In the absence of natural killer cell activation donor-specific antibody mediates chronic, but not acute, kidney allograft rejection.
In the absence of natural killer cell activation donor-specific antibody mediates chronic, but not acute, kidney allograft rejection.
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在缺乏自然杀伤细胞激活的情况下，供体特异性抗体介导慢性而非急性肾同种异体移植排斥。
DOI：
10.1016/j.kint.2018.08.041
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发表时间：
2019
影响因子：
19.6
通讯作者：
Fairchild,RobertL
中科院分区：
文献类型：
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作者：
Yagisawa,Takafumi;Tanaka,Toshiaki;Miyairi,Satoshi;Tanabe,Kazunari;Dvorina,Nina;Yokoyama,WayneM;Valujskikh,Anna;Baldwin3rd,WilliamM;Fairchild,RobertL
抗体介导的排斥反应（ABMR）是移植肾长期存活的主要障碍。在ccr5缺陷小鼠移植完全主要组织相容性复合体（MHC）错配的同种异体肾移植后，会诱导供体特异性抗体（DSA）反应失调，自然杀伤（NK）细胞在移植物损伤和排斥反应中起关键作用。我们研究了高DSA滴度对移植肾移植结果的影响，无论移植肾中是否存在NK细胞活化。在完全MHC不匹配的A/J同种异体移植和半同种异体（A/J x B6） F1肾移植的ccr5缺陷B6受体中，诱导了相同的血清DSA滴度，在移植后第14天达到峰值。A/J同种异体移植物在第16-28天发生排斥反应，而B6等异体移植物和半同种异体移植物在第65天存活。移植后第7天，A/J同种异体移植物的NK细胞浸润由表达高水平和低水平表面抗原NK1.1的不同群体组成，其中NK1.1低水平的细胞反映了最高水平的活化。NK细胞数量随移植后时间的延长而增加。半同种异体移植物第7天的NK细胞浸润完全由nk1.1高细胞组成，此后逐渐减少。移植后第65天，半同种异体移植物出现严重的间质纤维化、肾小球病变和动脉病变，并伴有促纤维化基因的表达。这些结果表明NK细胞与DSA协同作用导致急性肾移植排斥反应，而在没有NK细胞激活的情况下，高DSA滴度不会引起急性ABMR，而是诱导间质纤维化和肾小球损伤的惰性发展，导致移植晚期衰竭。
Antibody mediated rejection (ABMR) is a major barrier to long-term kidney graft survival. Dysregulated donor-specific antibody (DSA) responses are induced in CCR5-deficient mice transplanted with complete major histocompatibility complex (MHC)-mismatched kidney allografts, and natural killer (NK) cells play a critical role in graft injury and rejection. We investigated the consequence of high DSA titers on kidney graft outcomes in the presence or absence of NK cell activation within the graft. Equivalent serum DSA titers were induced in CCR5-deficient B6 recipients of complete MHC mismatched A/J allografts and semi-allogeneic (A/J x B6) F1 kidney grafts, peaking by day 14 post-transplant. A/J allografts were rejected between days 16-28, whereas B6 isografts and semi-allogeneic grafts survived past day 65. On day 7 post-transplant, NK cell infiltration into A/J allografts was composed of distinct populations expressing high and low levels of the surface antigen NK1.1, with NK1.1lowcells reflecting the highest level of activation. These NK cell populations increased with time post-transplant. In contrast, NK cell infiltration into semi-allogeneic grafts on day 7 was composed entirely of NK1.1highcells that decreased thereafter. On day 65 post-transplant the semi-allogeneic grafts had severe interstitial fibrosis, glomerulopathy, and arteriopathy, accompanied by expression of pro-fibrogenic genes. These results suggest that NK cells synergize with DSA to cause acute kidney allograft rejection, whereas high DSA titers in the absence of NK cell activation cannot provoke acute ABMR but instead induce the indolent development of interstitial fibrosis and glomerular injury that leads to late graft failure.