kinase inhibitor Veliparib In support of this assumption, Liesz et al. repeated their experiment in 30min and 90min temporary MACO models and proved that the effects of CD25+ Treg depletion were evident in mice with small infarcts (~15mm3, after 30min MCAO), but not in mice with larger damage (>100mm3 after 90min occlusion). Moreover, experiments in animal models with lesions of intermediate volumes (~50mm3 after 60min MCAO) [60, 61] failed to illustrate a significant result.Secondly, the disagreement posed by Liesz et al. and Kleinschnitz et al. may originate from different method of Treg depletion. Liesz et al. achieved the depletion via anti-CD25 mAb while Kleinschnitz et al. introduced a genetic mouse model.
Comparatively, the latter model conferred to a higher specificity as CD25 was also upregulated on activated T cells [40], and anti-CD25 mAb would therefore block CD25+ T cells other than Tregs to confound the outcome. In addition, the existence of CD25-negative Tregs subpopulations limits the interpretation of the data [15].4.2. Whether Exogenous Treg Adoption Benefits or Exacerbates OutcomeAdministration of exogenous Tregs induces another paradox. Li et al. proved that the adoption within 24 hours after the ischemic onset would exert a therapeutic effect that occurred by day 3 and lasted up to 28 days while Kleinschnitz et al. implemented the adoption 1 day before MCAO and ended up with evidently enlarged lesions in the transferred group by day 1.This discrepancy might be justified by multiple reasons. Firstly, the quantities of Tregs delivered differed remarkably between these two protocols.
Li et al. recommended a therapeutic dosage of 2 �� 106/mouse and noted that a concentration <1 �� 106 cells/mouse would fail to offer any early protection at all [53], whereas Kleinschnitz et al. used an even lower concentration of Entinostat 7.5 �� 105/mouse. Moreover, the different timing of Treg delivery might be another probable interpretation of the divergence as well. Li et al. transferred the cells after the ischemic attack while Kleinschnitz et al. administered Tregs one day before stroke, and the preischemic increase of Tregs might be counterproductive, since the immune milieu before stroke may not be permissive for proper Treg action [53], and the delivery itself may disrupt the natural balance of immune system. Finally, these two studies focused on different stages after stroke.
The former experiment emphasized the delayed effect in a long term with an observation period for a month while the latter concentrated on the short term efficacy within an acute phase of 24 hours and this divergence may count for the disagreement to a certain extent.5. Prospective and Conclusion Current data is gradually revealing the contribution and mechanism of Tregs in post-stroke inflammation.