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Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases.

  • Author(s): McNally, Jonathan P
  • Millen, Scott H
  • Chaturvedi, Vandana
  • Lakes, Nora
  • Terrell, Catherine E
  • Elfers, Eileen E
  • Carroll, Kaitlin R
  • Hogan, Simon P
  • Andreassen, Paul R
  • Kanter, Julie
  • Allen, Carl E
  • Henry, Michael M
  • Greenberg, Jay N
  • Ladisch, Stephan
  • Hermiston, Michelle L
  • Joyce, Michael
  • Hildeman, David A
  • Katz, Jonathan D
  • Jordan, Michael B
  • et al.
Abstract

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.

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