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JNCI Journal of the National Cancer Institute 1996 88(12):824-831; doi:10.1093/jnci/88.12.824
© 1996 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 88, No. 12, 824-831, June 19, 1996
© 1996 Oxford University Press

Prevention of Murine Radiogenic Thymic Lymphomas by Tumor Necrosis Factor or by Marrow Grafting

Chantal Humblet, Roland Greimers, Philippe Delvenne, Johanne Deman, Jacques Boniver, Marie Paule Defresne

Laboratory of Pathological Anatomy and Cytopathology, University Hospital of Liège Belgium

Correspondence to: Marie Paule Defresne, M.D., Laboratory of Pathological Anatomy and Cytopathology, University Hospital of Liège, Sart Tilman B35, B-4000 Liège, Belgium.

BACKGROUND: Split-dose irradiation (1.75 Gy given weekly for 4 weeks) of C57BL/Ka mice induces the emergence of preleukemic cells (PLCs). These cells develop into leukemic cells after a latency period of 3–6 months. The survival and transformation of PLCs are dependent on radiation-induced alterations of the thymic epithelium and of resident lymphocyte (i.e., thymocyte) subpopulations in the thymus. PLCs can be eliminated, concomitantly with the restoration of the thymus, by grafting bone marrow cells immediately after the last irradiation. Our hypothesis was that any agent able to restore the thymus after leukemogenic irradiation would exert the same effects as a bone marrow graft. Tumor necrosis factor-{alpha} (TNF-{alpha}) is one such possible agent, since it has been shown to modulate some functions of the thymic epithelium and thymocyte subpopulations.

PURPOSE:: The goal of this study was to assess the ability of repeated intraperitoneal injections of TNF-{alpha} to functionally replace bone marrow transplantation in the restoration of normal intrathymic lymphopoiesis and in the prevention of thymic lymphomas in split-dose-irradiated mice.

METHODS:: We replaced the bone marrow graft with repeated injections of TNF-{alpha} (25 000 U/injection) in the split-dose-irradiated (4 x 1.75 Gy) C57BL/Ka mouse model. We analyzed the expression of the cell differentiation markers CD4 and CD8 on thymocytes by flow cytometry. We also studied the thymic environment by isolating thymic nurse cells, the bone marrow prothymocyte activity by analyzing thymic repopulation, and the evolution of PLCs by an in vivo transplantation assay. Local production of TNF-{alpha} after bone marrow grafting was examined by in situ hybridization. Injections of anti-TNF-{alpha} antibodies were given to split-dose-irradiated mice to test the effect of neutralizing TNF-{alpha} in vivo. One-way analysis of variance and New-man-Keuls two-tailed tests were used to test statistical significance.

RESULTS:: Multiple injections of TNF-{alpha} into split-dose-irradiated mice did not influence bone marrow prothymocyte activity but restored thymocyte subpopulations and thymic epithelium, induced the disappearance of PLCs, and prevented the development of lymphomas. Moreover, a bone marrow graft significantly stimulated intrathymic production of TNF-{alpha} messenger RNA (P<.01), and anti-TNF-{alpha} antibodies partially inhibited the antilymphomatous effects of bone marrow graft in split-dose-irradiated mice (P<.05).

CONCLUSION:: These data strongly suggest that TNF-{alpha} is a mediator that is involved in the mechanisms by which bone marrow transplantation functions to prevent thymic lymphomas in split-dose-irradiated mice.

IMPLICATIONS:: Cytokines might be used in some biological systems, particularly in the hemopoietic system, as a therapeutic agent for the secondary prevention of cancer.


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