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* Emory Vaccine Research Center, Emory University School of Medicine, Atlanta, GA 30329;
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30329;
Department of Surgery, Emory University School of Medicine, Atlanta, GA 30329;
Department of Animal Resources, Emory University School of Medicine, Atlanta, GA 30329;
¶ Johns Hopkins University School of Medicine, Department of Dermatology, Baltimore, MD 21205;
|| The Immunomodulation Research Center, University of Ulsan, Ulsan, Republic of Korea; and
# Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030
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-
, IFN-
, 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 V
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants R01 CA85860 and R01 AI0592 (to R.S.M.) and RO1-AI52108 (to A.T.V.).
2 L.N., S.S., and B.H. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Robert S. Mittler, Emory Vaccine Center, 954 Gatewood Road, Atlanta, GA 30329. E-mail address: rmittler{at}rmy.emory.edu
4 Abbreviations used in this paper: DC, dendritic cell; ASC, Ab-secreting cell; BM, bone marrow; CBC, complete blood count; Dbl. Neg., double negative; Dbl. Pos., double positive; LN, lymph node; S1P, sphingosine-1-phosphate; S1P1, S1P receptor 1.
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  S. J. Robertson, R. J. Messer, A. B. Carmody, R. S. Mittler, C. Burlak, and K. J. Hasenkrug CD137 Costimulation of CD8+ T Cells Confers Resistance to Suppression by Virus-Induced Regulatory T Cells J. Immunol., April 15, 2008; 180(8): 5267 - 5274. [Abstract] [Full Text] [PDF]
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