TRANSPLANTATION TOLERANCE AND AGE I45 



the modality of response is to be immunity or tolerance is the 

 antigenic dosage. On this basis, referred to earher as the "quanti- 

 tative hypothesis", it should be feasible to provoke immunity in 

 the newborn subject in place of tolerance, simply by reducing the 

 dosage of injected cells. 



In the course of unsuccessful attempts to induce tolerance in 

 nev^born A mice by injection of lethally irradiated CBA cells 

 (Howard and Michie, 1961), a number of cases were observed 

 where the effects of the treatment appeared to point in the 

 "wrong " direction. On the supposition, subsequently confirmed, 

 that the antigenicity of the inoculum had been reduced by irradia- 

 tion, so that it no longer amounted to a tolerance-inducing dose, 

 the above-mentioned observations were followed up in detail. 



The role of dosage was investigated by inoculating newborn 

 pure-strain mice with varying numbers of normal (non- 

 irradiated) spleen cells taken from F^ hybrids between the recipient 

 strain and the strain of the intended donor. Two days later the 

 young mice were challenged with an inoculum of donor-strain 

 spleen cells at a dose sufficient to induce graft-versus-host disease 

 (measured by the splenomegaly phenomenon) in their untreated 

 litter-mates. A high neonatal dose was expected to induce 

 tolerance to the donor strain, and so abrogate what feeble resis- 

 tance the infant hosts might offer when challenged two days later. 

 By contrast, if low doses induced immunity, this would appear as 

 enhanced resistance to the challenging inoculum of homologous 

 spleen cells, with a concomitant reduction in splenomegaly 

 towards the level of unchallenged control htter-mates. In Fig. 3 

 an illustrative result taken from these tests has been plotted in 

 graphic form. While the top dose indicates tolerance, as expected, 

 signs of acquired resistance appear at lower levels, the effect being 

 maximal at a dose of 2 x 10^ cells. 



Similar resistance to challenge was also induced by neonatal 

 injection of homologous spleen cells irradiated to 1500 r., but at a 

 much higher total cell dose (usually 20-30 million). The pheno- 



