PMID- 8637049
OWN - NLM
STAT- MEDLINE
DCOM- 19960711
LR  - 20190512
IS  - 0027-8874 (Print)
IS  - 0027-8874 (Linking)
VI  - 88
IP  - 12
DP  - 1996 Jun 19
TI  - Prevention of murine radiogenic thymic lymphomas by tumor necrosis factor or by 
      marrow grafting.
PG  - 824-31
AB  - 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 Newman-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.
FAU - Humblet, C
AU  - Humblet C
AD  - Laboratory of Pathological Anatomy and Cytopathology, University Hospital of 
      Liege, Belgium.
FAU - Greimers, R
AU  - Greimers R
FAU - Delvenne, P
AU  - Delvenne P
FAU - Deman, J
AU  - Deman J
FAU - Boniver, J
AU  - Boniver J
FAU - Defresne, M P
AU  - Defresne MP
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Natl Cancer Inst
JT  - Journal of the National Cancer Institute
JID - 7503089
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - *Bone Marrow Transplantation
MH  - Disease Models, Animal
MH  - Fluorescent Antibody Technique
MH  - Incidence
MH  - Lymphoma/etiology/pathology/*prevention & control
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neoplasms, Radiation-Induced/pathology/*prevention & control
MH  - Radiotherapy Dosage
MH  - Thymus Neoplasms/etiology/pathology/*prevention & control
MH  - Tumor Necrosis Factor-alpha/*therapeutic use
EDAT- 1996/06/19 00:00
MHDA- 1996/06/19 00:01
CRDT- 1996/06/19 00:00
PHST- 1996/06/19 00:00 [pubmed]
PHST- 1996/06/19 00:01 [medline]
PHST- 1996/06/19 00:00 [entrez]
AID - 10.1093/jnci/88.12.824 [doi]
PST - ppublish
SO  - J Natl Cancer Inst. 1996 Jun 19;88(12):824-31. doi: 10.1093/jnci/88.12.824.