Ascitic growth of a spontaneous transplantable T cell lymphoma induces thymic involution. 2. Induction of apoptosis in thymocytes

• Published in: Tumor biology 2000-11, Vol.21 (6), p.315-327
• Main Authors: SHANKER, Anil, MAHENDRA, Sukh, SINGH AJIT SODHI
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - pharmacology; Apoptosis - genetics; Apoptosis - physiology; Apoptosis Inducing Factor; Ascites - pathology; Ascitic Fluid - metabolism; Biological and medical sciences; Caspase Inhibitors; Cell Division - physiology; Culture Media; Cysteine Proteinase Inhibitors - pharmacology; DNA Fragmentation; Fas Ligand Protein; Female; Flavoproteins - blood; Flavoproteins - metabolism; Hematologic and hematopoietic diseases; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, T-Cell - blood; Lymphoma, T-Cell - pathology; Male; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - immunology; Membrane Proteins - blood; Membrane Proteins - metabolism; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Nucleosomes - metabolism; Nucleosomes - pathology; Oligopeptides - pharmacology; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Thymus Gland - immunology; Thymus Gland - pathology
• ISSN: 1010-4283; 1423-0380
• DOI: 10.1159/000030137

It has been observed that the progressive ascitic growth of a transplantable T cell lymphoma of spontaneous origin, designated as Dalton's lymphoma (DL), induces inhibition of various immune responses and is associated with an involution of the thymus accompanied by a massive depletion of the cortical region and alteration in the distribution of thymocytes, with a decrease in CD4+CD8+, CD4+CD8- and CD4-CD8+ thymocytes. Morphological evaluation of thymocytes from DL-bearing mice revealed that with the progression of DL, a majority of thymocytes exhibited morphological features characteristic of apoptotic cell death, which included contracted cell bodies, condensed, uniformly circumscribed and densely stained chromatin, and membrane-bound apoptotic bodies containing one or more nuclear fragments. Quantitative and qualitative analysis of the DNA extracted from the thymocytes of DL-bearing mice revealed DNA fragmentation that increased concomitantly with the progression of DL and showed an oligonucleosomal DNA ladder pattern upon agarose gel electrophoresis, a hallmark of apoptotic cell death. Attempts to identify apoptotic factor(s) showed that the serum of DL-bearing mice contained certain soluble factor(s) that augmented the induction of apoptotis in thymocytes in a time- and dose-dependent manner. Although DL cells or their products, such as DL-cell-conditioned medium or DL-cell-free ascitic fluid, could also induce apoptosis of thymocytes in vitro, the magnitude of the same was consistently lower than that induced by the serum of DL-bearing mice. Further, elucidation of the mechanism of apoptosis induction in thymocytes with respect to the involvement of apoptosis-related genes revealed that the death pathway followed an interleukin-1 beta-converting-enzyme-dependent, Fas-mediated apoptotic cascade, with a concomitant increase in the protein products of the bax, bad, p53, fas and fasL genes and cleavage of the 23-kD N-terminal fragment of Bcl-2 that exhibited Bax-like death effector properties.