Cytokine-mediated disruption of lymphocyte trafficking, hemopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137-treated mice

L Niu, S Strahotin, B Hewes, B Zhang… - The Journal of …, 2007 - journals.aai.org
L Niu, S Strahotin, B Hewes, B Zhang, Y Zhang, D Archer, T Spencer, D Dillehay, B Kwon…
The Journal of Immunology, 2007journals.aai.org
CD137-mediated signals costimulate T cells and protect them from activation-induced
apoptosis; they induce curative antitumor immunity and enhance antiviral immune
responses in mice. In contrast, anti-CD137 agonistic mAbs can suppress T-dependent
humoral immunity and reverse the course of established autoimmune disease. These results
have provided a rationale for assessing the therapeutic potential of CD137 ligands in human
clinical trials. In this study, we report that a single 200-μg injection of anti-CD137 given to …
Abstract
CD137-mediated signals costimulate T cells and protect them from activation-induced apoptosis; they induce curative antitumor immunity and enhance antiviral immune responses in mice. In contrast, anti-CD137 agonistic mAbs can suppress T-dependent humoral immunity and reverse the course of established autoimmune disease. These results have provided a rationale for assessing the therapeutic potential of CD137 ligands in human clinical trials. In this study, we report that a single 200-μg injection of anti-CD137 given to otherwise naive BALB/c or C57BL/6 mice led to the development of a series of immunological anomalies. These included splenomegaly, lymphadenopathy, hepatomegaly, multifocal hepatitis, anemia, altered trafficking of B cells and CD8 T cells, loss of NK cells, and a 10-fold increase in bone marrow (BM) cells bearing the phenotype of hemopoietic stem cells. These events were dependent on CD8 T cells, TNF-α, IFN-γ, and type I IFNs. BM cells up-regulated Fas, and there was a significant increase in the number of CD8+ T cells that correlated with a loss of CD19+ and Ab-secreting cells in the BM. TCR Vαβ usage was random and polyclonal among liver-infiltrating CD8 T cells, and multifocal CD8+ T cell infiltrates were resolved upon termination of anti-CD137 treatment. Anti-CD137-treated mice developed lymphopenia, thrombocytopenia, and anemia, and had lowered levels of hemoglobin and increased numbers of reticulocytes.
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