针对HLA-A2转基因小鼠皮肤移植物的排斥反应更接近急性排斥反应
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摘要
同种异型移植排斥反应所识别的靶抗原主要是表达于移植物细胞表面的主要组织相容性复合物(MHc)分子，由于几类主要组织相容性复合物(HLA)基因的丰富多态性，很难在几体水平研究单个异体HLA分子在移植排斥中的具体作用。HLA．A2转基因小鼠的出现为体内研究移植排斥反应机制与干预措施提供了理想的动物模型。本课题以c57BL／6来源的HLA-A2转基因小鼠(以下简称A2小鼠)为主要实验对象，建立仅HLA-A2基因差别所引起的皮肤移植排斥反应动物模型，并通过比较HLA-A2基因差别所引起的移植排斥反应与典型急性排斥反应和慢性排斥反应的异同，探讨这种移植排斥反应的类型与机制。本研究的主要内容及结果如下：
1利用HLA-A2特异性引物RT-PcR及HLA-A2分子特异性抗体BB7.2检测显示HLA-A2转基因小鼠细胞表面表达HLA-A2分子。
2以普通c57BL/6雄性小鼠为受者，雄性A2小鼠为供者，建立仅HLA-A2基因差别所引起的皮肤移植排斥反应动物模型，结果发现针对A2小鼠皮肤移植物的排斥反应发生迅速，9～13天出现皮片排斥反应。将两者脾细胞进行混合淋巴细胞培养结果显示c57BL／6来源的T细胞在体外受A2小鼠的细胞刺激后明显增殖。
3与同种异基因小鼠皮肤移植所引起的急性排斥反应及雌雄异体移植所引起的慢性排斥反应相比较，针对HLA-A2转基因小鼠皮肤移植物的排斥反应及体外同种反应表现出发生迅速，反应强度大等急性排斥反应的特点。
由于供受者之间仅存在HLA-A2的差别，而针对A2小鼠皮肤移植排斥反应更接近急性排斥反应，因此该动物模型可用于进一步认识移植排斥中直接识别机制和探讨移植排斥反应的防治手段。
The antigens detected by T cells in allograft rejection are mostly derived from a highly polymorphic region of the genome called the major histocompatibiloity complexe (MHC). The concrete efforts of single MHC molecule in allograft rejection are not easy to understant thoroughly for the MHC polymorphism. The HLA-A2 transgenic mouse provides us with a possible model to understand the graft rejection. We have used the HLA-A2 transgenic mouse of C57BL/6 origin (A2 mouse) as donors to test the rejection of skin grafts, in order to find a in vivo model of rejection against HLA-A2, therefore, the model can be used to study the mechanisms of acute rejection and to develop new approaches to treat and prevent the rejection. In this study, we establish the skin graft model from A2 mouse to normal C57BL/6 mouse though back to back full-thickness skins transplantation. The rejection was observed and compared with the the acute rejection of allogeneic skins transplantation and the chronic one across the sex. The results list below:
1 -, The expression of HLA-A2 molecule on the transgenic mouse cell's surface was detected by both RT-PCR with specific primers of HLA-A2 extra-cellular domain and the HLA-A2 allelic specific antibody BB7.2.
2^ Set up the skin graft animal model (recipient: normal C57BL/6 male mice, donor: A2 male mice) in which HLA-A2 molecule is expected to be the sole rejection antigen. Results showed that A2 mouse skin grafts were rapidly rejected in 9—13 days, and the T cells proliferation of the recipient was stronger in mixed lymphocyte culture.
3 -, Compared to the chronic rejection reaction caused by the unmatch sex between recipient and donor, the reaction against the HLA-A2 molecule is more likely to be the acute rejection of allogeneic skin graft, because which occurs rapid in time and intensity in inflammatory response.
The rejection against HLA-A2 molecule in the animal model provides us with an in vivo model which would be useful for us to further understand the direct and the indirect recognition in the graft rejection and to induce the graft tolerance.
1利用HLA-A2特异性引物RT-PcR及HLA-A2分子特异性抗体BB7.2检测显示HLA-A2转基因小鼠细胞表面表达HLA-A2分子。
2以普通c57BL/6雄性小鼠为受者，雄性A2小鼠为供者，建立仅HLA-A2基因差别所引起的皮肤移植排斥反应动物模型，结果发现针对A2小鼠皮肤移植物的排斥反应发生迅速，9～13天出现皮片排斥反应。将两者脾细胞进行混合淋巴细胞培养结果显示c57BL／6来源的T细胞在体外受A2小鼠的细胞刺激后明显增殖。
3与同种异基因小鼠皮肤移植所引起的急性排斥反应及雌雄异体移植所引起的慢性排斥反应相比较，针对HLA-A2转基因小鼠皮肤移植物的排斥反应及体外同种反应表现出发生迅速，反应强度大等急性排斥反应的特点。
由于供受者之间仅存在HLA-A2的差别，而针对A2小鼠皮肤移植排斥反应更接近急性排斥反应，因此该动物模型可用于进一步认识移植排斥中直接识别机制和探讨移植排斥反应的防治手段。
The antigens detected by T cells in allograft rejection are mostly derived from a highly polymorphic region of the genome called the major histocompatibiloity complexe (MHC). The concrete efforts of single MHC molecule in allograft rejection are not easy to understant thoroughly for the MHC polymorphism. The HLA-A2 transgenic mouse provides us with a possible model to understand the graft rejection. We have used the HLA-A2 transgenic mouse of C57BL/6 origin (A2 mouse) as donors to test the rejection of skin grafts, in order to find a in vivo model of rejection against HLA-A2, therefore, the model can be used to study the mechanisms of acute rejection and to develop new approaches to treat and prevent the rejection. In this study, we establish the skin graft model from A2 mouse to normal C57BL/6 mouse though back to back full-thickness skins transplantation. The rejection was observed and compared with the the acute rejection of allogeneic skins transplantation and the chronic one across the sex. The results list below:
1 -, The expression of HLA-A2 molecule on the transgenic mouse cell's surface was detected by both RT-PCR with specific primers of HLA-A2 extra-cellular domain and the HLA-A2 allelic specific antibody BB7.2.
2^ Set up the skin graft animal model (recipient: normal C57BL/6 male mice, donor: A2 male mice) in which HLA-A2 molecule is expected to be the sole rejection antigen. Results showed that A2 mouse skin grafts were rapidly rejected in 9—13 days, and the T cells proliferation of the recipient was stronger in mixed lymphocyte culture.
3 -, Compared to the chronic rejection reaction caused by the unmatch sex between recipient and donor, the reaction against the HLA-A2 molecule is more likely to be the acute rejection of allogeneic skin graft, because which occurs rapid in time and intensity in inflammatory response.
The rejection against HLA-A2 molecule in the animal model provides us with an in vivo model which would be useful for us to further understand the direct and the indirect recognition in the graft rejection and to induce the graft tolerance.
引文
[1] Rapaport FT, Dausset J, Converse JM et al. Biological and Ultrastructural Studies ofLeucocyte Fractions as Transplantation Antigens in Man[J]. Transplantation. 1965, 3:490-500.
[2] Watschinger B. How T cells recognize alloantigen: evidence for two pathways ofallorecognition[J].Nephrol Dial Transplant. 1995, 10(9): 1556-1558.
[3] York IA, Rock KL. Antigen processing and presentation by the class I majorhistocompatibility complex[J]. Annu Rev Immunol. 1996, 14: 369-396.
[4] Mirenda V, Berton I, Read J et al. Modified dendritic cells coexpressing self andallogeneic major histocompatability complex molecules: an efficient way to induceindirect pathway regulation[J]. J Am Soc Nephrol. 2004, 15(4): 987-997.
[5] Benichou G, Valujskikh A, Heeger PS. Contributions of direct and indirect T cellall ore activity during allograft rejection in mice[J]. J Immunol. 1999, 162(1): 352-358.
[6] Auchincloss H, Jr., Lee R, Shea S et al. The role of "indirect" recognition in initiatingrejection of skin grafts from major histocompatibility complex class II-deficientmice[J]. Proc Natl Acad Sci USA. 1993, 90(8): 3373-3377.
[7] Lee RS, Grusby MJ, Glimcher LH et al. Indirect recognition by helper cells caninduce donor-specific cytotoxic T lymphocytes in vivo[J]. J Exp Med. 1994, 179(3):865-872.
[8] Cheuk E, D'Souza C, Hu N et al. Human MHC class I transgenic mice deficient forH2 class I expression facilitate identification and characterization of new HLA classI-restricted viral T cell epitopes[J]. J Immunol. 2002, 169(10): 5571-5580.
[9] Pascolo S, Bervas N, Ure JM et al. HLA-A2.1-restricted education and cytolyticactivity of CD8(+) T lymphocytes from beta2 microglobulin (beta2m) HLA-A2.1monochain transgenic H-2Db beta2m double knockout mice[J]. J Exp Med. 1997,185(12): 2043-2051.
[10]龚非力，沈关心，李卓娅医学免疫学第二版；2003
[11] Chalasani, MD; G, Lakkis et al. Immunologic ignorance of organ allografts. In:Current Opinion in Organ Transplantation; 2001:83-88. [ 12] Vitiello A, Marchesini D, Furze J et al. Analysis of the HLA-restrictedinfluenza-specific cytotoxic T lymphocyte response in transgenic mice carrying achimeric human-mouse class I major histocompatibility complex[J]. J Exp Med. 1991,173(4): 1007-1015.
[13] Kalinke U, Arnold B, Hammerling GJ. Strong xenogeneic HLA response intransgenic mice after introducing an alpha 3 domain into HLA B27[J]. Nature. 1990,348(6302): 642-644.
[14] Skaletsky H, Kuroda-Kawaguchi T, Minx PJ et al. The male-specific region of thehuman Y chromosome is a mosaic of discrete sequence classes[J]. Nature. 2003,423(6942): 825-837.
[15] Abastado JP, Lone YC, Casrouge A et al. Dimerization of soluble maj orhistocompatibility complex-peptide complexes is sufficient for activation of T cellhybridoma and induction of unresponsiveness[J]. J Exp Med. 1995, 182(2): 439-447.
[16]梁智辉等翁吴sHLAA0201原肽四聚体的构建与功能检测[Jll中国免疫学杂志2006：54．57
[17]翁秀芳，梁智辉，卢小玲et al自身肽结合于HLA-A2分子上能够在体外诱导抗原肽特异性的同种T细胞[Jll中国科学(c辑：生命科学)2007，(01期)
[18] Weng X, Zhong M, Liang Z et al. Peptide-dependent inhibition of alloreactive T-cell response by soluble divalent HLA-A2/IgG molecule in vitro [J]. Transplantation. 2007, 84(10): 1298-1306
[1] Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways intransplant rejection[J]. NEngl JMed. 1998,338(25): 1813-1821.
[2] Lombardi G, Sidhu S, Batchelor JR et al. All ore cognition of DR1 by T cells from aDR4/DRwl3 responder mimics self-restricted recognition of endogenous peptides[J].Proc Natl Acad Sci USA. 1989, 86(11): 4190-4194.
[3] Benichou G, Takizawa PA, Olson CA et al. Donor major histocompatibility complex(MHC) peptides are presented by recipient MHC molecules during graft rejection[J]. JExp Med. 1992, 175(1): 305-308.
[4] Gould DS, Auchincloss H, Jr. Direct and indirect recognition: the role of MHCantigens in graft rejection[J]. Immunol Today. 1999, 20(2): 77-82.
[5] Sester U, Thijssen S, van Bentum K et al. Rapid identification of preformedalloreactive T cells for use in a clinical setting[J]. Transplantation. 2004, 78(4):607-614.
[6] Hornick P, Lechler R. Direct and indirect pathways of alloantigen recognition:relevance to acute and chronic allograft rejection[J]. Nephrol Dial Transplant. 1997,12(9): 1806-1810.
[7] Wang W, Man S, Gulden PH et al. Class I-restricted alloreactive cytotoxic Tlymphocytes recognize a complex array of specific MHC-associated peptides [J]. JImmunol. 1998, 160(3): 1091-1097.
[8] Warrens AN, Lombardi G, Lechler RI. Presentation and recognition of major andminor histocompatibility antigens [J]. Transpl Immunol. 1994, 2(2): 103-107.
[9] Whitelegg A, Barber LD. The structural basis of T-cell allorecognition[J]. TissueAntigens. 2004, 63(2): 101-108.
[10] Matzinger P, Bevan MJ. Hypothesis: why do so many lymphocytes respond to majorhistocompatibility antigens?[J]. Cell Immunol. 1977,29(1): 1-5.
[11]翁秀芳，梁智辉，卢小玲et al自身肽结合于HLA-A2分子上能够在体外诱导抗原肽特异性的同种T细胞[Jll中国科学(c辑：生命科学)2007，(01期)
[12] Heath WR, Kane KP, Mescher MF et al. Alloreactive T cells discriminate among adiverse set of endogenous peptides[J]. Proc Natl Acad Sci USA. 1991, 88(12):5101-5105.
[13] Tallquist MD, Yun TJ, Pease LR. A single T cell receptor recognizes structurallydistinct MHC/peptide complexes with high specificity[J]. J Exp Med. 1996, 184(3):1017-1026.
[14] Alexander-Miller MA, Burke K, Koszinowski UH et al. Alloreactive cytotoxic Tlymphocytes generated in the presence of viral-derived peptides show exquisitepeptide and MHCspecificity[J].J Immunol. 1993, 151(1): 1-10.
[15] Smith PA, Brunmark A, Jackson MR et al. Peptide-independent recognition byalloreactive cytotoxic T lymphocytes (CTL)[J]. J Exp Med. 1997, 185(6): 1023-1033.
[16] Elliott TJ, Eisen HN. Cytotoxic T lymphocytes recognize a reconstituted class Ihistocompatibility antigen (HLA-A2) as an allogeneic target molecule [J]. Proc NatlAcad Sci USA. 1990, 87(13): 5213-5217.
[17] Ljunggren HQ Stam NJ, Ohlen C et al. Empty MHC class I molecules come out inthe cold[J]. Nature. 1990, 346(6283): 476-480. [ 18] Germain RN, Hendrix LR. MHC class II structure, occupancy and surfaceexpression determined by post-endoplasmic reticulum antigen binding[J]. Nature.1991,353(6340): 134-139.
[19] Benichou G, Valujskikh A, Heeger PS. Contributions of direct and indirect T cellall ore activity during allograft rejection in mice[J]. J Immunol. 1999, 162(1): 352-358.
[20] Pietra B, Rizeq M, Bolwerk A et al. CD4 T cells acutely reject cardiac allografts viadirect donor recognition[J]. Transplant Proc. 1999, 31(1-2): 92.
[21] Hornick PI, Mason PD, Yacoub MH et al. Assessment of the contribution that directall ore cognition makes to the progression of chronic cardiac transplant rejection inhumans[J]. Circulation. 1998, 97(13): 1257-1263.
[22] Ford ML, Evavold BD. Degenerate recognition of T cell epitopes: impact of T cellreceptor reserve and stability of peptide:MHC complexes[J]. Mol Immunol. 2004,40(14-15): 1019-1025.
[23] Krensky AM, Weiss A, Crabtree G et al. T-lymphocyte-antigen interactions intransplant rejection[J]. N Engl J Med. 1990, 322(8): 510-517.
[24] Auchincloss H, Jr., Lee R, Shea S et al. The role of "indirect" recognition ininitiating rejection of skin grafts from major histocompatibility complex classII-deficientmice[J]. Proc Natl Acad Sci USA. 1993, 90(8): 3373-3377.
[25] Singer A, Munitz TI, Golding H et al. Recognition requirements for the activation,differentiation and function of T-helper cells specific for class I MHC alloantigens[J].Immunol Rev. 1987, 98: 143-170.
[26] Rosenberg AS, Singer A. Cellular basis of skin allograft rejection: an in vivo modelof immune-mediated tissue destruction[J]. Annu Rev Immunol. 1992, 10: 333-358.
[27] Vella JP, Spadafora-Ferreira M, Murphy B et al. Indirect all ore cognition of majorhistocompatibility complex allopeptides in human renal transplant recipients withchronic graft dysfunction[J]. Transplantation. 1997, 64(6): 795-800.
[28] Ichikawa T, Nakayama E, Uenaka A et al. Effector cells in allelic H-2 classI-incompatible skin graft rejection[J]. J Exp Med. 1987, 166(4): 982-990.
[29] Sawada T, Wu Y, Sachs DH et al. CD4+ T cells are able to reject class I disparateallografts[J]. Transplantation. 1997, 64(2): 335-340.
[30] Grade JA, Bolton EM, Porteous C et al. T cell requirements for the rejection of renalallografts bearing an isolated class I MHC disparity[J]. J Exp Med. 1990, 172(6):1547-1557.
[31] Rosenberg AS, Munitz TI, Maniero TG et al. Cellular basis of skin allograft rejectionacross a class I major histocompatibility barrier in mice depleted of CD8+ T cells invivo[J]. JExpMed. 1991, 173(6): 1463-1471.
[32] Wise M, Zelenika D, Bemelman F et al. CD4 T cells can reject majorhistocompatibility complex class I-incompatible skin grafts [J]. Eur J Immunol. 1999,29(1): 156-167.
[33] Game DS, Lechler RI. Pathways of al lore cognition: implications for transplantationtolerance[J]. Transpl Immunol. 2002, 10(2-3): 101-108.
[34] Marrack P, Kappler J. The T cell receptor [J]. Science. 1987, 238(4830): 1073-1079.
[35] Mandelbrot DA, Kishimoto K, Auchincloss H, Jr. et al. Rejection of mouse cardiacallografts by costimulation in trans[J]. J Immunol. 2001, 167(3): 1174-1178.
[36] Auchincloss H, Jr., Sultan H. Antigen processing and presentation intransplantation[J]. Curr Opin Immunol. 1996, 8(5): 681-687.
[2] Watschinger B. How T cells recognize alloantigen: evidence for two pathways ofallorecognition[J].Nephrol Dial Transplant. 1995, 10(9): 1556-1558.
[3] York IA, Rock KL. Antigen processing and presentation by the class I majorhistocompatibility complex[J]. Annu Rev Immunol. 1996, 14: 369-396.
[4] Mirenda V, Berton I, Read J et al. Modified dendritic cells coexpressing self andallogeneic major histocompatability complex molecules: an efficient way to induceindirect pathway regulation[J]. J Am Soc Nephrol. 2004, 15(4): 987-997.
[5] Benichou G, Valujskikh A, Heeger PS. Contributions of direct and indirect T cellall ore activity during allograft rejection in mice[J]. J Immunol. 1999, 162(1): 352-358.
[6] Auchincloss H, Jr., Lee R, Shea S et al. The role of "indirect" recognition in initiatingrejection of skin grafts from major histocompatibility complex class II-deficientmice[J]. Proc Natl Acad Sci USA. 1993, 90(8): 3373-3377.
[7] Lee RS, Grusby MJ, Glimcher LH et al. Indirect recognition by helper cells caninduce donor-specific cytotoxic T lymphocytes in vivo[J]. J Exp Med. 1994, 179(3):865-872.
[8] Cheuk E, D'Souza C, Hu N et al. Human MHC class I transgenic mice deficient forH2 class I expression facilitate identification and characterization of new HLA classI-restricted viral T cell epitopes[J]. J Immunol. 2002, 169(10): 5571-5580.
[9] Pascolo S, Bervas N, Ure JM et al. HLA-A2.1-restricted education and cytolyticactivity of CD8(+) T lymphocytes from beta2 microglobulin (beta2m) HLA-A2.1monochain transgenic H-2Db beta2m double knockout mice[J]. J Exp Med. 1997,185(12): 2043-2051.
[10]龚非力，沈关心，李卓娅医学免疫学第二版；2003
[11] Chalasani, MD; G, Lakkis et al. Immunologic ignorance of organ allografts. In:Current Opinion in Organ Transplantation; 2001:83-88. [ 12] Vitiello A, Marchesini D, Furze J et al. Analysis of the HLA-restrictedinfluenza-specific cytotoxic T lymphocyte response in transgenic mice carrying achimeric human-mouse class I major histocompatibility complex[J]. J Exp Med. 1991,173(4): 1007-1015.
[13] Kalinke U, Arnold B, Hammerling GJ. Strong xenogeneic HLA response intransgenic mice after introducing an alpha 3 domain into HLA B27[J]. Nature. 1990,348(6302): 642-644.
[14] Skaletsky H, Kuroda-Kawaguchi T, Minx PJ et al. The male-specific region of thehuman Y chromosome is a mosaic of discrete sequence classes[J]. Nature. 2003,423(6942): 825-837.
[15] Abastado JP, Lone YC, Casrouge A et al. Dimerization of soluble maj orhistocompatibility complex-peptide complexes is sufficient for activation of T cellhybridoma and induction of unresponsiveness[J]. J Exp Med. 1995, 182(2): 439-447.
[16]梁智辉等翁吴sHLAA0201原肽四聚体的构建与功能检测[Jll中国免疫学杂志2006：54．57
[17]翁秀芳，梁智辉，卢小玲et al自身肽结合于HLA-A2分子上能够在体外诱导抗原肽特异性的同种T细胞[Jll中国科学(c辑：生命科学)2007，(01期)
[18] Weng X, Zhong M, Liang Z et al. Peptide-dependent inhibition of alloreactive T-cell response by soluble divalent HLA-A2/IgG molecule in vitro [J]. Transplantation. 2007, 84(10): 1298-1306
[1] Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways intransplant rejection[J]. NEngl JMed. 1998,338(25): 1813-1821.
[2] Lombardi G, Sidhu S, Batchelor JR et al. All ore cognition of DR1 by T cells from aDR4/DRwl3 responder mimics self-restricted recognition of endogenous peptides[J].Proc Natl Acad Sci USA. 1989, 86(11): 4190-4194.
[3] Benichou G, Takizawa PA, Olson CA et al. Donor major histocompatibility complex(MHC) peptides are presented by recipient MHC molecules during graft rejection[J]. JExp Med. 1992, 175(1): 305-308.
[4] Gould DS, Auchincloss H, Jr. Direct and indirect recognition: the role of MHCantigens in graft rejection[J]. Immunol Today. 1999, 20(2): 77-82.
[5] Sester U, Thijssen S, van Bentum K et al. Rapid identification of preformedalloreactive T cells for use in a clinical setting[J]. Transplantation. 2004, 78(4):607-614.
[6] Hornick P, Lechler R. Direct and indirect pathways of alloantigen recognition:relevance to acute and chronic allograft rejection[J]. Nephrol Dial Transplant. 1997,12(9): 1806-1810.
[7] Wang W, Man S, Gulden PH et al. Class I-restricted alloreactive cytotoxic Tlymphocytes recognize a complex array of specific MHC-associated peptides [J]. JImmunol. 1998, 160(3): 1091-1097.
[8] Warrens AN, Lombardi G, Lechler RI. Presentation and recognition of major andminor histocompatibility antigens [J]. Transpl Immunol. 1994, 2(2): 103-107.
[9] Whitelegg A, Barber LD. The structural basis of T-cell allorecognition[J]. TissueAntigens. 2004, 63(2): 101-108.
[10] Matzinger P, Bevan MJ. Hypothesis: why do so many lymphocytes respond to majorhistocompatibility antigens?[J]. Cell Immunol. 1977,29(1): 1-5.
[11]翁秀芳，梁智辉，卢小玲et al自身肽结合于HLA-A2分子上能够在体外诱导抗原肽特异性的同种T细胞[Jll中国科学(c辑：生命科学)2007，(01期)
[12] Heath WR, Kane KP, Mescher MF et al. Alloreactive T cells discriminate among adiverse set of endogenous peptides[J]. Proc Natl Acad Sci USA. 1991, 88(12):5101-5105.
[13] Tallquist MD, Yun TJ, Pease LR. A single T cell receptor recognizes structurallydistinct MHC/peptide complexes with high specificity[J]. J Exp Med. 1996, 184(3):1017-1026.
[14] Alexander-Miller MA, Burke K, Koszinowski UH et al. Alloreactive cytotoxic Tlymphocytes generated in the presence of viral-derived peptides show exquisitepeptide and MHCspecificity[J].J Immunol. 1993, 151(1): 1-10.
[15] Smith PA, Brunmark A, Jackson MR et al. Peptide-independent recognition byalloreactive cytotoxic T lymphocytes (CTL)[J]. J Exp Med. 1997, 185(6): 1023-1033.
[16] Elliott TJ, Eisen HN. Cytotoxic T lymphocytes recognize a reconstituted class Ihistocompatibility antigen (HLA-A2) as an allogeneic target molecule [J]. Proc NatlAcad Sci USA. 1990, 87(13): 5213-5217.
[17] Ljunggren HQ Stam NJ, Ohlen C et al. Empty MHC class I molecules come out inthe cold[J]. Nature. 1990, 346(6283): 476-480. [ 18] Germain RN, Hendrix LR. MHC class II structure, occupancy and surfaceexpression determined by post-endoplasmic reticulum antigen binding[J]. Nature.1991,353(6340): 134-139.
[19] Benichou G, Valujskikh A, Heeger PS. Contributions of direct and indirect T cellall ore activity during allograft rejection in mice[J]. J Immunol. 1999, 162(1): 352-358.
[20] Pietra B, Rizeq M, Bolwerk A et al. CD4 T cells acutely reject cardiac allografts viadirect donor recognition[J]. Transplant Proc. 1999, 31(1-2): 92.
[21] Hornick PI, Mason PD, Yacoub MH et al. Assessment of the contribution that directall ore cognition makes to the progression of chronic cardiac transplant rejection inhumans[J]. Circulation. 1998, 97(13): 1257-1263.
[22] Ford ML, Evavold BD. Degenerate recognition of T cell epitopes: impact of T cellreceptor reserve and stability of peptide:MHC complexes[J]. Mol Immunol. 2004,40(14-15): 1019-1025.
[23] Krensky AM, Weiss A, Crabtree G et al. T-lymphocyte-antigen interactions intransplant rejection[J]. N Engl J Med. 1990, 322(8): 510-517.
[24] Auchincloss H, Jr., Lee R, Shea S et al. The role of "indirect" recognition ininitiating rejection of skin grafts from major histocompatibility complex classII-deficientmice[J]. Proc Natl Acad Sci USA. 1993, 90(8): 3373-3377.
[25] Singer A, Munitz TI, Golding H et al. Recognition requirements for the activation,differentiation and function of T-helper cells specific for class I MHC alloantigens[J].Immunol Rev. 1987, 98: 143-170.
[26] Rosenberg AS, Singer A. Cellular basis of skin allograft rejection: an in vivo modelof immune-mediated tissue destruction[J]. Annu Rev Immunol. 1992, 10: 333-358.
[27] Vella JP, Spadafora-Ferreira M, Murphy B et al. Indirect all ore cognition of majorhistocompatibility complex allopeptides in human renal transplant recipients withchronic graft dysfunction[J]. Transplantation. 1997, 64(6): 795-800.
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