4．6476 Experimentally acquired resistance to tumor transplantation and rejection of skin isografts in mice
Induction of a Shwartzman-type local reaction in a mass of Ehrlich solid carcinoma in mice leads to necrosis of carcinoma cells and subsequent cure of solid carcinoma with a high success rate. This procedure not only induces necrosis of carcinoma cells, but also provides cured mice with strong anti-transplant immunity, as evidenced by the failure of a subcutaneous rechallenge of carcinoma cells in all experimental mice. At the same time, no specific antibody was detected in the sera of these mice, and acquired immunity was not transferred to progeny through the placenta 1, 2).
We suggest a similarity between this immunological phenomenon and immune response observed in the skin and organ transplantation. This report describes our finding wherein mice resistant to subcutaneous transplantation of Ehrlich carcinoma cells rejected skin isografts.
Experimental procedures and results
Reciprocal skin transplants (n=31) were performed between normal untreated isogeneic female mice and female mice (DD) resistant to subcutaneous transplantation of Ehrlich carcinoma cells, obtained as previously described 1). After the mice were ether-anesthetized and the skin of the flank and back was disinfected with alcohol, a circle of full-thickness skin, 6 mm in diameter, was excised and reciprocal transplantation of free skin grafts was performed between the 2 groups. Grafts were fixed with several silk sutures along the wound edge. To prevent infection, 0.2 ml of Abcid Injection (10% aqueous solution of a sulfonamide preparation) was injected subcutaneously into the inguinal region. Of the 31 skin grafts transplanted from normal untreated mice to mice resistant to subcutaneous transplantation of Ehrlich carcinoma cells, 24 grafts fell off in 8 to 11 days leaving exposed granulation tissue while 7 grafts significantly dried and shrunk; accelerated skin graft rejection was observed. In contrast, none of the skin grafts transplanted from resistant mice to untreated mice were rejected.
After 6 months, 5 x 106 Ehrlich carcinoma cells were transplanted subcutaneously onto the back of the mice on the skin-transplanted and non-transplanted sides. The resulting carcinoma grew into a soybean-sized mass in 20 untreated mice that had received skin grafts from resistant mice, although in 16 mice, masses were gradually reduced in size or absorbed and macroscopically resolved within 4 weeks. Carcinoma cells did not engraft in any of the mice which had been shown to be resistant to subcutaneous transplantation of Ehrlich carcinoma cells, confirming the establishment of strong anti-transplant immunity in these mice.
After 7 weeks, 5 x 106 Ehrlich carcinoma cells were intraperitoneally transplanted, resulting in death of all mice due to marked accumulation of ascites.
These findings demonstrate that the mice that acquired resistance to subcutaneous transplantation of Ehrlich carcinoma cells also acquired resistance to transplantation of skin isografts, suggesting that tumor transplantation immunity and skin transplantation immunity partially share common mechanisms.
The present experiment demonstrates that the anti-transplant immunity of subcutaneously transplanted Ehrlich carcinoma cells was transferred to isogeneic mice via skin transplantation.
The observation that the mice that had acquired strong resistance to subcutaneous transplantation of Ehrlich carcinoma cells did not acquire strong resistance to intraperitoneal transplantation of these cells is important when considering the mechanism of this type of immunological phenomena. Further investigation regarding this issue is in progress.
If we consider "development" and "bearing" of carcinoma as separate issues, and if we view carcinomas transplanted between laboratory animals as "isografts" and idiopathic carcinomas as "autografts", and if it is possible to calculate the total number of cells contributing to the life of an organism and the probability that normal cells undergo malignant transformation following exposure to radiation, chemical substances, viruses, and other unknown factors in the natural environment, then the following observation is true: the estimated incidence is far higher than the actual incidence of carcinoma in patients, which suggests that many emerging carcinoma cells are killed immediately by an eliminating mechanism shared by both anti-tumor and anti-transplant immunity and thus do not engraft. This also means that only those carcinomas that are resistant to the eliminating mechanism and do not resolve spontaneously are identified as carcinoma. Thus, acknowledging the presence of mechanisms shared by both anti-carcinoma and anti-tissue transplant immunity allows us to draw some theoretical implications regarding the spontaneous resolution of carcinomas. From the author's current viewpoint, such a daring speculation cannot be completely ruled out.
This abstract was presented at the 16th Annual Meeting of Japanese Society of Allergology.
The author would like to thank Prof. Motoki Yamanaka for his reviewing this manuscript.
- Y. Enoki: Medicine and Biology 70(4): 197-200 1965
- Y. Enoki: Medical Journal of Minami Osaka Hospital 14(1): 1-3 1966