Chan William F N, Razavy Haide, Luo Bin, Shapiro A M James, Anderson Colin C
Department of Medical Microbiology and Immunology, Surgical-Medical Research Institute, University of Alberta, Edmonton, Alberta, Canada.
J Immunol. 2008 Apr 15;180(8):5177-86. doi: 10.4049/jimmunol.180.8.5177.
Hematopoietic chimerism is considered to generate robust allogeneic tolerance; however, tissue rejection by chimeras can occur. This "split tolerance" can result from immunity toward tissue-specific Ags not expressed by hematopoietic cells. Known to occur in chimeric recipients of skin grafts, it has not often been reported for other donor tissues. Because chimerism is viewed as a potential approach to induce islet transplantation tolerance, we generated mixed bone marrow chimerism in the tolerance-resistant NOD mouse and tested for split tolerance. An unusual multilevel split tolerance developed in NOD chimeras, but not chimeric B6 controls. NOD chimeras demonstrated persistent T cell chimerism but rejected other donor hematopoietic cells, including B cells. NOD chimeras also showed partial donor alloreactivity. Furthermore, NOD chimeras were split tolerant to donor skin transplants and even donor islet transplants, unlike control B6 chimeras. Surprisingly, islet rejection was not a result of autoimmunity, since NOD chimeras did not reject syngeneic islets. Split tolerance was linked to non-MHC genes of the NOD genetic background and was manifested recessively in F(1) studies. Also, NOD chimeras but not B6 chimeras could generate serum alloantibodies, although at greatly reduced levels compared with nonchimeric controls. Surprisingly, the alloantibody response was sufficiently cross-reactive that chimerism-induced humoral tolerance extended to third-party cells. These data identify split tolerance, generated by a tolerance-resistant genetic background, as an important new limitation to the chimerism approach. In contrast, the possibility of humoral tolerance to multiple donors is potentially beneficial.
造血嵌合体被认为可产生强大的同种异体耐受性；然而，嵌合体也可能发生组织排斥。这种“分裂耐受性”可能源于针对造血细胞未表达的组织特异性抗原的免疫反应。已知在皮肤移植的嵌合受体中会发生这种情况，但在其他供体组织中并不常见。由于嵌合体被视为诱导胰岛移植耐受性的一种潜在方法，我们在耐受性较强的非肥胖糖尿病（NOD）小鼠中产生了混合骨髓嵌合体，并测试了其是否存在分裂耐受性。在NOD嵌合体中出现了一种不寻常的多级分裂耐受性，但在嵌合的B6对照小鼠中未出现。NOD嵌合体表现出持续的T细胞嵌合现象，但排斥其他供体造血细胞，包括B细胞。NOD嵌合体还表现出部分供体同种异体反应性。此外，与对照B6嵌合体不同，NOD嵌合体对供体皮肤移植甚至供体胰岛移植具有分裂耐受性。令人惊讶的是，胰岛排斥并非自身免疫的结果，因为NOD嵌合体不排斥同基因胰岛。分裂耐受性与NOD遗传背景的非主要组织相容性复合体（MHC）基因相关，并在F(1)研究中呈隐性表现。此外，NOD嵌合体而非B6嵌合体能够产生血清同种异体抗体，尽管与非嵌合对照相比水平大幅降低。令人惊讶的是，同种异体抗体反应具有足够的交叉反应性，以至于嵌合体诱导的体液耐受性扩展到了第三方细胞。这些数据表明，由耐受性较强的遗传背景产生的分裂耐受性是嵌合体方法的一个重要新限制。相比之下，对多个供体产生体液耐受性的可能性可能具有潜在益处。
