Data from Instability of Foxp3 Expression Limits the Ability of Induced Regulatory T Cells to Mitigate Graft versus Host Disease
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<div>Abstract<p><b>Purpose:</b> Graft versus host disease (GVHD) is the major complication of allogeneic bone marrow transplantation (BMT) and limits the therapeutic efficacy of this modality. Although the role of natural T-regulatory cells (nTreg) in attenuating GVHD has been extensively examined, the ability of induced T-regulatory cells (iTreg) to mitigate GVHD is unknown. The purpose of this study was to examine the ability of <i>in vitro</i> and <i>in vivo</i> iTregs to abrogate GVHD.</p><p><b>Experimental Design:</b> We examined the ability of <i>in vitro</i> differentiated and <i>in vivo</i> iTregs to reduce the severity of GVHD in a clinically relevant mouse model of BMT. The effect of blockade of interleukin (IL) 6 signaling on the efficacy of these Treg populations was also studied.</p><p><b>Results:</b> <i>In vitro</i> differentiated iTregs fail to protect mice from lethal GVHD even when administered at high Treg:effector T-cell ratios. Lack of GVHD protection was associated with loss of Foxp3 expression and <i>in vivo</i> reversion of these cells to a proinflammatory phenotype characterized by secretion of IFN-γ. Phenotypic reversion could not be abrogated by blockade of IL-6 signaling or by <i>in vitro</i> exposure of iTregs to all-trans retinoic acid. In contrast, the <i>in vivo</i> induction of iTregs was significantly augmented by IL-6 blockade and this resulted in reduced GVHD.</p><p><b>Conclusion:</b> Instability of Foxp3 expression limits the utility of adoptively transferred iTregs as a source of cellular therapy for the abrogation of GVHD. Blockade of IL-6 signaling augments the ability of <i>in vivo</i> iTregs to prevent GVHD but has no effect on <i>in vitro</i> differentiated iTregs. <i>Clin Cancer Res; 17(12); 3969–83. ©2011 AACR</i>.</p></div>Keywords:
Reversion
Proinflammatory cytokine
A spontaneous spore-colour mutation located in the gene b2 of A. immersus gives a high frequency of reversion. 8 distinct revertant phenotypes have been defined. The mutations corresponding to these revertants are located at the same site or very near the original mutation. The hypothesis that the mutation by itself is responsable for the observed reversions is advanced.
Reversion
Mutation frequency
Suppressor mutation
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The reversion of the protoplasts of two strains Bac. subtilis on 3 nutritive media: DP of Elliott et al., DM3 of Chang and Cohen and MRG of Bourne and Dancer, is studied. Special attention is devoted to the role of the components gelatin, bovine serum albumin and osmotic stabilizer. In relation to the conclusions drawn in the study a new medium for reversion of protoplasts is suggested--the glucitole reversion agar GRA ensuring continuous 20-40% reversion of the sown protoplasts.
Reversion
Protoplast
Gelatin
Mean reversion
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Abstract Variants from polyoma virus transformed cells in which reversion was not associated with a loss of the virus genome have been studied at 3 and 33 weeks after clone isolation. The variants re‐reverted during this in vitro cultivation for properties which were initially suppressed. This re‐reversion was associated with an increase in the total chromosome number from a lower to a higher subtetraploid chromosome number.
Reversion
clone (Java method)
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The effects of the anti-reversion agent SR534 on the properties of NR compound were experimentally investigated and compared to those of anti-reversion agent PK900.The results showed that MH,scorch time and t90 of NR compound changed a little when the addition level of the anti-reversion agent SR534 was less than 2 phr;the reversion percentage of NR compound was decreased,the anti-reversion characteristic was improved as the addition level of the anti-reversion agent SR534 increased.The anti-reversion characteristic of SR534 was better than that of PK900 with the same addition amount;the anti-reversion agent SR534 and PK900 could be used to improve the physical properties of NR vulcanizate when the cure time was up to 60 min.
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Mean reversion
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The spontaneous reversion frequency of homocysteine requiring strain (4-24) of Ustilago maydis was determined as 23×10-5 per sporidium on the minimal media supplemented with 1×10-5mg/ml methionine. This genetic block in the biochemical pathway between cystathionine and homocysteine has been elucidated as due to one genic step. In contrast to the current opininon, the reversion in the present strain, now observed, does not take place in one step but step by step through two distinct transient steps. It reverted in sequence of 4-24→PRT 1→PRT 2→CRT; where PRT and CRT denoted respectively, partial reversion type and complete reversion type. It is noted that the two transient types, PRT 1and PRT 1, are as stable as the original strain.Studies of the growth rate of these reversion types have shown that the present partial reversion is explicable by the leakage, the mechanism of which, however, is not yet settled in the present experiments.
Reversion
Ustilago
Strain (injury)
Mean reversion
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Reversion
Polyoma virus
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Reversion
Repressor lexA
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Reversion
Transposition (logic)
Mutation frequency
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Abstract The stability of the reverted state has been analysed in revertants from polyomavirus‐transformed cells in which reversion was not associated with a loss of the virus genome. The regaining of two transformed properties, the ability to form colonies at high temperature (41° C) and in soft agar, were used as markers for re‐reversion. The frequency of re‐reversion was studied in 12 cloned revertants after different periods of in vitro cultivation. When tested at 45 days after isolation, there were no temperature re‐revertants and 2 to 184 agar re‐revertants per 5 × 10 4 cells. At 90 days after isolation, there were 14 to 784 temperature re‐revertants, and 242 to 1160 agar re‐revertants per 5 × 10 4 cells. The stability of the reverted state was thus decreased by in vitro cultivation. The study of isolated re‐revertants has indicated that, once a transformed property has been regained during re‐reversion, the immediate progeny of the re‐revertant may contain a high frequency of segregants which had lost this regained property. The re‐reverted state was more stable in re‐revertants from revertants that were 100 days after isolation, than in re‐revertants from revertants that were 55 days after isolation. Re‐reversion for one transformed property was not necessarily associated with re‐reversion for the other transformed property. The different degrees of stability are explained by differences in the balance between chromosomally located factors that determine the expression and suppression of transformed properties.
Reversion
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Reversion
Mutation frequency
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