Cytokine-mediated disruption of lymphocyte trafficking, hemopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137-treated mice.
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-mug 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-alpha, IFN-gamma, 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 Valphabeta 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.
Niu
Liguo
L
Emory Vaccine Research Center, Emory University School of Medicine, Atlanta, GA 30329, USA.
Strahotin
Simona
S
Hewes
Becker
B
Zhang
Benyue
B
Zhang
Yuanyuan
Y
Archer
David
D
Spencer
Trent
T
Dillehay
Dirck
D
Kwon
Byoung
B
Chen
Lieping
L
Vella
Anthony T
AT
Mittler
Robert S
RS
D000740:Anemia / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity; D002465:Cell Movement; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006402:Hematologic Diseases / Q000276:immunology*; D006410:Hematopoiesis / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology; D008231:Lymphopenia / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013921:Thrombocytopenia / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9