., Lam A.A., Ovington N.R., Allen J., Adlem E., Leung H.T., Wallace C., Howson J.M., Guja C., Ionescu-Tirgoviste C. Genetics of Type 1 Diabetes in Finland, Simmonds M.J., Heward J.M., Gough S.C. Wellcome Trust Case Control Consortium, Dunger D.B., Wicker L.S., Clayton D.G. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes //Nat. Genet. - 2007. - 39. - Р. 857-864.Todd J.A., Walker N.M., Cooper J.D., Smyth D.J., Downes K., Plagnol V., Bailey R., Nejentsev S., Field S.F., Payne F., Lowe C.E., Szeszko J.S., Hafler J.P., Zeitels L., Yang J.H., Vella A., Nutland S., Stevens H.E., Schuilenburg H., Coleman G., Maisuria M., Meadows W., Smink L.J., Healy B., Burren O.S., Lam A.A., Ovington N.R., Allen J., Adlem E., Leung H.T., Wallace C., Howson J.M., Guja C., Ionescu-Tirgoviste C. Genetics of Type 1 Diabetes in Finland, Simmonds M.J., Heward J.M., Gough S.C. Wellcome Trust Case Control Consortium, Dunger D.B., Wicker L.S., Clayton D.G. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes //Nat. Genet. - 2007. - 39. - Р. 857-864.Noorchashm H., Noorchashm N., Kern J., Rostami S.Y., Barker C.F., Naji A.B-cells are required for the initiation of insulitis and sialitis in nonobese diabetic mice //Diabetes. - 1997. - 46. - Р. 941-946.Noorchashm H., Noorchashm N., Kern J., Rostami S.Y., Barker C.F., Naji A.B-cells are required for the initiation of insulitis and sialitis in nonobese diabetic mice //Diabetes. - 1997. - 46. - Р. 941-946.Winau F., Hegasy G., Weiskirchen R., Weber S., Cassan C., Sieling P.A., Modlin R.L., Liblau R.S., Gressner A.M., Kaufmann S.H. Ito cells are liver-resident antigen-presenting cells for activating T-cell responses //Immunity. - 2007. - 26. - Р. 117-129.Winau F., Hegasy G., Weiskirchen R., Weber S., Cassan C., Sieling P.A., Modlin R.L., Liblau R.S., Gressner A.M., Kaufmann S.H. Ito cells are liver-resident antigen-presenting cells for activating T-cell responses //Immunity. - 2007. - 26. - Р. 117-129.Todd J.A., Bell J.I., McDevitt H.O. HLA-DQb gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus //Nature. - 1987. - 329. - Р. 599-604.Todd J.A., Bell J.I., McDevitt H.O. HLA-DQb gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus //Nature. - 1987. - 329. - Р. 599-604.Morel P.A., Dorman J.S., Todd J.A., McDevitt H.O., Trucco M.: Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study //Proc. Natl. Acad. Sci. USA. - 1988. - 85. - Р. 8111- 8115.Morel P.A., Dorman J.S., Todd J.A., McDevitt H.O., Trucco M.: Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study //Proc. Natl. Acad. Sci. USA. - 1988. - 85. - Р. 8111- 8115.Greenbaum C.J., Schatz D.A., Cuthbertson D., Zeiler A., Eisenbarth G.S., Krischer J.P. Islet cell antibody-positive relatives with human leukocyte antigen DQA1*0102, DQB1*0602: identification by the Diabetes Prevention Trial-type 1 //J. Clin. Endocrinol. Metab. - 2000. - 85. - 1255-1260.Greenbaum C.J., Schatz D.A., Cuthbertson D., Zeiler A., Eisenbarth G.S., Krischer J.P. Islet cell antibody-positive relatives with human leukocyte antigen DQA1*0102, DQB1*0602: identification by the Diabetes Prevention Trial-type 1 //J. Clin. Endocrinol. Metab. - 2000. - 85. - 1255-1260.Valdes A.M., Erlich H.A., Noble J.A. Human leukocyte antigen class I B and C loci contribute to type 1 diabetes (T1D) susceptibility and age at T1D onset //Hum. Immunol. - 2005. - 66. - Р. 301-313.Valdes A.M., Erlich H.A., Noble J.A. Human leukocyte antigen class I B and C loci contribute to type 1 diabetes (T1D) susceptibility and age at T1D onset //Hum. Immunol. - 2005. - 66. - Р. 301-313.Nejentsev S., Howson J.M., Walker N.M., Szeszko J., Field S.F., Stevens H.E., Reynolds P., Hardy M., King E., Masters J., Hulme J., Maier L.M., Smyth D., Bailey R., Cooper J.D., Ribas G., Campbell R.D., Clayton D.G., Todd J.A. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A //Nature. - 2007. - 450. - Р. 887- 892.Nejentsev S., Howson J.M., Walker N.M., Szeszko J., Field S.F., Stevens H.E., Reynolds P., Hardy M., King E., Masters J., Hulme J., Maier L.M., Smyth D., Bailey R., Cooper J.D., Ribas G., Campbell R.D., Clayton D.G., Todd J.A. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A //Nature. - 2007. - 450. - Р. 887- 892.Nakayama M., Abiru N., Moriyama H., Babaya N., Liu E., Miao D., Yu L., Wegmann D.R., Hutton J.C., Elliott J.F., Eisenbarth G.S.. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice // Nature. - 2005. - 435. - Р. 220-223.Nakayama M., Abiru N., Moriyama H., Babaya N., Liu E., Miao D., Yu L., Wegmann D.R., Hutton J.C., Elliott J.F., Eisenbarth G.S.. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice // Nature. - 2005. - 435. - Р. 220-223.Kent S.C., Chen Y., Bregoli L., Clemmings S.M., Kenyon N.S., Ricordi C., Hering B.J., Hafler D.A. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope // Nature. - 2005. - 435. - Р. 224 -228.Kent S.C., Chen Y., Bregoli L., Clemmings S.M., Kenyon N.S., Ricordi C., Hering B.J., Hafler D.A. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope // Nature. - 2005. - 435. - Р. 224 -228.Reijonen H., Mallone R., Heninger A.K., Laughlin E.M., Kochik S.A., Falk B., Kwok W.W., Greenbaum C., Nepom G.T. GAD65-specific CD4+ T-cells with high antigen avidity are prevalent in peripheral blood of patients with type 1 diabetes // Diabetes. - 2004. - 53. - Р. 1987- 1994.Reijonen H., Mallone R., Heninger A.K., Laughlin E.M., Kochik S.A., Falk B., Kwok W.W., Greenbaum C., Nepom G.T. GAD65-specific CD4+ T-cells with high antigen avidity are prevalent in peripheral blood of patients with type 1 diabetes // Diabetes. - 2004. - 53. - Р. 1987- 1994.Wong F.S., Karttunen J., Dumont C., Wen L., Visintin I., Pilip I.M., Shastri N., Pamer E.G., Janeway C.A. Jr: Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library // Nat. Med. - 1999. - 5. - Р. 1026-1031.Wong F.S., Karttunen J., Dumont C., Wen L., Visintin I., Pilip I.M., Shastri N., Pamer E.G., Janeway C.A. Jr: Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library // Nat. Med. - 1999. - 5. - Р. 1026-1031.Lieberman S.M., Evans A.M., Han B., Takaki T., Vinnitskaya Y., Caldwell J.A., Serreze D.V., Shabanowitz J., Hunt D.F., Nathenson S.G., Santamaria P., DiLorenzo T.P. Identification of the beta cell antigen targeted by a prevalent population of pathogenic CD8+T cells in autoimmune diabetes // Proc. Nat. Acad. Sci. USA. - 2003. - 100. - Р. 8384-8388.Lieberman S.M., Evans A.M., Han B., Takaki T., Vinnitskaya Y., Caldwell J.A., Serreze D.V., Shabanowitz J., Hunt D.F., Nathenson S.G., Santamaria P., DiLorenzo T.P. Identification of the beta cell antigen targeted by a prevalent population of pathogenic CD8+T cells in autoimmune diabetes // Proc. Nat. Acad. Sci. USA. - 2003. - 100. - Р. 8384-8388.Zeggini E., Weedon M.N., Lindgren C.M., Frayling T.M., Elliott K.S., Lango H., Timpson N.J., Perry J.R., Rayner N.W., Freathy R.M., Barrett J.C., Shields B., Morris A.P., Ellard S., Groves C.J., Harries L.W., Marchini J.L., Owen K.R., Knight B., Cardon L.R. Replication of genomewide association signals in UK samples reveals risk loci for type 2 diabetes // Science. - 2007. - 316. - Р. 1336-1341.Zeggini E., Weedon M.N., Lindgren C.M., Frayling T.M., Elliott K.S., Lango H., Timpson N.J., Perry J.R., Rayner N.W., Freathy R.M., Barrett J.C., Shields B., Morris A.P., Ellard S., Groves C.J., Harries L.W., Marchini J.L., Owen K.R., Knight B., Cardon L.R. Replication of genomewide association signals in UK samples reveals risk loci for type 2 diabetes // Science. - 2007. - 316. - Р. 1336-1341.Nagamine K., Peterson P., Scott H.S., Kudoh J., Minoshima S., Heino M., Krohn K.J.E., Lalioti M.D., Mullis P.E., Antonarkis S.E., Kawasaki K., Asakawa S., Ito F., Shimizu N. Positional cloning of the APECED gene // Nat. Genet. - 1997. - 17. - Р. 393-398.Nagamine K., Peterson P., Scott H.S., Kudoh J., Minoshima S., Heino M., Krohn K.J.E., Lalioti M.D., Mullis P.E., Antonarkis S.E., Kawasaki K., Asakawa S., Ito F., Shimizu N. Positional cloning of the APECED gene // Nat. Genet. - 1997. - 17. - Р. 393-398.Bacchetta R., Passerini L., Gambineri E., Dai M., Allan S.E., Perroni L., Dagna-Bricarelli F., Sartirana C., Matthes-Martin S., Lawitschka A., Azzari C., Ziegler S.F., Levings M.K., Roncarolo M.G. Defective regulatory and effector T-cell functions in patients with FOXP3 mutations // J. Clin. Invest. - 2006. - 116. - Р. 1713-1722.Bacchetta R., Passerini L., Gambineri E., Dai M., Allan S.E., Perroni L., Dagna-Bricarelli F., Sartirana C., Matthes-Martin S., Lawitschka A., Azzari C., Ziegler S.F., Levings M.K., Roncarolo M.G. Defective regulatory and effector T-cell functions in patients with FOXP3 mutations // J. Clin. Invest. - 2006. - 116. - Р. 1713-1722.Gavanescu I., Kessler B., Ploegh H., Benoist C., Mathis D. Loss of Airedependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity // Proc. Natl. Acad. Sci. USA. - 2007. - 104. - Р. 4583-4587.Gavanescu I., Kessler B., Ploegh H., Benoist C., Mathis D. Loss of Airedependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity // Proc. Natl. Acad. Sci. USA. - 2007. - 104. - Р. 4583-4587.Palmer J.P., Asplin C.M., Clemons P., Lyen K., Tatpati O., Raghu P.K., Paquette T.L. Insulin antibodies in insulin-dependent diabetics before insulin treatment // Science. - 1983. - 222. - Р. 1337-1339.Palmer J.P., Asplin C.M., Clemons P., Lyen K., Tatpati O., Raghu P.K., Paquette T.L. Insulin antibodies in insulin-dependent diabetics before insulin treatment // Science. - 1983. - 222. - Р. 1337-1339.Lan M.S., Lu J., Goto Y., Notkins A.L. Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma // DNA Cell. Biol. - 1994. - 13. - Р. 505-514.Lan M.S., Lu J., Goto Y., Notkins A.L. Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma // DNA Cell. Biol. - 1994. - 13. - Р. 505-514.Wenzlau J.M., Juhl K., Yu. L., Moua O., Sarkar S.A., Gottlieb P., Rewers M., Eisenbarth G.S., Jensen J., Davidson H.W., Hutton J.C. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes // Proc. Natl. Acad. Sci. USA. - 2007. - 104. - Р. 17040-17045.Wenzlau J.M., Juhl K., Yu. L., Moua O., Sarkar S.A., Gottlieb P., Rewers M., Eisenbarth G.S., Jensen J., Davidson H.W., Hutton J.C. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes // Proc. Natl. Acad. Sci. USA. - 2007. - 104. - Р. 17040-17045.Pinkse G.G., Tysma O.H., Bergen C.A., Kester M.G., Ossendorp F., van Veelen P.A., Keymeulen B., Pipeleers D., Drijfhout J.W., Roep B.O. Autoreactive CD8 T-cells associated with beta cell destruction in type 1 diabetes // Proc. Natl. Acad. Sci. USA 102. - 2005. - Р. 18425- 18430.Pinkse G.G., Tysma O.H., Bergen C.A., Kester M.G., Ossendorp F., van Veelen P.A., Keymeulen B., Pipeleers D., Drijfhout J.W., Roep B.O. Autoreactive CD8 T-cells associated with beta cell destruction in type 1 diabetes // Proc. Natl. Acad. Sci. USA 102. - 2005. - Р. 18425- 18430.Verge C.F., Gianani R., Kawasaki E., Yu L., Pietropaolo M., Jackson R.A., Chase P.H., Eisenbarth G.S. Prediction of type I diabetes mellitus in first degree relatives using a combination of insulin, glutamic acid decarboxylase and ICA512bdc/IA-2 autoantibodies // Diabetes. - 1996. - 45. - Р. 926-933.Verge C.F., Gianani R., Kawasaki E., Yu L., Pietropaolo M., Jackson R.A., Chase P.H., Eisenbarth G.S. Prediction of type I diabetes mellitus in first degree relatives using a combination of insulin, glutamic acid decarboxylase and ICA512bdc/IA-2 autoantibodies // Diabetes. - 1996. - 45. - Р. 926-933.Von Herrath M., Sanda S., Herold K. Type 1 diabetes as a relapsing-remitting disease? // Nat. Rev. Immunol. - 2007. - 7. - Р. 988-994.Von Herrath M., Sanda S., Herold K. Type 1 diabetes as a relapsing-remitting disease? // Nat. Rev. Immunol. - 2007. - 7. - Р. 988-994.Pietropaolo M., Yu S., Libman I.M., Pietropaolo S.L., Riley K., LaPorte R.E., Drash A.L., Mazumdar S., Trucco M., Becker D.J. Cytoplasmic islet cell antibodies remain valuable in defining risk of progression to type 1 diabetes in subjects with other islet autoantibodies // Pediatr Diabetes. - 2005. - 6. - Р. 184-192.Pietropaolo M., Yu S., Libman I.M., Pietropaolo S.L., Riley K., LaPorte R.E., Drash A.L., Mazumdar S., Trucco M., Becker D.J. Cytoplasmic islet cell antibodies remain valuable in defining risk of progression to type 1 diabetes in subjects with other islet autoantibodies // Pediatr Diabetes. - 2005. - 6. - Р. 184-192.Krishnamurthy B., Dudek N.L., McKenzie M.D., Purcell A.W., Brooks A.G., Gellert S., Colman P.G., Harrison L.C., Lew A.M., Thomas H.E., Kay T.W. Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP // J. Clin. Invest. - 2006. - 116. - Р. 3258 -3265.Krishnamurthy B., Dudek N.L., McKenzie M.D., Purcell A.W., Brooks A.G., Gellert S., Colman P.G., Harrison L.C., Lew A.M., Thomas H.E., Kay T.W. Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP // J. Clin. Invest. - 2006. - 116. - Р. 3258 -3265.Holst J., Szymczak-Workman A.L., Vignali K.M., Burton A.R., Workman C.J., Vignali D.A. Generation of T-cell receptor retrogenic mice // Nat. Protoc. - 2006. - 1. - Р. 406-417.Holst J., Szymczak-Workman A.L., Vignali K.M., Burton A.R., Workman C.J., Vignali D.A. Generation of T-cell receptor retrogenic mice // Nat. Protoc. - 2006. - 1. - Р. 406-417.Pietropaolo M., Surhigh J.M., Nelson P.W., Eisenbarth G.S. Primer: Immunity and autoimmunity // Diabetes. - 2008. - 57. - Р. 2872-2882.Pietropaolo M., Surhigh J.M., Nelson P.W., Eisenbarth G.S. Primer: Immunity and autoimmunity // Diabetes. - 2008. - 57. - Р. 2872-2882.Homann D., Eisenbarth G.S. An immunologic homunculus for type 1 diabetes // J. Clin. Invest. - 2006. - 116. - Р. 1212-1215.Homann D., Eisenbarth G.S. An immunologic homunculus for type 1 diabetes // J. Clin. Invest. - 2006. - 116. - Р. 1212-1215.Levisetti M.G., Suri A., Petzold S.J., Unanue E.R. The insulin-specific Tcells of nonobese diabetic mice recognize a weak MHC-binding segment in more than one form // J. Immuno. - 2007. - 178. - Р. 6051-6057.Levisetti M.G., Suri A., Petzold S.J., Unanue E.R. The insulin-specific Tcells of nonobese diabetic mice recognize a weak MHC-binding segment in more than one form // J. Immuno. - 2007. - 178. - Р. 6051-6057.Zekzer D., Wong F.S., Wen L., Altieri M., Gurlo T., von Grafenstein H., Sherwin R.S. Inhibition of diabetes by an insulin-reactive CD4 T-cell clone in the nonobese diabetic mouse // Diabetes. - 1997. - 46. - Р. 1124- 1132.Zekzer D., Wong F.S., Wen L., Altieri M., Gurlo T., von Grafenstein H., Sherwin R.S. Inhibition of diabetes by an insulin-reactive CD4 T-cell clone in the nonobese diabetic mouse // Diabetes. - 1997. - 46. - Р. 1124- 1132.Pugliese A., Zeller M., Fernandez A.Jr., Zalcberg L.J., Barlett R.J., Ricordi C., Pietropaolo M., Eisenbarth G.S., Bennett S.T., Patel D.D.. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes // Nat Genet. - 1997. - 15. - Р. 293-297.Pugliese A., Zeller M., Fernandez A.Jr., Zalcberg L.J., Barlett R.J., Ricordi C., Pietropaolo M., Eisenbarth G.S., Bennett S.T., Patel D.D.. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes // Nat Genet. - 1997. - 15. - Р. 293-297.Mathews C.E., Pietropaolo S.L., Pietropaolo M. Reduced thymic expression of islet antigen contributes to loss of self tolerance // Ann. N.-Y. Acad. Sci. - 2003. - 1005. - Р. 412- 417.Mathews C.E., Pietropaolo S.L., Pietropaolo M. Reduced thymic expression of islet antigen contributes to loss of self tolerance // Ann. N.-Y. Acad. Sci. - 2003. - 1005. - Р. 412- 417.Pietropaolo M., Giannoukakis N., Trucco M. Cellular environment and freedom of gene expression // Nat. Immunol. - 2002. - 3. - Р. 335.Pietropaolo M., Giannoukakis N., Trucco M. Cellular environment and freedom of gene expression // Nat. Immunol. - 2002. - 3. - Р. 335.Anderson M.S., Venanzi E.S., Chen Z., Berzins S.P., Benoist C., Mathis D. The cellular mechanism of Aire control of T-cell tolerance // Immunity. - 2005. - 23. - Р. 227-239.Anderson M.S., Venanzi E.S., Chen Z., Berzins S.P., Benoist C., Mathis D. The cellular mechanism of Aire control of T-cell tolerance // Immunity. - 2005. - 23. - Р. 227-239.Hoglund P., Mintern J., Waltzinger C., Heath W., Benoist C., Mathis D. Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes // J. Exp. Med. - 1999. - 189. - Р. 331-339.Hoglund P., Mintern J., Waltzinger C., Heath W., Benoist C., Mathis D. Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes // J. Exp. Med. - 1999. - 189. - Р. 331-339.McGeachy M.J., Cua D.J. T cells doing it for themselves: TGF-beta regulation of Th1 and Th17 cells // Immunity. - 2007. - 26. - Р. 547-549.McGeachy M.J., Cua D.J. T cells doing it for themselves: TGF-beta regulation of Th1 and Th17 cells // Immunity. - 2007. - 26. - Р. 547-549.Davidson T.S., DiPaolo R.J., Andersson J., Shevach E.M. Cutting edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3 T-regulatory cells // J. Immunol. - 2007. - 178. - Р. 4022-4026.Davidson T.S., DiPaolo R.J., Andersson J., Shevach E.M. Cutting edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3 T-regulatory cells // J. Immunol. - 2007. - 178. - Р. 4022-4026.Ivanov I.I., McKenzie B.S., Zhou L., Tadokoro C.E., Lepelley A., Lafaille J.J., Cua D.J., Littman D.R. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17 T-helper cells // Cell. - 2006. - 126. - Р. 1121-1133.Ivanov I.I., McKenzie B.S., Zhou L., Tadokoro C.E., Lepelley A., Lafaille J.J., Cua D.J., Littman D.R. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17 T-helper cells // Cell. - 2006. - 126. - Р. 1121-1133.Chen Z., O'Shea J.J. Th17 cells: a new fate for differentiating helper T cells // Immunol. Res. Jan. 3. - 2008.Chen Z., O'Shea J.J. Th17 cells: a new fate for differentiating helper T cells // Immunol. Res. Jan. 3. - 2008.Jain R., Tartar D.M., Gregg R.K., Divekar R.D., Bell J.J., Lee H.H., Yu. P., Ellis J.S., Hoeman C.M., Franklin C.L., Zaghouani H. Innocuous interferon gamma induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production // J. Exp. Med. - 2008. - 205. - Р. 207-218.Jain R., Tartar D.M., Gregg R.K., Divekar R.D., Bell J.J., Lee H.H., Yu. P., Ellis J.S., Hoeman C.M., Franklin C.L., Zaghouani H. Innocuous interferon gamma induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production // J. Exp. Med. - 2008. - 205. - Р. 207-218.Muir A., Peck A., Clare-Salzler M., Song Y-H., Cornelius J., Luchetta R., Krischer J., Maclaren N. Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon gamma transcription // J. Clin. Invest. - 1995. - 95. - Р. 628-634.Muir A., Peck A., Clare-Salzler M., Song Y-H., Cornelius J., Luchetta R., Krischer J., Maclaren N. Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon gamma transcription // J. Clin. Invest. - 1995. - 95. - Р. 628-634.Hancock W.W., Polanski M., Zhang J., Blogg N., Weiner H.L. Suppression of insulitis in nonobese diabetic (NOD) mice by oral insulin administration is associated with selective expression of interleukin-4 and -10, transforming growth factor-beta, and prostaglandin-E // Am. J. Pathol. - 1995. - 147. - Р. 1193-1199.Hancock W.W., Polanski M., Zhang J., Blogg N., Weiner H.L. Suppression of insulitis in nonobese diabetic (NOD) mice by oral insulin administration is associated with selective expression of interleukin-4 and -10, transforming growth factor-beta, and prostaglandin-E // Am. J. Pathol. - 1995. - 147. - Р. 1193-1199.Foulis A.K., Farquharson M.A., Meager A. Immunoreactive interferon alpha in insulin secreting beta cells in type 1 diabetes mellitus // Lancet. - 1987. - Р. 1423-1427.Foulis A.K., Farquharson M.A., Meager A. Immunoreactive interferon alpha in insulin secreting beta cells in type 1 diabetes mellitus // Lancet. - 1987. - Р. 1423-1427.Huang X., Yuan J., Goddard A., Foulis A., James R.F.L., Lernmark A., Pujol- Borrell R., Rabinovitch A., Somoza N., Stewart T.A. Interferon expression in the pancreases of patients with type 1 diabetes // Diabetes. - 1995. - 44. - Р. 658-664.Huang X., Yuan J., Goddard A., Foulis A., James R.F.L., Lernmark A., Pujol- Borrell R., Rabinovitch A., Somoza N., Stewart T.A. Interferon expression in the pancreases of patients with type 1 diabetes // Diabetes. - 1995. - 44. - Р. 658-664.Somoza N., Vargas F., Roura-Mir C., Vives-Pi M., Fernandez-FiguerasM.T., Ariza A., Gomis R., Bragado R., Marti M., Jaraquemada D., Pujol-Borrell R. Pancreas in recent onset insulindependent diabetes mellitus: Changes in HLA, adhesion molecules and autoantigens, restricted TCR Vb usage, and cytokine profile // J. Immunol. - 1994,. - 153. - Р. 1360-1377.Somoza N., Vargas F., Roura-Mir C., Vives-Pi M., Fernandez-FiguerasM.T., Ariza A., Gomis R., Bragado R., Marti M., Jaraquemada D., Pujol-Borrell R. Pancreas in recent onset insulindependent diabetes mellitus: Changes in HLA, adhesion molecules and autoantigens, restricted TCR Vb usage, and cytokine profile // J. Immunol. - 1994,. - 153. - Р. 1360-1377.Foulis A.K., McGill M., Farquharson M.A. Insulitis in type 1 (insulin-dependent) diabetes mellitus in man: Macrophages, lymphocytes, and interferon gamma containing cells // J. Pathol. - 1991. - 165. - Р. 97-103.Foulis A.K., McGill M., Farquharson M.A. Insulitis in type 1 (insulin-dependent) diabetes mellitus in man: Macrophages, lymphocytes, and interferon gamma containing cells // J. Pathol. - 1991. - 165. - Р. 97-103.Mandrup-Poulsen T., Helqvist S., Wogensen L.D., Movig J., Pociot F., Johannesen J., Nerup J.Cytokines and free radicals as effector molecules in the destruction of pancreatic beta cells // Curr. Top. Microbiol. Immunol. - 1990. - 164. - Р. 169-193.Mandrup-Poulsen T., Helqvist S., Wogensen L.D., Movig J., Pociot F., Johannesen J., Nerup J.Cytokines and free radicals as effector molecules in the destruction of pancreatic beta cells // Curr. Top. Microbiol. Immunol. - 1990. - 164. - Р. 169-193.Rabinovitch A. Roles of cytokines in IDDM pathogenesis and islet b cell destruction // Diabetes. Rev. - 1993. - 1. - Р. 215-240.Rabinovitch A. Roles of cytokines in IDDM pathogenesis and islet b cell destruction // Diabetes. Rev. - 1993. - 1. - Р. 215-240.Harrison L.C., Campbell I.L., Colman P.G., et al. Type 1 diabetes: Immunopathology and immunotherapy // Adv. Endocrinol. Metab. - 1990. - 1. - Р. 35-94.Harrison L.C., Campbell I.L., Colman P.G., et al. Type 1 diabetes: Immunopathology and immunotherapy // Adv. Endocrinol. Metab. - 1990. - 1. - Р. 35-94.Hanninen A., Jalkanen S., Salmi M., Toikkanen S., Nikolakaros G., SimellO. Macrophages, T-cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulindependent diabetes mellitus // J. Clin. Invest. - 1992. - 90. - Р. 1901-1910.Hanninen A., Jalkanen S., Salmi M., Toikkanen S., Nikolakaros G., SimellO. Macrophages, T-cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulindependent diabetes mellitus // J. Clin. Invest. - 1992. - 90. - Р. 1901-1910.Itoh N., Hanafusa T., Miyazaki A., Miyagawa J.I., Yamagata K., Yamamoto K., Waguri M., Imagawa A., Tamura S., Inada M., Kawata S., Tarui S., KonoN., Matsuzawa Y. Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients // J. ClinInvest. - 1993. - 92. - Р. 2313-2322.Itoh N., Hanafusa T., Miyazaki A., Miyagawa J.I., Yamagata K., Yamamoto K., Waguri M., Imagawa A., Tamura S., Inada M., Kawata S., Tarui S., KonoN., Matsuzawa Y. Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients // J. ClinInvest. - 1993. - 92. - Р. 2313-2322.Stassi G., Todaro M., Richiusa P., Giordano M., Mattina A., Sbriglia M.S., LoMonte A., Buscemi G., Galluzzo A., Giordano C. Expression of apoptosisinducing CD95 (Fas/Apo-1) on human beta cells sorted by flow-cytometry and cultured in vitro // Transplant. Proc. - 1995. - 27. - Р. 3271-3275.Stassi G., Todaro M., Richiusa P., Giordano M., Mattina A., Sbriglia M.S., LoMonte A., Buscemi G., Galluzzo A., Giordano C. Expression of apoptosisinducing CD95 (Fas/Apo-1) on human beta cells sorted by flow-cytometry and cultured in vitro // Transplant. Proc. - 1995. - 27. - Р. 3271-3275.Giordano C., Stassi G., Todaro M., Richiusa P., De Maria R., GiordanoM., Mattina A., Sbriglia M.S., Galluzzo A. Triggering of Fas (Apo-1/CD95)-induced apoptosis in human pancreatic beta cells // Diabetologia. - 1996. - 39 (suppl. 1). - Р. A10.Giordano C., Stassi G., Todaro M., Richiusa P., De Maria R., GiordanoM., Mattina A., Sbriglia M.S., Galluzzo A. Triggering of Fas (Apo-1/CD95)-induced apoptosis in human pancreatic beta cells // Diabetologia. - 1996. - 39 (suppl. 1). - Р. A10.Stassi G., De Maria R., Trucco G., et al. Nitric oxide primes pancreatic beta cells for Fas-mediated destruction in insulin-dependent diabetes mellitus // J. Exp. Med. - 1997. - 186. - Р. 1193-1200.Stassi G., De Maria R., Trucco G., et al. Nitric oxide primes pancreatic beta cells for Fas-mediated destruction in insulin-dependent diabetes mellitus // J. Exp. Med. - 1997. - 186. - Р. 1193-1200.Stewart T.A., Hultgren B., Huang X., Pitts-Meek S., Hully J., MacLachlanN.J. Induction of type 1 diabetes by interferon alpha in transgenic mice //Science. - 993. - 260. - Р. 1942-1946.Stewart T.A., Hultgren B., Huang X., Pitts-Meek S., Hully J., MacLachlanN.J. Induction of type 1 diabetes by interferon alpha in transgenic mice //Science. - 993. - 260. - Р. 1942-1946.Chakrabarti D., Hultgren B., Stewart T.A. Interferon alpha induces autoimmune T-cells through the induction of intracellular adhesion molecule-1 and B7.2 // J. Immunol. - 1996. - 157. - Р. 522-528.Chakrabarti D., Hultgren B., Stewart T.A. Interferon alpha induces autoimmune T-cells through the induction of intracellular adhesion molecule-1 and B7.2 // J. Immunol. - 1996. - 157. - Р. 522-528.Cavallo M.G., Pozzilli P., Bird C., Rudert W., Testi R., Galluzzo A., Giordano C., Trucco M. Cytokines in sera from insulindependent diabetic patients at diagnosis // Clin. Exp. Immunol. - 1991. - 86. - Р. 256-259.Cavallo M.G., Pozzilli P., Bird C., Rudert W., Testi R., Galluzzo A., Giordano C., Trucco M. Cytokines in sera from insulindependent diabetic patients at diagnosis // Clin. Exp. Immunol. - 1991. - 86. - Р. 256-259.Ciampolillo A., Guastamacchia E., Caragiulo L., Lollino G., De Robertis O., Lattanzi V., Giorgino R. In vitro secretion of interleukin 1 beta and interferon gamma by peripheral blood lymphomononuclear cells in diabetic patients // Diabetes. Res. Clin. Pract. - 1993. - 21. - Р. 87-93.Ciampolillo A., Guastamacchia E., Caragiulo L., Lollino G., De Robertis O., Lattanzi V., Giorgino R. In vitro secretion of interleukin 1 beta and interferon gamma by peripheral blood lymphomononuclear cells in diabetic patients // Diabetes. Res. Clin. Pract. - 1993. - 21. - Р. 87-93.Kallmann B.A., Hu. ther M., Tubes M., Feldkamp J., Bertrams J., Gries F.A., Lampeter E.F., Kolb H. Systemic bias of cytokine production toward cell-mediated immune regulation in IDDM and toward humoral immunity in Graves' disease // Diabetes. - 1997. - 46. - Р. 237-243.Kallmann B.A., Hu. ther M., Tubes M., Feldkamp J., Bertrams J., Gries F.A., Lampeter E.F., Kolb H. Systemic bias of cytokine production toward cell-mediated immune regulation in IDDM and toward humoral immunity in Graves' disease // Diabetes. - 1997. - 46. - Р. 237-243.Harrison L.C., Honeyman M.C., DeAizpurua H.J., Schmidli R.S., Colman P.G., Tait B.D., Cram D.S. Inverse relation of humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes // Lancet. - 993. - 341,. - Р. 1365-1369.Harrison L.C., Honeyman M.C., DeAizpurua H.J., Schmidli R.S., Colman P.G., Tait B.D., Cram D.S. Inverse relation of humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes // Lancet. - 993. - 341,. - Р. 1365-1369.Yu L., Gianani R., Eisenbarth G.S. Quantitation of glutamic acid decarboxylase autoantibody levels in prospectively evaluated relatives of patients with type I diabetes // Diabetes. - 1994. - 43. - Р. 1229-1233.Yu L., Gianani R., Eisenbarth G.S. Quantitation of glutamic acid decarboxylase autoantibody levels in prospectively evaluated relatives of patients with type I diabetes // Diabetes. - 1994. - 43. - Р. 1229-1233.Kaufman D.L., Clare-Salzler M., Tian J., Forsthuber T., Ting G.S.P., Robinson P., Atkinson M.A., Sercarz E.E., Tobin A.J., Lehmann P.V. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes // Nature. - 1993. - 366. - Р.69-72.Kaufman D.L., Clare-Salzler M., Tian J., Forsthuber T., Ting G.S.P., Robinson P., Atkinson M.A., Sercarz E.E., Tobin A.J., Lehmann P.V. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes // Nature. - 1993. - 366. - Р.69-72.Tisch R., Yang X-D., Singer S.M., Liblau R.S., Fugger L., McDevitt H.O. Immune response to glutamic acid decarboxylase correlates with insulitis in nonobese diabetic mice // Nature. - 1993. - 366. - Р. 72-75.Tisch R., Yang X-D., Singer S.M., Liblau R.S., Fugger L., McDevitt H.O. Immune response to glutamic acid decarboxylase correlates with insulitis in nonobese diabetic mice // Nature. - 1993. - 366. - Р. 72-75.Ramiya V., Muir A., Maclaren N. Insulin prophylaxis in insulin-dependent diabetes mellitus: Immunological rationale and therapeutic use // Clin. Immunother. - 1995. - 3. - Р. 177-183.Ramiya V., Muir A., Maclaren N. Insulin prophylaxis in insulin-dependent diabetes mellitus: Immunological rationale and therapeutic use // Clin. Immunother. - 1995. - 3. - Р. 177-183.Wilson S.B., Kent S.C., Patton K.T., Orban T., Jackson R.A., Exley M., Porcelli S., Schatz D.A., Atkinson M.A., Balk S.P., Strominger J.L., Hafler D.A. Extreme Th1 bias of regulatory Va24JaQ T-cells in type 1 diabetes // Nature. - 1998. - 391. - Р. 177-181.Wilson S.B., Kent S.C., Patton K.T., Orban T., Jackson R.A., Exley M., Porcelli S., Schatz D.A., Atkinson M.A., Balk S.P., Strominger J.L., Hafler D.A. Extreme Th1 bias of regulatory Va24JaQ T-cells in type 1 diabetes // Nature. - 1998. - 391. - Р. 177-181.Tian J., Atkinson M.A., Clare-Salzler M.C., Herschenfeld A., Forsthuber T., Lehmann P.V., Kaufman D.L. Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes // J. Exp. Med. - 1996. - 183. - Р. 1561-1567. 68. Ma S-W., Zhao D-L., Yin Z-Q., Mukherjee R., Singh B., Qin H-Y.,Tian J., Atkinson M.A., Clare-Salzler M.C., Herschenfeld A., Forsthuber T., Lehmann P.V., Kaufman D.L. Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes // J. Exp. Med. - 1996. - 183. - Р. 1561-1567. 68. Ma S-W., Zhao D-L., Yin Z-Q., Mukherjee R., Singh B., Qin H-Y.,Stiller C.R., Jevnikar A.M. Transgenic plants expressing autoantigens fed to mice to induce oral immune tolerance // Nature Med. - 1997. - 3. - Р. 793-796.Stiller C.R., Jevnikar A.M. Transgenic plants expressing autoantigens fed to mice to induce oral immune tolerance // Nature Med. - 1997. - 3. - Р. 793-796.Zhang Z.J., Davidson L.E., Eisenbarth G., Weiner H.L. Suppression of diabetes in NOD mice by oral administration of porcine insulin // Proc. Natl. Acad. Sci. USA. - 1991. - 88. - Р. 10252-10256.Zhang Z.J., Davidson L.E., Eisenbarth G., Weiner H.L. Suppression of diabetes in NOD mice by oral administration of porcine insulin // Proc. Natl. Acad. Sci. USA. - 1991. - 88. - Р. 10252-10256.Bergerot I., Fabien N., Maguer V., Thivolet C. Oral administration of human insulin to NOD mice generates CD4+ T-cells that suppress adoptive transfer of diabetes // J. Autoimmun. - 1994. - 7. - Р. 655-663.Bergerot I., Fabien N., Maguer V., Thivolet C. Oral administration of human insulin to NOD mice generates CD4+ T-cells that suppress adoptive transfer of diabetes // J. Autoimmun. - 1994. - 7. - Р. 655-663.Daniel D., Wegmann D.R. Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-chain (9-23) // Proc. Natl. Acad. Sci. USA. - 1996. - 93. - Р. 956- 958.Daniel D., Wegmann D.R. Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-chain (9-23) // Proc. Natl. Acad. Sci. USA. - 1996. - 93. - Р. 956- 958.Polanski M., Melican N.S., Zhang J., Weiner H.L. Oral administration of the immunodominant B-chain of insulin reduces diabetes in a cotransfer model of diabetes in the NOD mouse and is associated with a switch from Th1 to Th2 cytokines // J. Autoimmun. - 1997. - 10. - Р. 339-346.Polanski M., Melican N.S., Zhang J., Weiner H.L. Oral administration of the immunodominant B-chain of insulin reduces diabetes in a cotransfer model of diabetes in the NOD mouse and is associated with a switch from Th1 to Th2 cytokines // J. Autoimmun. - 1997. - 10. - Р. 339-346.Ploix C., Bergerot I., Fabien N., Perche S., Moulin V., Thivolet C. Protection against autoimmune diabetes with oral insulin is associated with the presence of IL-4 type 2 T-cells in the pancreas and pancreatic lymph nodes // Diabetes. - 1998. - 47. - Р. 39-44.Ploix C., Bergerot I., Fabien N., Perche S., Moulin V., Thivolet C. Protection against autoimmune diabetes with oral insulin is associated with the presence of IL-4 type 2 T-cells in the pancreas and pancreatic lymph nodes // Diabetes. - 1998. - 47. - Р. 39-44.Harrison L.C., Dempsey-Collier M., Kramer D.R., Takahashi K. Aerosol insulin induces regulatory CD8 T-cells that prevent murine insulin-dependent diabetes // J. Exp. Med. - 1996. - 184. - Р. 2167-2174.Harrison L.C., Dempsey-Collier M., Kramer D.R., Takahashi K. Aerosol insulin induces regulatory CD8 T-cells that prevent murine insulin-dependent diabetes // J. Exp. Med. - 1996. - 184. - Р. 2167-2174.

The authors declare that there are no conflicts of interest present.