We have previously shown that the progressive ascitic growth of a transplantable T cell lymphoma of spontaneous origin in a murine host, designated as Dalton's lymphoma (DL), induces the inhibition of various immune responses. In a quest to understand the mechanism(s) of tumor-growth-dependent immunosuppression, we were interested to investigate if the thymus, the center for the differentiation of immunocompetent T cells, undergoes any alteration concomitant with the growth of DL. Thus, DL was grown as an ascitic tumor in BALB/c mice for a period of 4 or 17 days, designated as the early and late tumor stages, respectively, and the thymuses were examined immediately after sacrifice of the animals on the 4th or 17th day of tumor transplantation. Progressive growth of DL was observed to be associated with thymic atrophy, as well as an involution of thymic organization and a depletion of cell mass. Histological sections of thymus from DL-bearing mice revealed a complete disintegration of the thymic architecture with a massive depletion of the cortical region and disappearance of the corticomedullary junctions. Flow cytometric analysis of alterations in the distribution of thymocytes revealed a decrease in CD4+CD8-, CD4-CD8+ and CD4+CD8+ cell populations, whereas the CD4-CD8- population showed an increase, suggesting an impairment in thymocyte differentiation at an early T cell maturation stage. Furthermore, tumor growth was shown to suppress the proliferation ability of thymocytes. Moreover, an increase in thymocytes of smaller size was also found with the progression of DL, which is an indication that a large fraction of thymocytes of a small, abnormal size could be apoptotic cells. Furthermore, the paper discusses the immunological implications of thymic atrophy in a host bearing a T cell lymphoma.

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

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.

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