| First Author | Burton BR | Year | 2014 |
| Journal | Nat Commun | Volume | 5 |
| Pages | 4741 | PubMed ID | 25182274 |
| Mgi Jnum | J:295376 | Mgi Id | MGI:6212959 |
| Doi | 10.1038/ncomms5741 | Citation | Burton BR, et al. (2014) Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy. Nat Commun 5:4741 |
| abstractText | Antigen-specific immunotherapy combats autoimmunity or allergy by reinstating immunological tolerance to target antigens without compromising immune function. Optimization of dosing strategy is critical for effective modulation of pathogenic CD4(+) T-cell activity. Here we report that dose escalation is imperative for safe, subcutaneous delivery of the high self-antigen doses required for effective tolerance induction and elicits anergic, interleukin (IL)-10-secreting regulatory CD4(+) T cells. Analysis of the CD4(+) T-cell transcriptome, at consecutive stages of escalating dose immunotherapy, reveals progressive suppression of transcripts positively regulating inflammatory effector function and repression of cell cycle pathways. We identify transcription factors, c-Maf and NFIL3, and negative co-stimulatory molecules, LAG-3, TIGIT, PD-1 and TIM-3, which characterize this regulatory CD4(+) T-cell population and whose expression correlates with the immunoregulatory cytokine IL-10. These results provide a rationale for dose escalation in T-cell-directed immunotherapy and reveal novel immunological and transcriptional signatures as surrogate markers of successful immunotherapy. |
