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

  • Author(s): McNally, JP
  • Millen, SH
  • Chaturvedi, V
  • Lakes, N
  • Terrell, CE
  • Elfers, EE
  • Carroll, KR
  • Hogan, SP
  • Andreassen, PR
  • Kanter, J
  • Allen, CE
  • Henry, MM
  • Greenberg, JN
  • Ladisch, S
  • Hermiston, ML
  • Joyce, M
  • Hildeman, DA
  • Katz, JD
  • Jordan, MB
  • 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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