Schurmans S, Brighouse G, Kramer G, Wen L, Izui S, Merino J, Lambert P H
Department of Pathology, CMU, Geneva, Switzerland.
J Immunol. 1991 Apr 1;146(7):2152-60.
The neonatal injection of semiallogeneic F1 spleen cells into newborn parental mice results in the induction of tolerance to the corresponding alloantigen (alloAg) and chimerism. In these F1 cell-injected mice, we have previously observed that this state of specific tolerance is associated with the development of a transient lupus-like autoimmune syndrome. In this study, we show that neonatal injection of mice with spleen cells differing from the host at major histocompatibility complex (MHC) class I, class II, class (I + II), or minor lymphocyte stimulating (Mls) alloAg induced a state of specific tolerance characterized by the absence of alloreactive CTL and/or Th cell responses in the spleen and the thymus of 6- to 12-week-old injected mice. However, in mice rendered tolerant to MHC class II or class (I + II) alloAg, the presence of high levels of IgG1 antibodies, of circulating immune complexes, of anti-ssDNA autoantibodies, and of tissue lesions were transiently observed. In these mice, an increased Ia Ag expression on lymphoid spleen cells was also detected at 1 wk. The elevated production of IgG1 and the overexpression of Ia Ag were almost completely prevented by treatment with an anti-IL-4 mAb. Such manifestations of B cell activation and autoimmunity were not observed in mice neonatally injected with F1 cells differing from the host only at MHC class I Ag. In mice neonatally tolerized to Mls Ag, a transient increase in IgG2a production and an overexpression of Ia Ag were detected without features of autoimmunity, and were prevented by anti-INF-gamma mAb treatment. In mice rendered tolerant to MHC class II, class (I + II), or Mls alloAg at birth, the manifestations of B cell activation were associated with the presence of in vivo-activated alloreactive CD4+ T cells in the spleen--but not the thymus--of 1-wk-old injected mice. Together, these results suggest that in mice neonatally injected with semiallogeneic F1 cells, the process of tolerance induction is not efficient during the early postnatal period, and could allow the maturation and peripheralization of some alloreactive CD4+ T cells, leading to transient B cell activation and, depending on the alloAg, to autoimmunity.
将半同种异体F1脾细胞注射到新生亲代小鼠体内，可诱导对相应同种异体抗原（alloAg）的耐受和嵌合现象。在这些注射了F1细胞的小鼠中，我们之前观察到这种特异性耐受状态与短暂的狼疮样自身免疫综合征的发生有关。在本研究中，我们发现，新生小鼠注射在主要组织相容性复合体（MHC）I类、II类、（I + II）类或次要淋巴细胞刺激（Mls）同种异体抗原上与宿主不同的脾细胞后，6至12周龄的注射小鼠的脾脏和胸腺中会出现一种特异性耐受状态，其特征为缺乏同种异体反应性CTL和/或Th细胞反应。然而，在对MHC II类或（I + II）类同种异体抗原产生耐受的小鼠中，短暂观察到高水平的IgG1抗体、循环免疫复合物、抗单链DNA自身抗体以及组织损伤的存在。在这些小鼠中，1周时还检测到淋巴脾细胞上Ia抗原表达增加。用抗IL-4单克隆抗体治疗几乎完全阻止了IgG1的产生增加和Ia抗原的过度表达。在新生时仅注射在MHC I类抗原上与宿主不同的F1细胞的小鼠中，未观察到这种B细胞活化和自身免疫的表现。在新生时对Mls抗原产生耐受的小鼠中，检测到IgG2a产生短暂增加和Ia抗原过度表达，但无自身免疫特征，并且抗INF-γ单克隆抗体治疗可阻止这种情况。在出生时对MHC II类、（I + II）类或Mls同种异体抗原产生耐受的小鼠中，B细胞活化的表现与1周龄注射小鼠脾脏（而非胸腺）中体内活化的同种异体反应性CD4 + T细胞的存在有关。总之，这些结果表明，在新生小鼠注射半同种异体F1细胞后，耐受诱导过程在出生后早期并不有效，并且可能允许一些同种异体反应性CD4 + T细胞成熟并进入外周，导致短暂的B细胞活化，并根据同种异体抗原的不同引发自身免疫。
