DISCUSSION l6l 



maximal response in the direction of immunity and then as you in- 

 crease the dosage, it turns over into its opposite and takes the form of 

 tolerance. We expect that you could reproduce this curve, with its 

 null zone, in animals of any age by adjusting the whole dosage scale 

 correspondingly. 



Medawar: Proportionate adjustment of dosage scales? 



Michie: No. We have talked cabalistically about a figure of 200-fold 

 which was based on the comparison between tolerance threshold in 

 the newborn and the tolerance threshold in the adult, and a similar 

 figure of 200-fold is reasonable for the difference between the immuniz- 

 ing threshold in the newborn and the immunizing threshold in the 

 adult — if what we have shown is immunity. That second point is 

 much more shaky but I think it is possible that you would have to 

 shift the whole dosage scale up by a factor of the order of hundreds. 



Woodruff: In speaking of dosage, though, one ought perhaps to 

 emphasize the "effective" dose. This is illustrated by another part of 

 the experiment in the adult animals in which we found that if the 

 recipients were splenectomized, then the same dose of cells didn't 

 produce acceptance of the graft but produced immunity. The most 

 obvious explanation is that splenectomy revives one of the sites in 

 which the injected cells normally settle, and in consequence many of 

 them perish for want of a home. 



Michie: I have a comment in connexion with the point made by 

 Dr. Hildemann, about the effect of changing the dosage on the response 

 to injection of parent-strain cells into F^ hybrids. This is using intra- 

 peritoneal injection and taking spleen enlargement as the index of the 

 reaction — which is an index of an early stage in the reaction. Then if 

 you adjust dosage, that is the number of cells, to the body weight of the 

 animal you get the same response right the way from birth up to adult 

 life. I think that may be relevant here. The disproportion comes in 

 when we are considering tolerance induction and not the capacity of 

 the inoculum to settle in the business parts of the animal and to produce 

 a graft-versus-host reaction. 



Brent: Go wland and I would agree with Hildemann that the neutral 

 period is probably a myth. The experiments which I mentioned 

 earher in this discussion indicate that an animal, which might have been 

 in the neutral period as far as a dose of five milhon cells is concerned, is 



