150 HOWARD, MICHIE AND WOODRUFF 



their suggestion, namely, the greater difficulty of inducing toler- 

 ance to heterologous than to homologous tissues, in terms of 

 dosage-relations, and seek to know whether these relations show 

 some form of consistency irrespective of the age of the subject. 



A generally consistent principle, relating the nature of the 

 antigen to the size of the dose required to confer tolerance, does 

 seem to emerge, even when attention is confmed to antigenic 

 differences between members of the same species. It is well known 

 that the tolerance-inducing dose for newborn mice is directly 

 related to the strength of the immune reaction provoked by the 

 same antigens administered to adults — or, as we would prefer now 

 to say, by the same antigens administered, whether to newborns 

 or to adults, in immunizing rather than paralysing dosage. Thus, 

 for tolerance-induction, an H-2 antigenic difference such as 

 CBA->A requires the intravenous injection of 4-10 million 

 homologous spleen cells (Billingham and Brent, 1959), whereas 

 the male-specific antigen(s) requires no more than 100,000 

 (Lustgraaf, Fuson and Eichwald, i960). We have been unable to 

 fmd pubhshed quantitative data for non-H-2 strain-specific 

 antigens, but circumstantial evidence suggests that the critical 

 dose is probably below one million spleen cells. 



Interpreting, as we now feel justified in doing, induced unres- 

 ponsiveness to homografts in adults as based on tolerance, we can 

 fmd a similar relationship in the work summarized in Table V. 

 By comparison with the newborn, the tolerance-inducing dose 

 has simply been stepped up by a factor of about 200 for each 

 category of antigen. 



What, then, determines the magnitude of this factor ? It is 

 clearly not the growth in absolute mass of the animal, for the adult 

 mouse has only about 20 times the weight of the newborn. We 

 suggest that it is rather the total number of immunologically 

 competent cells, which proliferate disproportionately in early 

 postnatal life. Regarding these as the target both of immunizing 

 and of tolerance-inducing procedures, we suggest that the issue 



