THE FACTOR OF IMMUNIZATION 207 



enlargement by their proliferation are mainly cells of the host, 

 as Davies and Doak (i960) have shown to be true in the mouse. 



The choice betw^een hypotheses 



I have offered both explanations of the observed differences in 

 my study of the Factor of Immunization, as I am unable for the 

 moment to decide which, if either, is more likely to be correct. 



The "tolerance" explanation has the unattractive side to it that 

 tolerance itself is left entirely unexplained. 



The hypothesis of clonal selection on the basis of loss mutations 

 has, in contrast, the virtue that it at least helps to explain how 

 tolerance can be achieved more easily with weak than with 

 strong antigenic combinations. If an antigen is weak because cells 

 with affinity for it are numerically small to begin with, it is 

 obviously easier to overload them with antigen to such an extent 

 that their reactivity becomes abolished or suppressed. 



In strong combinations, on the other hand, the antigenic load 

 will have to be higher and probably of longer duration. The 

 chances of achieving tolerance in this situation may depend on the 

 possibility that some clones may exist, or arise, which do not 

 have affinity to an otherwise obligatory antigen. When the anti- 

 genic load is of sufficiently long duration (as in parabiosis of 

 parental strain with Fj hybrid), these exceptional clones will be 

 favoured by a selection pressure, provided exhaustive sensiti- 

 zation (Simonsen, 1960^) ultimately inactivates the reacting clones. 

 Admittedly, exhaustive sensitization could equally weU be 

 regarded as favouring the growth of tolerant cells arising from 

 stem cells with no genetically predetermined affinity. I believe, 

 however, that I have recently provided some rather suggestive 

 evidence against the stem cell hypothesis (Simonsen, 1962), and 

 would, therefore, prefer to regard the development of tolerance 

 as having some basis in the heterogeneity of the population of 

 immunologically competent cells rather than in postulated differ- 

 ences between stem cells and differentiated cells. 



