DISCUSSION 159 



intravenously plus 15 niilHon intraperitoneally, and in some variants it 

 was 10 million intravenously and 10 million intraperitoneally. 



Medawar: That is a very large dose. You may think I am making 

 difficulties, but this claim is so important that it is our bounden duty to 

 be highly critical. Isn't it possible that when you inject 20 or 30 million 

 irradiated cells they are simply pre-occupying all the positions that the 

 CBA cells injected at day 2 might otherwise have occupied? 



Michie: That is met by the isologous controls, which are equal space 

 occupiers, and also by the case when they are homologous irradiated 

 cells but not presenting an H-2 difference. 



Medawar: I think that meets it then. 



Mitchison: I would like to raise the question of concentration as 

 opposed to cell dosage. I find it difficult to understand why dosage per 

 host cell can matter more than the concentration of antigen in the 

 mouse. I feel that particularly because of my own experiment on 

 erythrocytes in chickens where, over the first eight days of life or so, 

 very little growth takes place and therefore the concentration of anti- 

 gen produced by the injection of a given mass of cells hardly changes. 

 Yet the total mass needed to produce tolerance increases very greatly 

 during that period. 



Michie: You mean that the correct ratio to look for is between anti- 

 gen and, say, the total number of host lymphocytes ? There is a " weak 

 form and a "strong" form of that point of view: the "strong" form 

 regards the immunologically mature cell as the cell which is made 

 tolerant; the "weak" form of the same point of view includes your 

 behef, that it is a question of how much of the donor inoculum can 

 get through the immune "fire" of the host for long enough for a 

 new population of cells to grow up in the presence of the antigen and 

 the old population of immunized cells to die away. I think you referred 

 to these two theories in a review recently as the homogeneous and the 

 heterogeneous hypotheses. It would be nice to find critical ways of 

 distinguishing between them. It is quite possible, though, that they 

 are both compatible with the "weak" form of our suggestion, that 

 ease of induction of tolerance would be inversely proportional to the 

 strength of immune resistance put up by the host, which in turn would 

 be correlated closely with the total lymphocyte population. But we 

 have no intention of pressing the "strong" form. 



