vtioВестник трансплантологии и искусственных органовRussian Journal of Transplantology and Artificial Organs1995-1191Academician V.I.Shumakov National Medical Research Center of Transplantology and Artificial Organs", Ministry of Health of the Russian Federation10.15825/1995-1191-2015-4-104-117vtio-597Research ArticleОбзор литературыLiterature ReviewsПУТИ РАСПОЗНАВАНИЯ ЧУЖЕРОДНЫХ АНТИГЕНОВ ПРИ АДАПТИВНОМ ИММУННОМ ОТВЕТЕ НА АЛЛОГЕННУЮ ТРАНСПЛАНТАЦИЮ ОРГАНОВPATHWAYS OF RECOGNITION OF FOREIGN ANTIGENS IN THE ADAPTIVE IMMUNE RESPONSE TO ALLOGENEIC ORGAN TRANSPLANTATIONБеркосА. С.BerkosA. S.aberkos@yandex.ruНиколаевГ. В.NikolaevG. V.ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА России», Санкт-Петербург, Российская ФедерацияРоссияRussian Research Institute of Hematology and Transfusiology, Saint Petersburg, Russian FederationRussian FederationФГБУ «Северо-Западный федеральный медицинский исследовательский центр» Минздрава России, Санкт-Петербург, Российская ФедерацияРоссияFederal State Institution «Federal North-West Medical Research Centre» of the Ministry of Healthcare of the Russian Federation, Saint Petersburg, Russian FederationRussian Federation201514012016174104117Copyright © Беркос А.С., Николаев Г.В., 20162016Беркос А.С., Николаев Г.В.Berkos A.S., Nikolaev G.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.transpl.ru/vtio/article/view/597

В основе реакции иммунологического отторжения аллогенного трансплантата лежит процесс распознавания донорских антигенов Т-клеточными рецепторами. В качестве антигенов, как правило, выступают молекулы главного комплекса гистосовместимости, экспрессированные клетками тканей донорского органа. По своей активности иммунный ответ на аллогенный трансплантат в значительной степени превышает реакцию на обычную инфекцию и характеризуется стойкой иммунологической памятью. При этом базовые механизмы распознавания антигена при инфекции и аллотрансплантации, по-видимому, должны быть сходными. В данном обзоре рассматриваются три основных пути распознавания аллоантигенов, принципиально различающиеся природой антигенпрезентирующих клеток, кинетикой и продолжительностью своего влияния на формирование аллоиммунитета: прямой, непрямой и смешанный. Установление взаимосвязи механизмов аллораспознавания с проявлениями реакции отторжения трансплантата имеет важное клиническое значение. 

Immunological allograft rejection is based on the process of recognition of donor antigens by T-cell receptors. Antigens are generally represented by molecules of major hystocompatibility complex (MHC), expressed by the donor organ tissue cells. Immune response to allogeneic transplant in its activity is greatly higher than response to conventional infection wherein the basic mechanisms of recognition of infectious antigens and alloantigens seem to be similar. In this review we have analyzed three main pathways of recognition of alloantigens. Those pathways are differentiated by the nature of antigen presenting cells, kinetics and duration of its influence on the formation of alloimmunity: direct, indirect and semidirect. Establishing the relationship between mechanisms of allorecognition and manifestations of graft rejection is of great clinical importance. 

аллогенный трансплантаталлораспознаваниеглавный комплекс гистосовместимостиантигенпрезентирующие клеткиТ-клеточный рецепторallograftallorecognitionmajor histocompatibility complexantigen presenting cellsT-cell receptorReferencesAfzali B, Lombardi G and Lechler R. Pathways of major histocompatibility complex allorecognition. Curr Opin Organ Transplant. 2008; 13 (4): 1–12.Afzali B, Lombardi G and Lechler R. Pathways of major histocompatibility complex allorecognition. Curr Opin Organ Transplant. 2008; 13 (4): 1–12.D’Orsogna LJ, Roelen DL, Doxiadis IIN and Claas FHG. TCR cross-reactivity and allorecognition: new insights into the immunogenetics of allorecognition. Immunogenetics. 2012; 64: 77–85.D’Orsogna LJ, Roelen DL, Doxiadis IIN and Claas FHG. TCR cross-reactivity and allorecognition: new insights into the immunogenetics of allorecognition. Immunogenetics. 2012; 64: 77–85.Heeger PS. T-Cell Allorecognition and Transplant Rejection: A Summary and Update. American Journal of Transplantation. 2003; 3: 525–533.Heeger PS. T-Cell Allorecognition and Transplant Rejection: A Summary and Update. American Journal of Transplantation. 2003; 3: 525–533.Bracamonte-Baran W, Burlingham W. Non-inherited Maternal Antigens, Pregnancy and Allotolerance. Biomed J. 2015; 38 (1): 39–51.Bracamonte-Baran W, Burlingham W. Non-inherited Maternal Antigens, Pregnancy and Allotolerance. Biomed J. 2015; 38 (1): 39–51.Zinkernagel RM, Doherty PC. Immunological surveillance against alteredself components by sensitized T-lymphocytes in lymphocytic choriomeningitis. Nature. 1974; 251: 547–548.Zinkernagel RM, Doherty PC. Immunological surveillance against alteredself components by sensitized T-lymphocytes in lymphocytic choriomeningitis. Nature. 1974; 251: 547–548.Marsh SGE, Albert ED, Bodmer WF et al. Nomenclature for factors of the HLA system. Tissue Antigens. 2010; 75: 291–455.Marsh SGE, Albert ED, Bodmer WF et al. Nomenclature for factors of the HLA system. Tissue Antigens. 2010; 75: 291–455.Шевченко ОП, Орлова ОВ, Халилулин ТА. Иммуносупрессия, иммунная толерантность и костимуляция Т-лимфоцитов. Иммуносупрессия при трансплантации солидных органов / Под ред. С.В. Готье. М.–Тверь: Триада, 2008: 472. Shevchenko OP, Orlova OV, Halilulin TA. Immunosupressija, immunnaja tolerantnost' i kostimuljacija T-limfocitov. Immunosupressija pri transplantacii solidnyh organov / Pod red. S.V. Got'e. M.–Tver': Triada, 2008: 472.Шевченко ОП, Орлова ОВ, Халилулин ТА. Иммуносупрессия, иммунная толерантность и костимуляция Т-лимфоцитов. Иммуносупрессия при трансплантации солидных органов / Под ред. С.В. Готье. М.–Тверь: Триада, 2008: 472. Shevchenko OP, Orlova OV, Halilulin TA. Immunosupressija, immunnaja tolerantnost' i kostimuljacija T-limfocitov. Immunosupressija pri transplantacii solidnyh organov / Pod red. S.V. Got'e. M.–Tver': Triada, 2008: 472.Рабсон А, Ройт А, Делвз П. Основы медицинской иммунологии. М.: Мир, 2006. Rabson A, Roitt A, Delvz P. Osnovi medizinskoy immunologii. M.: Mir, 2006.Рабсон А, Ройт А, Делвз П. Основы медицинской иммунологии. М.: Мир, 2006. Rabson A, Roitt A, Delvz P. Osnovi medizinskoy immunologii. M.: Mir, 2006.Rolls HK, Kishimoto K, Dong VM et al. T-cell response to cardiac myosin persists in the absence of an alloimmune response in recipients with chronic cardiac allograft rejection. Transplantation. 2002; 74 (7): 1053–1057.Rolls HK, Kishimoto K, Dong VM et al. T-cell response to cardiac myosin persists in the absence of an alloimmune response in recipients with chronic cardiac allograft rejection. Transplantation. 2002; 74 (7): 1053–1057.Sivaganesh S, Harper SJ, Conlon TM et al. Co-presentation of intact and processed MHC alloantigen by recipient dendritic cells enables delivery of linked help to alloreactive CD8 T-cells by indirect-pathway CD4 T-cells. J. Immunol. 2013; 190 (11): 5829–5838.Sivaganesh S, Harper SJ, Conlon TM et al. Co-presentation of intact and processed MHC alloantigen by recipient dendritic cells enables delivery of linked help to alloreactive CD8 T-cells by indirect-pathway CD4 T-cells. J. Immunol. 2013; 190 (11): 5829–5838.Benichou G, Yamada Y, Yun S et al. Immune recognition and rejection of allogeneic skin grafts. Immunotherapy. 2011; 3 (6): 757–770.Benichou G, Yamada Y, Yun S et al. Immune recognition and rejection of allogeneic skin grafts. Immunotherapy. 2011; 3 (6): 757–770.Gould DS, Auchincloss HJr. Direct and indirect recognition: the role of MHC antigens in graft rejection. Immunol. Today. 1999; 20 (2): 77–82.Gould DS, Auchincloss HJr. Direct and indirect recognition: the role of MHC antigens in graft rejection. Immunol. Today. 1999; 20 (2): 77–82.Ingulli E. Mechanism of cellular rejection in transplantation. Pediatr. Nephrol. 2010; 25: 61–74.Ingulli E. Mechanism of cellular rejection in transplantation. Pediatr. Nephrol. 2010; 25: 61–74.Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T-cells. Annu. Rev. Immunol. 2003; 21: 139–176.Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T-cells. Annu. Rev. Immunol. 2003; 21: 139–176.Ross JO, Melichar HJ, Au-Yeung BB et al. Distinct phases in the positive selection of CD8 T cells distinguished by intrathymic migration and T-cell receptor signaling patterns. PNAS. 2014; 2550–2558.Ross JO, Melichar HJ, Au-Yeung BB et al. Distinct phases in the positive selection of CD8 T cells distinguished by intrathymic migration and T-cell receptor signaling patterns. PNAS. 2014; 2550–2558.Reiser JB, Darnault C, Gregoire C et al. CDR3 loop flexibility contributes to the degeneracy of TCR recognition. Nat. Immunol. 2003; 4 (3): 241.Reiser JB, Darnault C, Gregoire C et al. CDR3 loop flexibility contributes to the degeneracy of TCR recognition. Nat. Immunol. 2003; 4 (3): 241.Salomon B, Bluestone JA. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu. Rev. Immunol. 2001; 19: 225–252.Salomon B, Bluestone JA. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu. Rev. Immunol. 2001; 19: 225–252.Lee KH, Holdorf AD, Dustin ML et al. T-cell receptor signaling precedes immunological synapse formation. Science. 2002; 295: 1539–1542.Lee KH, Holdorf AD, Dustin ML et al. T-cell receptor signaling precedes immunological synapse formation. Science. 2002; 295: 1539–1542.Lopez-Neblina F, Toledo AH, Toledo-Pereyra LH. Molecular biology of apoptosis in ischemia and reperfusion. J. Invest. Surg. 2005; 18: 335–350.Lopez-Neblina F, Toledo AH, Toledo-Pereyra LH. Molecular biology of apoptosis in ischemia and reperfusion. J. Invest. Surg. 2005; 18: 335–350.Warger T, Hilf N, Rechtsteiner G et al. Interaction of TLR2 and TLR4 ligands with the N-terminal domain of Gp96 amplifies innate and adaptive immune responses. J. Biol. Chem. 2006; 281: 22 545–22 553.Warger T, Hilf N, Rechtsteiner G et al. Interaction of TLR2 and TLR4 ligands with the N-terminal domain of Gp96 amplifies innate and adaptive immune responses. J. Biol. Chem. 2006; 281: 22 545–22 553.Piotti G, Palmisano A, Maggiore U et al. Vascular endothelium as a target of immune response in renal transplant rejection. Frontiers in immunology. 2014; 505 (5): 1–9.Piotti G, Palmisano A, Maggiore U et al. Vascular endothelium as a target of immune response in renal transplant rejection. Frontiers in immunology. 2014; 505 (5): 1–9.Lee RS, Grusby MJ, Glimcher LH et al. Indirect recognition by helper cells can induce donor-specific cytotoxic T-lymphocytes in vivo. J. Exp. Med. 1994; 179 (3): 865–872.Lee RS, Grusby MJ, Glimcher LH et al. Indirect recognition by helper cells can induce donor-specific cytotoxic T-lymphocytes in vivo. J. Exp. Med. 1994; 179 (3): 865–872.Schoenberger SP, Toes RE, van der Voort EI et al. T-cell help for cytotoxic T-lymphocytes is mediated by CD40–CD40L interactions. Nature. 1998; 393 (6684): 480–483.Schoenberger SP, Toes RE, van der Voort EI et al. T-cell help for cytotoxic T-lymphocytes is mediated by CD40–CD40L interactions. Nature. 1998; 393 (6684): 480–483.Bharat A and Mohanakumar T. Allopeptides and the Alloimmune Response. Cell Immunol. 2007; 248 (1): 31–43.Bharat A and Mohanakumar T. Allopeptides and the Alloimmune Response. Cell Immunol. 2007; 248 (1): 31–43.Jiang S, Herrera O, Lechler RI. New spectrum of allorecognition pathways: implications for graft rejection and transplantation tolerance. Curr. Opin. Immunol. 2004; 16: 550–557.Jiang S, Herrera O, Lechler RI. New spectrum of allorecognition pathways: implications for graft rejection and transplantation tolerance. Curr. Opin. Immunol. 2004; 16: 550–557.Benichou G, Fedoseyeva E, Lehmann PV et al. Limited T-cell response to donor MHC peptides during allograft rejection. Implications for selective immune therapy in transplantation. J. Immunol. 1994; 153 (3): 938–945.Benichou G, Fedoseyeva E, Lehmann PV et al. Limited T-cell response to donor MHC peptides during allograft rejection. Implications for selective immune therapy in transplantation. J. Immunol. 1994; 153 (3): 938–945.Demaria S, Bushkin Y. Soluble HLA proteins with bound peptides are released from the cell surface by the membrane metalloproteinase. Hum. Immunol. 2000: 61 (12): 1332–1338.Demaria S, Bushkin Y. Soluble HLA proteins with bound peptides are released from the cell surface by the membrane metalloproteinase. Hum. Immunol. 2000: 61 (12): 1332–1338.Denton MD, Geehan CS, Alexander SI et al. Endothelial cells modify the costimulatory capacity of transmigrating leukocytes and promote CD28-mediated CD4 (+) Tcell alloactivation. J. Exp. Med. 1999; 190 (4): 555–566.Denton MD, Geehan CS, Alexander SI et al. Endothelial cells modify the costimulatory capacity of transmigrating leukocytes and promote CD28-mediated CD4 (+) Tcell alloactivation. J. Exp. Med. 1999; 190 (4): 555–566.Rogers NJ and Lechler RI. Allorecognition. American Journal of Transplantation. 2001; 1: 97–102.Rogers NJ and Lechler RI. Allorecognition. American Journal of Transplantation. 2001; 1: 97–102.Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class Irestricted CTLs. Nature. 1998; 392: 86–89.Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class Irestricted CTLs. Nature. 1998; 392: 86–89.Taylor AL, Negus SL, Negus M et al. Pathways of helper CD4 T-cell allorecognition in generating alloantibody and CD8 T-cell alloimmunity. Transplantation. 2007; 83: 931–937.Taylor AL, Negus SL, Negus M et al. Pathways of helper CD4 T-cell allorecognition in generating alloantibody and CD8 T-cell alloimmunity. Transplantation. 2007; 83: 931–937.Arakelov A, Lakkis FG. The alloimmune response and effector mechanisms of allograft rejection. Semin Nephrol. 2000; 20: 95–102.Arakelov A, Lakkis FG. The alloimmune response and effector mechanisms of allograft rejection. Semin Nephrol. 2000; 20: 95–102.Benichou G, Tam RC, Soares LR et al. Indirect T-cell allorecognition: perspectives for peptide-based therapy in transplantation. Immunol. Today. 1997; 18 (2): 67–71.Benichou G, Tam RC, Soares LR et al. Indirect T-cell allorecognition: perspectives for peptide-based therapy in transplantation. Immunol. Today. 1997; 18 (2): 67–71.Rechavi O, Goldstein I, Kloog Y. Intercellular exchange of proteins: The immune cell habit of sharing. FEBS Letters. 2009; 583: 1792–1799.Rechavi O, Goldstein I, Kloog Y. Intercellular exchange of proteins: The immune cell habit of sharing. FEBS Letters. 2009; 583: 1792–1799.Smyth LA, Afzali B, Tsang J et al. Intercellular Transfer of MHC and Immunological Molecules: Molecular Mechanisms and Biological Significance. Am. J. Transplant. 2007; 7 (6): 1–14.Smyth LA, Afzali B, Tsang J et al. Intercellular Transfer of MHC and Immunological Molecules: Molecular Mechanisms and Biological Significance. Am. J. Transplant. 2007; 7 (6): 1–14.Hudson L, Sprent J, Miller JF et al. B cell-derived immunoglobulin on activated mouse T-lymphocyte. Nature. 1974; 251: 60–62.Hudson L, Sprent J, Miller JF et al. B cell-derived immunoglobulin on activated mouse T-lymphocyte. Nature. 1974; 251: 60–62.Merkenschlager M. Tracing interactions of thymocytes with individual stromal cell partners. Eur. J. Immunol. 1996; 26: 892–896.Merkenschlager M. Tracing interactions of thymocytes with individual stromal cell partners. Eur. J. Immunol. 1996; 26: 892–896.Herrera OB, Golshayan D, Tibbott R et al. A novel pathway of alloantigen presentation by dendritic cells. J. Immunol. 2004; 173: 4828–4837.Herrera OB, Golshayan D, Tibbott R et al. A novel pathway of alloantigen presentation by dendritic cells. J. Immunol. 2004; 173: 4828–4837.Smyth LA, Herrera OB, Golshayan D et al. A novel pathway of antigen presentation by dendritic and endothelial cells: implications for allorecognition and infectious diseases. Transplantation. 2006; 82: S15–S18.Smyth LA, Herrera OB, Golshayan D et al. A novel pathway of antigen presentation by dendritic and endothelial cells: implications for allorecognition and infectious diseases. Transplantation. 2006; 82: S15–S18.Game DS, Rogers NJ, Lechler RI. Acquisition of HLADR and costimulatory molecules by T-cells from allogeneic antigen presenting cells. Am. J. Transplant. 2005; 5: 1614–1625.Game DS, Rogers NJ, Lechler RI. Acquisition of HLADR and costimulatory molecules by T-cells from allogeneic antigen presenting cells. Am. J. Transplant. 2005; 5: 1614–1625.Morelli AE, Larregina AT, Shufesky WJ et al. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood. 2004; 104: 3257–3266.Morelli AE, Larregina AT, Shufesky WJ et al. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood. 2004; 104: 3257–3266.de Candia P, Torri A, Pagani M et al. Serum microRNAs as biomarkers of human lymphocyte activation in health and disease. Front Immunol. 2014; 5: 43.de Candia P, Torri A, Pagani M et al. Serum microRNAs as biomarkers of human lymphocyte activation in health and disease. Front Immunol. 2014; 5: 43.Raposo G, Stoorvogel W. Extracellular vesicles: Exosomes, microvesicles and friends. J. Cell Biol. 2013; 200: 373-83.Raposo G, Stoorvogel W. Extracellular vesicles: Exosomes, microvesicles and friends. J. Cell Biol. 2013; 200: 373-83.Fevrier B and Raposo G. Exosomes: endosomal-derived vesicles shipping extracellular messages. Curr. Opin. Cell Biol. 2004; 16: 415–442.Fevrier B and Raposo G. Exosomes: endosomal-derived vesicles shipping extracellular messages. Curr. Opin. Cell Biol. 2004; 16: 415–442.Delamarre L, Pack M, Chang H et al. Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science. 2005; 307: 1630–1634.Delamarre L, Pack M, Chang H et al. Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science. 2005; 307: 1630–1634.Montecalvo A, Larregina AT, Morelli AE. Methods of analysis of dendritic cell-derived exosomes-shuttle micro RNA and its horizontal propagation between dendritic cells. Methods Mol. Biol. 2013; 1024: 19–40.Montecalvo A, Larregina AT, Morelli AE. Methods of analysis of dendritic cell-derived exosomes-shuttle micro RNA and its horizontal propagation between dendritic cells. Methods Mol. Biol. 2013; 1024: 19–40.

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