156 DISCUSSION 



Michie: Repeated dosage, as opposed to a single shot, in addition to 

 having a significance with respect to time in the obvious sense, is also 

 significant with respect to the effective dosage — because the larger the 

 number of cells in one inoculum, the greater the fraction of that you 

 are simply pouring down the sink. Dr. Simonsen and I have done 

 some roughly quantitative tests of this and, at any rate in quite young 

 (nestling) mice, this is so. 



Another awkward point is that whichever point of view is right, the 

 one that you are putting forward or the one that we have hesitantly 

 suggested, one might still expect to find that the tolerance threshold is 

 determined by the ratio between the dosage and the total number of 

 mature lymphocytes in the host animal. This seems to me to make 

 your observation at 12 days with 300 million cells not easy to reconcile 

 with either view. It should have been enough — unless you are losing a 

 great fraction of the single-shot inoculum by wastage, so that it doesn't 

 turn up in the spleen and lymph nodes. 



Brent: Or unless one stipulates that tolerance does depend on the 

 elimination of mature cells, and that in order to eliminate them by 

 contact with antigen they first need to be exquisitely sensitized. This 

 could be achieved by repeated doses of antigen, but not by a single dose. 



Lontit: I would like to ask about the experiments on the mature 

 irradiated animals. You suggested three explanations for the specific 

 unresponsiveness to skin grafts in these animals: replacement, inertia, 

 and enhancement. You have shown that there is a replacement with a 

 final population of about 5:1 (5 of the hybrid and i of the host); but 

 you test for inertia not in the chimera host itself but in the transfer 

 system. Perhaps my question should be addressed to Prof. Woodruff: 

 is there any clinical evidence of inertia or inactivity in the animal itself? 

 Is the patient a good thrifty animal or a weakened animal ? Are there 

 any clinical or clinico-pathological signs in the animal itself which 

 would suggest that these cells are inert or active ? 



Woodruff: The patients are doing remarkably well. I should think 

 that the capacity to reject third-party skin would exclude the possibility 

 that the animals were immunologically inert. Unfortunately the capa- 

 city to reject C57BL skin was tested in only two animals, and one of 

 them died, so our evidence on this point is insufficient. 



Loutit: Yes, but general immunological competence could be due to 



