PREVENTION OF MURINE RADIOGENIC THYMIC LYMPHOMAS BY TUMOR-NECROSIS-FACTOR OR BY MARROW GRAFTING

Background: Split-dose irradiation (1.75 Gy given weekly for 4 weeks) of C57BL/Ka mice induces the emergence of preleukemic cells (PLCs). Th ese cells develop into leukemic cells after a latency period of 3-6 mo nths. The survival and transformation of PLCs are dependent on radiati on-induced alterations of the thymic epithelium and of resident lympho cyte (i.e., thymocyte) subpopulations in the thymus. PLCs can be elimi nated, concomitantly with the restoration of the thymus, by grafting b one marrow cells immediately after the last irradiation. Our hypothesi s was that any agent able to restore the thymus after leukemogenic irr adiation would exert the same effects as a bone marrow graft. Tumor ne crosis factor-alpha (TNF-alpha) is one such possible agent, since it h as been shown to modulate some functions of the thymic epithelium and thymocyte subpopulations. Purpose: The goal of this study was to asses s the ability of repeated intraperitoneal injections of TNF-alpha to f unctionally replace bone marrow transplantation in the restoration of normal intrathymic lymphopoiesis and in the prevention of thymic lymph omas in split-dose-irradiated mice. Methods: We replaced the bone marr ow 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 anal yzed 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 m arrow grafting was examined by in situ hybridization. Injections of an ti-TNF-alpha antibodies were given to split-dose-irradiated mice to te st the effect of neutralizing TNF-alpha in vivo. One-way analysis of v ariance and Newman-Keuls two-tailed tests were used to test statistica l significance. Results: Multiple injections of TNF-alpha into split-d ose-irradiated mice did not influence bone marrow prothymocyte activit y 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 p roduction of TNF-alpha messenger RNA (P<.01), and anti-TNF-alpha antib odies partially inhibited the antilymphomatous effects of bone marrow graft in split-dose-irradiated mice (P<.05). Conclusion: These data st rongly suggest that TNF-alpha is a mediator that is involved in the me chanisms by which bone marrow transplantation functions to prevent thy mic lymphomas in split-dose-irradiated mice. Implications: Cytokines m ight be used in some biological systems, particularly in the hemopoiet ic system, as a therapeutic agent for the secondary prevention of canc er.