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A study has been made of cytological and histological changes in lymph nodes draining grafts of allogeneic skin or tumour. The two types of graft provoked mitosis of both thymus- and bone-marrow-derived lymphocytes; this activity was associated with reactive changes initially in the paracortex and then in germinal centrts and medullary cords. Grafts of allogeneic skin evoked two peaks of mitosis which declined rapidly as the graft was rejected. Transient mitotic activity also occurred in response to (control) syngeneic skin, coinciding with increased lymph-node weight and some paracortical hyperplasia but (cf. changes found after allografting), other parts of the node did not respond. Allogeneic EL4 lymphoma cells gave rise to a greater and more rapid immunological response than did skin grafting. The mitotic response to the injected tumour cells failed, at least in the draining lymph nodes, long before death of the host due to progressive tumour growth. It is suggested that both the greater mitotic response, and its later failure, are related to the progressive growth of the tumour and to the everincreasing antigenic burden which such a tumour represents.

The growth of the EL4 lymphoma has been studied in thymus-deprived, reconstituted and normal CBA/Lac mice. In normal mice the lymphoma grew slowly and progressively after intradermal injection, killing the host between 39 and 64 days later, depending upon the number of cells injected: no metastases were seen. In deprived mice the tumour grew more rapidly and killed all mice between 17 and 20 days: 50% had distant metastases. Reconstituted mice resembled normal mice. Intravenous injection of lymphoma cells was also followed by early death, within 16 days, of deprived mice: all had widespread tumour growth in the viscera. Normal and reconstituted mice survived considerably longer, some being free of tumour at over 200 days after injection; death was associated with localized tumour growth in soft tissues. Studies of the clearance of 125IUDR-labelled tumour cells and an examination of early histological changes showed that this difference in the distribution of tumour growth was not due to differences in rate of clearance of cells from the blood or lungs. It appeared likely that the differences between thymus-deprived and reconstituted mice were due to the survival of rather small numbers of tumour cells in a variety of tissues.

To study the function of different lymphocyte populations in the Moloney strain of murine sarcoma virus (M-MuSV) tumorigenesis, we gave M-MuSV injections to CBA mice selectively deprived of thymus (T) lymphocytes by thymectomy, X-rradiation, and syngeneic bone marrow injection. Although no tumors appeared in the control group, 80% of the derived mice had tumors that grew progressively and ultimately killed them. In deprived mice, grafted with a syngeneic thymus (reconstituted mice) before or after an M-MuSV injection, tumors regressed or did not develop. Histologically, the lymph nodes and spleens of reconstituted mice, compared to those of deprived animals, showed repopulation of the thymus-dependent areas and prominent follicles in the cortex. Moreover, tumor tissue of reconstituted mice was extensively infiltrated by lymphocytes. To evaluate the number of lymphoid cells needed to prevent or regress M-MuSV tumors, we injected varying amounts of lymphoid cells into deprived mice. Even low lymphocyte numbers (10(6) cells) were sufficient to exert, in some cases, protection against M-MuSV tumorigenesis. This effect was not abolished by subsequent splenectomy or antilymphocyte serum treatment. Finally, deprived mice, given repeated injections of antiserum (hyperimmune) against M-MuSV, had tumors which appeared only after a prolonged latency. From these results, it is concluded that T-cell population integrity is important in affording total host protection against the M-MuSV tumors.

Regression of the L-asparaginase-sensitive Gardner lymphosarcoma was investigated in normal CBA mice and in CBA mice deficient in thymus-processed lymphocytes (T cells). In normal animals, solid subcutaneous grafts of the tumour disappeared completely following one intraperitoneal injection of L-asparaginase (50 IU) given 10 days after tumour inoculation. The local tumour was impalpable after 3 or 4 days and there was early and massive destruction of the graft though surviving tumour cells persisted in the vicinity of blood vessels for up to 24 h after treatment. These cells subsequently disappeared and there was an intense local inflammatory response dominated by macrophages. In mice deficient in T cells, the Gardner lymphosarcoma initially regressed as in the normal group but the small perivascular accumulations of surviving tumour cells did not disappear; they persisted and all the animals eventually died with local and disseminated lymphosarcoma 22–24 days later. Their recurrent tumours were invariably asparaginase-resistant. These results indicate that, although the main effect of L-asparaginase is the biochemical destruction of sensitive tumour cells, residual asparaginase-resistant cells are normally destroyed by the host's immune response. In T-cell-deficient mice, the immune component does not operate effectively and asparaginase-resistant tumour cells grow back and kill the animals. T cells appear to be involved in the immune response to the Gardner lymphosarcoma and some possible modes of action of T cells are discussed.