Ensminger Stephan M, Spriewald Bernd M, Witzke Oliver, Morrison Karen, Pajaro Octavio E, Morris Peter J, Rose Marlene L, Wood Kathryn J
Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Transplantation. 2002 Apr 15;73(7):1068-74. doi: 10.1097/00007890-200204150-00009.
Transplant arteriosclerosis is still the major complication for long-term allograft survival in clinical transplantation. The aim of our study was to investigate the impact of MHC disparity on the kinetics of the development of transplant arteriosclerosis.
MHC-class I mismatched CBK (H2k+Kb) or fully allogeneic C57BL/10 (H2b) aortic allografts were transplanted into CBA.CA (H2k) recipients; syngeneic grafts were used as controls. Aortic grafts were analyzed on days 7, 14, and 30 after transplantation by performing morphometry, immunohistochemistry and quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) for the detection of intragraft cytokine mRNA production. Donor specific alloantibody production was measured by FACS analysis.
Intimal proliferation developed more rapidly in fully allogeneic grafts (direct and indirect allorecognition by CD4+ T cells) compared to MHC-class I mismatched grafts (indirect allorecognition only by CD4+ T cells) (day 7: 6+/-7 vs. 2+/-3%; day 14: 17+/-8 vs. 5+/-1%; day 30: 65+/-5 vs. 38+/-7% (C57BL/10 vs. CBK). However, by day 60, the level of intimal proliferation in the MHC-class I mismatched grafts was equivalent to that observed with fully allogeneic grafts on day 30. There was also a marked delay in the kinetics of graft infiltration by CD4+, CD8+, CD11b+, and CD40+ leukocytes and alloantibody production when CD4+ T cells were only activated via indirect presentation (MHC-class I mismatched grafts). Expression of interferon-gamma, interleukin-2, and interleukin-4 correlated with the kinetics of leukocyte infiltration, whereas interleukin-10, interleukin-12p40, iNOS, and TGF-beta1 showed a distinct pattern of expression.
These data demonstrate that the degree of MHC incompatibility between donor and recipient markedly influences the kinetics of the development of transplant arteriosclerosis. The onset of disease was delayed when grafts were mismatched for only MHC-class I antigens, but ultimately reached the same levels as seen in fully allogeneic grafts. The pattern of leukocyte infiltration and the kinetics of cytokine production suggest that in the MHC-class I mismatched grafts CD4+ T cells responding via the indirect pathway might play an important role in the development of transplant arteriosclerosis.
移植动脉硬化仍然是临床移植中长期同种异体移植物存活的主要并发症。我们研究的目的是调查主要组织相容性复合体（MHC）差异对移植动脉硬化发展动力学的影响。
将MHC-I类错配的CBK（H2k + Kb）或完全同种异体的C57BL/10（H2b）主动脉同种异体移植物移植到CBA.CA（H2k）受体中；同基因移植物用作对照。在移植后第7、14和30天对主动脉移植物进行分析，通过形态计量学、免疫组织化学和定量逆转录聚合酶链反应（RT-PCR）检测移植物内细胞因子mRNA的产生。通过流式细胞术分析测量供体特异性同种异体抗体的产生。
与MHC-I类错配的移植物（仅由CD4 + T细胞进行间接同种异体识别）相比，完全同种异体移植物（由CD4 + T细胞进行直接和间接同种异体识别）内膜增生发展更快（第7天：6 +/- 7% 对2 +/- 3%；第14天：17 +/- 8% 对5 +/- 1%；第30天：65 +/- 5% 对38 +/- 7%（C57BL/10对CBK））。然而，到第60天时，MHC-I类错配移植物的内膜增生水平与第30天完全同种异体移植物中观察到的水平相当。当CD4 + T细胞仅通过间接呈递被激活时（MHC-I类错配移植物），CD4 +、CD8 +、CD11b +和CD40 +白细胞的移植物浸润动力学以及同种异体抗体产生也有明显延迟。干扰素-γ、白细胞介素-2和白细胞介素-4的表达与白细胞浸润动力学相关，而白细胞介素-10、白细胞介素-12p40、诱导型一氧化氮合酶和转化生长因子-β1表现出不同的表达模式。
这些数据表明供体和受体之间MHC不相容的程度显著影响移植动脉硬化发展的动力学。当移植物仅在MHC-I类抗原上错配时，疾病的发作会延迟，但最终会达到与完全同种异体移植物相同的水平。白细胞浸润模式和细胞因子产生动力学表明，在MHC-I类错配的移植物中，通过间接途径反应的CD4 + T细胞可能在移植动脉硬化的发展中起重要作用。
