J. P. McNally,
S. H. Millen,
V. Chaturvedi,
N. Lakes,
C. E. Terrell,
E. E. Elfers,
K. R. Carroll,
S. P. Hogan,
P. R. Andreassen,
J. Kanter,
C. E. Allen,
M. M. Henry,
J. N. Greenberg,
S. Ladisch,
M. L. Hermiston,
M. Joyce,
J. D. da HildemanKatz &
M. B. Jordan
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 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 or impairment of cell cycle checkpoints 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" ] 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.