Direct Imaging of Immune Rejection and Memory Induction by Allogeneic Mesenchymal Stromal Cells

间充质干细胞 生物 免疫系统 免疫学 CD8型 主要组织相容性复合体 癌症研究 移植 间质细胞 细胞生物学 医学 内科学
作者
Lior Zangi,Raanan Margalit,Shlomit Reich-Zeliger,Esther Bachar-Lustig,Andreas Beilhack,Robert S. Negrin,Yaīr Reisner
出处
期刊:Stem Cells [Oxford University Press]
卷期号:27 (11): 2865-2874 被引量:261
标识
DOI:10.1002/stem.217
摘要

Abstract Although mesenchymal stromal cells (MSCs) exhibit marked immunoregulatory activity through multiple mechanisms, their potential to completely evade rejection upon transplantation into allogeneic recipients is controversial. To directly address this controversy, the survival of luciferase-labeled MSCs (Luc+ MSCs) was evaluated by imaging in allogeneic recipients. This analysis showed that although MSCs exhibited longer survival compared to fibroblasts (Fib), their survival was significantly shorter compared to that exhibited in syngeneic or in immune-deficient Balb-Nude or non-obese diabetic severe combined immunodeficiency (NOD-SCID) recipients. Graft rejection in re-challenge experiments infusing Luc+ Fib into mice, which had previously rejected Luc+ MSCs, indicated potential induction of immune memory by the MSCs. This was further analyzed in T-cell antigen receptor (TCR) transgeneic mice in which either CD4 TEA mice or CD8 T cells (2C mice) bear a TCR transgene against a specific MHC I or MHC II, respectively. Thus, following a re-challenge with MSCs expressing the cognate MHC haplotype, an enhanced percentage of 2C CD8+ or TEA CD4+ T cells exhibited a memory phenotype (CD122+, CD44+, and CD62Llow). Collectively, these results demonstrate that MSCs are not intrinsically immune-privileged, and under allogeneic settings, these cells induce rejection, which is followed by an immune memory. Considering that the use of allogeneic or even a third party (“off the shelf”) MSCs is commonly advocated for a variety of clinical applications, our results strongly suggest that long-term survival of allogeneic MSCs likely represents a major challenge. Disclosure of potential conflicts of interest is found at the end of this article.
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