Confounding factors complicate conclusions in aly model
Confounding factors complicate conclusions in aly model
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混杂因素使 aly 模型的结论变得复杂
DOI：
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发表时间：
2001
期刊：
影响因子：
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通讯作者：
yang
中科院分区：
文献类型：
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作者：
R. Chin;P. Zhou;M. Alegre;yang
二级淋巴器官被广泛认为在协调适应性免疫反应中起关键作用，尽管直接证明很少。大多数现有证据使用缺乏周围淋巴结和Peyer 's斑块的淋巴增生（aly/aly）小鼠作为模型。最近，Lakkis和他的同事们证明，脾脏切除的aly/aly小鼠在免疫上对随后的心脏异体移植“一无所知”，而脾脏原位的aly/aly小鼠则永久接受皮肤异体移植。作者得出结论，次级淋巴器官在介导排斥反应中是必不可少的。虽然它们在某些反应中无疑是必要的，但我们尚不清楚次级淋巴器官在这里是否起重要作用。除了没有淋巴结外，aly/aly小鼠还存在多种其他严重的免疫缺陷，这些缺陷可能会混淆作者的发现，包括基线免疫球蛋白产生和同型转换降低，t细胞功能缺陷和错误的归巢反应。淋巴素-α -缺陷（Lta）和淋巴素-β-受体缺陷（Ltbr）小鼠同样缺乏淋巴结和Peyer 's斑块，但与aly/aly小鼠相关的其他缺陷很少。他们的t细胞反应确实表现得很平静。Lta小鼠对同种异体皮肤移植的排斥速度与野生型对照几乎相同（图1a），这一发现在Ltbr和脾切除Ltbr受体中得到证实（MST:14.2d, n = 9）。此外，脾切除的Lta和Ltbr受体仍然能够排斥BALB/c心脏同种异体移植物，有时仅在21天内（图1b）。这种延迟性排斥反应指出了次要淋巴器官对同种异体心脏移植排斥反应的重要性和可缺性。Lta和Ltbr受体在没有二级淋巴器官的情况下排斥心脏移植，这一发现挑战了Lakkis及其同事从他们的数据中得出的更广泛意义的结论，并表明除了淋巴结发育外，aly/aly小鼠中发现的独特的内在缺陷可能对他们的发现有重要贡献。他们为解决这些问题而进行的互惠性过继转移控制因稳态扩张和生存问题而变得复杂。Lakkis及其同事在aly/aly小鼠身上的发现无疑是重要的。然而，考虑到aly突变的多效性，以及Lta和Ltbr小鼠与aly/aly小鼠相比的相互矛盾的发现，对数据进行更谨慎的解释可能是谨慎的。很可能是aly/aly表型中多种免疫缺陷的总和，而不是淋巴结和Peyer ' s补片发育单独，可能是aly/aly小鼠免疫“无知”的原因。值得注意的是，其他关于aly/aly小鼠免疫反应的研究可能高估了次要淋巴器官的参与。
To the editor—Secondary lymphoid organs are widely understood to play a pivotal role in coordinating adaptive immune responses, though direct demonstrations are few. Most available evidence use as their model the alymphoplastic (aly/aly) mouse which lacks peripheral lymph nodes as well as Peyer’s patches. Most recently, Lakkis and colleagues demonstrated that splenectomized aly/aly mice are rendered immunologically ‘ignorant’ of their subsequent cardiac allograft, and aly/aly mice with spleens in place permanently accept skin allografts. The authors conclude that secondary lymphoid organs are essential for mediating rejection. Although they are undoubtedly necessary in certain responses, it is unclear to us that secondary lymphoid organs play an essential role here. Apart from the absence of lymph nodes, aly/aly mice host a variety of other serious immune defects which might confound the authors’ findings, including depressed baseline immunoglobulin production and isotype switching, defective T-cell function and faulty homing responses. Lymphotoxin-α–deficient (Lta) and lymphotoxin-β-receptor–deficient (Ltbr) mice are similarly devoid of lymph nodes and Peyer’s patches, but share few other defects additionally associated with aly/aly mice. Their T-cell responses indeed appear unperturbed. Lta mice reject allogeneic skin grafts in near identical tempo to wild-type controls (Fig. 1a), a finding confirmed in Ltbr and splenectomized Ltbr recipients (MST:14.2d, n = 9). Moreover, splenectomized Lta and Ltbr recipients remain capable of rejecting BALB/c cardiac allografts, sometimes in as few as 21 days (Fig. 1b). The delayed rejection points to the importance but also the dispensability of secondary lymphoid organs for rejection of cardiac allografts. The finding that Lta and Ltbr recipients reject heart transplants in the absence of secondary lymphoid organs challenges the wider significance of conclusions Lakkis and colleagues draw from their data, and suggests that concomitant intrinsic defects found uniquely in aly/aly mice— apart from lymph-node agenesis—may have contributed significantly to their findings. The reciprocal adoptive transfer controls they performed to address these concerns are complicated by issues of homeostatic expansion and survival. The findings of Lakkis and colleagues in aly/aly mice are no doubt important. However, given the pleiotropic effects of the aly mutation and in light of conflicting findings in Lta and Ltbr mice when compared with aly/aly mice, a more cautious interpretation of the data might be prudent. It is likely that the aggregate of diverse immune defects in the aly/aly phenotype together, rather than lymph node and Peyer’s patch agenesis alone, may be responsible for the immunological ‘ignorance’ witnessed in aly/aly mice. The salient consideration is that other studies of immune responses studied in aly/aly mice might overestimate the involvement of secondary lymphoid organs.