| First Author | McNally JP | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 24 | Pages | E4782-E4791 |
| PubMed ID | 28533414 | Mgi Jnum | J:244357 |
| Mgi Id | MGI:5913136 | Doi | 10.1073/pnas.1703683114 |
| Citation | McNally JP, et al. (2017) Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases. Proc Natl Acad Sci U S A 114(24):E4782-E4791 |
| abstractText | Antigen-activated lymphocytes undergo extraordinarily rapid cell division in the course of immune responses. We hypothesized that this unique aspect of lymphocyte biology leads to unusual genomic stress in recently antigen-activated lymphocytes and that targeted manipulation of DNA damage-response (DDR) signaling pathways would allow for selective therapeutic targeting of pathological T cells in disease contexts. Consistent with these hypotheses, we found that activated mouse and human T cells display a pronounced DDR in vitro and in vivo. Upon screening a variety of small-molecule compounds, we found that potentiation of p53 (via inhibition of MDM2) or impairment of cell cycle checkpoints (via inhibition of CHK1/2 or WEE1) led to the selective elimination of activated, pathological T cells in vivo. The combination of these strategies [which we termed "p53 potentiation with checkpoint abrogation" (PPCA)] displayed therapeutic benefits in preclinical disease models of hemophagocytic lymphohistiocytosis and multiple sclerosis, which are driven by foreign antigens or self-antigens, respectively. PPCA therapy targeted pathological T cells but did not compromise naive, regulatory, or quiescent memory T-cell pools, and had a modest nonimmune toxicity profile. Thus, PPCA is a therapeutic modality for selective, antigen-specific immune modulation with significant translational potential for diverse immune-mediated diseases. |
