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Injection of Human Primary Effusion Lymphoma Cells or Associated Macrophages into Severe Combined Immunodeficient Mice Causes Murine Lymphomas¹

Departments of Laboratory Medicine [E. Z., M. S. M.], Medicine [R. G., A. E., M. S. M.], and Pathology [M. D. W., M. S. M.], University of California, San Francisco, California 94110; Histology Laboratory, M. D. Anderson Cancer Center, Science Park, Smithville, Texas 78957 [N. W. A.]; SLIL Biomedical Corp., Menlo Park, California 94025 [L. K., J. R.]; School of Medicine, University of California, Davis, California 95616 [I. G.]; Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306 [C. M.]; and Department of Pathology, University of California, San Diego, California 92093 [B. G. H.]

The pathogenesis of immunodeficiency-associated lymphoma is poorly understood.During the past several years, numerous lines of evidence implicating a multistep process of malignant transformation, also known as sequential pathogenesis, have emerged. Tumor-associated macrophage production of specific lymphostimulatory products has been demonstrated and hypothesized to be central to this process. While attempting to establish primary effusion lymphoma in severe combined immunodeficient (SCID) mice, we discovered a potential model of murine lymphomagenesis consistent with the sequential pathogenesis model. This pathogenesis-based model of lymphoma could significantly impact the current thinking about posttransplantation and other immunodeficiency-related lymphoproliferative disorders. Human primary effusion lymphoma-derived CD14+ cell-injected SCID mice developed aggressive murine large cell lymphomas. Tumor cell preparations containing CD14 cells or isolated CD14 cells induced lymphoma/lymphoproliferative diseases in 74% (20 of 27) of injected SCID mice. No tumors were induced by tumor-associated CD3 cells (0 of 4), normal human macrophages (0 of 13), or a murine macrophage cell line (0 of 10). Human macrophages were detected in tumor-bearing animals up to 6 months postinjection in association with the murine T-cell tumors but were not detected in controls or unaffected animals. These observations are consistent with the macrophage-initiated sequential pathogenesis model of disease (M. S. McGrath et al., Acquir. Immune Defic. Syndr., 8: 379–385, 1995; M. S. McGrath et al., Infectious Causes of Cancer: Targets for Intervention, pp. 231–242, Totowa, NJ: Humana Press, 2000).

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