Allen R D, Marshall J D, Roths J B, Sidman C L
Jackson Laboratory, Bar Harbor, ME 04609.
Eur J Immunol. 1990 Sep;20(9):2057-66. doi: 10.1002/eji.1830200926.
Transfer of bone marrow (BM) from autoimmunity-prone mice homozygous for the lymphoproliferation (lpr) mutation to irradiated congenic +/+ recipients has previously been shown to result in a syndrome similar to chronic graft-vs.-host (GVH) disease. It has been suggested that this syndrome may be due to an antigenic difference caused by the lpr mutation itself or to antigenic differences at loci closely linked to the lpr locus (Theofilopoulos, A. N. et al., J. Exp. Med. 1985. 162:1; Mosbach-Ozmen, L. and Loor, F., Thymus 1987. 9:197). However, the results presented here indicate that alloantigenic differences do not play a role in this syndrome. Instead, the chronic disease observed in lpr/lpr----(+/+) BM chimeras appears to develop as a result of a functional defect associated with the lpr mutation which is expressed shortly after transfer of lpr/lpr BM to irradiated recipients. This defect causes an increase in the levels of serum IgG1 and IgG2, which peak at 4-5 weeks post-transfer and then decline to normal levels by 9-10 weeks post-transfer. Inflammation similar to that observed in classic GVH reactions accompanies excess IgG production in congenic +/+ recipients but not in lpr/lpr recipients of lpr/lpr BM. We demonstrate that the GVH-like response occurring in lpr/lpr----(+/+) chimeras is dependent on mature T cells, but that either lpr/lpr or (+/+) T cells can support this reaction. These results suggest that transfer of lpr/lpr BM to normal mice causes immunoregulatory disturbances which lead to nonspecific activation of T cells. We speculate that lpr/lpr BM causes a GVH-like reaction in +/+ recipients but a systemic lupus erythematosus-like syndrome in lpr/lpr recipients because of intrinsic differences in the +/+ and lpr/lpr host environments. Considering these findings, the lpr/lpr----+/+ GVH model may be useful for analysis of factors capable of inducing undesirable reactions in clinical BM transplantation between nominally histocompatible donors and recipients, in addition to being informative about the nature of the lpr mutation itself.
先前已表明，将纯合淋巴增殖（lpr）突变的自身免疫易感小鼠的骨髓（BM）移植到经照射的同基因 +/+ 受体中，会导致一种类似于慢性移植物抗宿主（GVH）病的综合征。有人提出，这种综合征可能是由于 lpr 突变本身引起的抗原差异，或者是由于与 lpr 基因座紧密连锁的基因座上的抗原差异（Theofilopoulos, A. N. 等人，《实验医学杂志》1985 年。162:1；Mosbach-Ozmen, L. 和 Loor, F.，《胸腺》1987 年。9:197）。然而，此处给出的结果表明，同种异体抗原差异在这种综合征中不起作用。相反，在 lpr/lpr----(+/+) 骨髓嵌合体中观察到的慢性疾病似乎是由于与 lpr 突变相关的功能缺陷所致，这种缺陷在将 lpr/lpr BM 移植到经照射的受体后不久就会表现出来。这种缺陷导致血清 IgG1 和 IgG2 水平升高，在移植后 4 - 5 周达到峰值，然后在移植后 9 - 10 周降至正常水平。在同基因 +/+ 受体中，与经典 GVH 反应中观察到的炎症类似的炎症伴随着过量 IgG 的产生，但在 lpr/lpr BM 的 lpr/lpr 受体中则没有。我们证明，在 lpr/lpr----(+/+) 嵌合体中发生的 GVH 样反应依赖于成熟 T 细胞，但 lpr/lpr 或 (+/+) T 细胞都可以支持这种反应。这些结果表明，将 lpr/lpr BM 移植到正常小鼠中会导致免疫调节紊乱，从而导致 T 细胞的非特异性激活。我们推测，由于 +/+ 和 lpr/lpr 宿主环境的内在差异，lpr/lpr BM 在 +/+ 受体中引起 GVH 样反应，但在 lpr/lpr 受体中引起系统性红斑狼疮样综合征。考虑到这些发现，lpr/lpr----+/+ GVH 模型除了有助于了解 lpr 突变本身的性质外，还可能有助于分析能够在名义上组织相容性的供体和受体之间的临床 BM 移植中诱导不良反应的因素。
