Inbred strains BALB/c and CBA and noninbred Swiss mice were used for transplanting skin autografts exposed before transplantation for approximately 48 h to (a) culturing in room air and (b) culturing in 45–48 % CO₂ in air. These pre-transplantation manipulations of skin autografts led to malignant lymphomas in the hosts. The lymphoma incidence was highest in the recipients of the CO₂-treated grafts; moreover, it was greater than the spontaneous incidence even in the recipients of grafts exposed to culturing in air alone, in some types of mice. The following abnormalities of the reticuloendothelial system were noted: (1) proliferation of lymph follicles into irregular masses of pleomorphic cells, (2) hyperplasia with concomitant atrophy of the lymphoid tissue, (3) replacement of the lymph follicles by malignant lymphoid cells. Renal lesions resembling membranous glomer-ulitis occurred occasionally. The occurrence varied in different strains.

Previously, malignant lymphomas in mice have been found to be the late sequelae of the autologous transplantation of skin grafts pretreated with CO(2); these did not occur with grafts cultured in air alone. The clinical result in this autologous system reflects environmental differences in vitro (Goldsmith & Narvaez 1975). In the present study the syngeneic transplantation in BALB/c mice of lymph node tissue resulted in the late appearance of malignant lymphomas (48-69%), irrespective of the pretransplantation treatment of the grafts. Lymph node grafts were exposed to three different environments before transplantation into syngeneic hosts: (1) to culture in air (24 hours); (2) to culture in an atmosphere of 45% CO(2) in air (24 hours); (3) direct transplantation without in vitro exposure. Transplantation of these three groups of differently treated grafts was followed by the same clinical results in their recipients. These were: (1) The development of lymphoma whereas the spontaneous incidence was zero. (2) The proliferation of T-lymphocytes in the spleen; the incidence of this abnormality correlates with the lymphoma incidence. (3) A higher than normal occurence of immune-associated lesions (amyloidosis, interstitial nephritis and myocarditis). Both syngeneic and autologous transplantations may serve as animal models for the study of clinical malignant lymphoma.

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SUMMARY: Metabolic carcinogenesis may be viewed as a process in which a chronic disturbance of metabolic homeostasis leads to malignancy . Fluctuation in the CO2 tension in tissues is accompanied by changes in the intracellular pH . This prompted investigations into the long-term clinical effects of high CO2 tensions on various normal tissues in mice by two different methods. The first consisted of exposing different tissues in vitro to a high C02% in air before transplantation into syngeneic or autologous hosts. The second method consisted of exposing intraperitoneal tissues in vivo to C02-infusion, thus avoiding graft-host interactions .This is a report of the most significant findings in the series of investigations analyzed, 1. High incidences of malignant lymphoma in strains of mice with a low or zero spontaneous incidence followed: (a) syngeneic transplantation , (b) autologous transplantation, (c) in vivo exposure to CO2-infusion.2. Syngeneic graft recipients developed similar high lymphoma incidences, irre spective of the tissue grafted or the pretransplantation treatment of the graft . 3. In the autologous system, however, the clinical results reflect the differences in the pretransplantation treatment, in contrast to those in the syngeneic system . 4. Whereas intraperitoneal CO2-infusion induced lymphoma , air-infusion did not. 5. Non-lymphoid grafts exposed in vitro to elevated CO2 induced only lymphoid malignancies. But non-lymphoid tissues exposed in vivo to elevated CO2 developed tumors of other tissues, such as lung tumor, in addition to lymphoid malignancies.6. The same morphological lymphoid abnormalities occurred in all lymphomadeveloping animals in these three experimental models. Hyperplasia in the splenic T-cell areas appeared most frequently.7. The presence of immune-associated lesions in experimental animals (amyloidosis, interstitial nephritis and myocarditis) points to the activation of immune mechanisms in this lymphoma development.

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