The introduction of mesenchymal stromal cells induces different immunological responses in the lungs of healthy and M. tuberculosis infected mice

PLoS One

Evgenii Tcyganov¹  Yana Serdyuk¹  Nikolai Adrianov¹  Anna Sukhanova¹  Irina Bocharova¹  Tatiana Nenasheva¹  Alexander Panteleev¹  Alexander Nikolaev¹  Leonid Nezlin¹  Daniar Diykanov²  Irina Lyadova²  Tatiana Radaeva³  Yuri Rubtsov⁴ 

[1] Central Tuberculosis Research Institute, Moscow, Russia;Department of Biochemistry and Molecular Medicine, Faculty of Fundamental Medicine, M.V. Lomonosov Moscow State University, Moscow, Russia;Koltzov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia;Pirogov Russian National Research Medical University, Moscow, Russia

关键词: Mycobacterium tuberculosis;    Cytokines;    Inflammation;    Cloning;    Lungs;    Chemokines;    Macrophages;    Tuberculosis;   

DOI  :  10.1371/journal.pone.0178983

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Mesenchymal stromal cells (MSC) have strong immunomodulatory properties and therefore can be used to control inflammation and tissue damage. It was suggested recently that MSC injections can be used to treat multi-drug resistant tuberculosis (TB). However, MSC trafficking and immunomodulatory effects of MSC injections during Mycobacterium tuberculosis (Mtb) infection have not been studied. To address this issue we have analyzed MSC distribution in tissues and local immunological effects of MSC injections in Mtb infected and uninfected mice. After intravenous injection, MSC accumulated preferentially in the lungs where they were located as cell aggregates in the alveolar walls. Immunological analysis of MSC effects included detection of activated, IFN-γ and IL-4 producing CD4+ lymphocytes, the frequency analysis of dendritic cells (CD11c+F4/80) and macrophages (CD11c-F4/80+) located in the lungs, the expression of IA/IE and CD11b molecules by these cells, and evaluation of 23 cytokines/chemokines in lung lysates. In the lungs of uninfected mice, MSC transfer markedly increased the percentage of IFN-γ+ CD4+ lymphocytes and dendritic cells, elevated levels of IA/IE expression by dendritic cells and macrophages, augmented local production of type 2 cytokines (IL-4, IL-5, IL-10) and chemokines (CCL2, CCL3, CCL4, CCL5, CXCL1), and downregulated type 1 and hematopoietic cytokines (IL-12p70, IFN-γ, IL-3, IL-6, GM-CSF). Compared to uninfected mice, Mtb infected mice had statistically higher “background” frequency of activated CD69+ and IFN-γ+ CD4+ lymphocytes and dendritic cells, and higher levels of cytokines in the lungs. The injections of MSC to Mtb infected mice did not show statistically significant effects on CD4+ lymphocytes, dendritic cells and macrophages, only slightly shifted cytokine profile, and did not change pathogen load or slow down TB progression. Lung section analysis showed that in Mtb infected mice, MSC could not be found in the proximity of the inflammatory foci. Thus, in healthy recipients, MSC administration dramatically changed T-cell function and cytokine/chemokine milieu in the lungs, most likely, due to capillary blockade. But, during Mtb infection, i.e., in the highly-inflammatory conditions, MSC did not affect T-cell function and the level of inflammation. The findings emphasize the importance of the evaluation of MSC effects locally at the site of their predominant post-injection localization and question MSC usefulness as anti-TB treatment.

【 授权许可】

CC BY