374 PAUL S. RUSSELL 



adequate size DBA/i skin grafts have also been applied to the 

 secondary recipients. No significant deviation from a normal 

 rejection w2ls observed in any case. Some of the animals receiving 

 the larger cell doses have not yet been skin grafted. It would 

 appear likely that failure to demonstrate tolerance in these 

 animals is the result of an insufficient initial dosage of DBA/i 

 antigens. The failure to demonstrate runt disease might be from 

 the same shortcoming or, at least partially, because of a reduction 

 in the capacity of the foreign cells to react against recipient-strain 

 antigens. Further work is now in progress to clarify this question 

 and some discussion of this point appears below. 



Discussion 



As one looks at the overall course of the graft-versus-host 

 reaction in this experimental arrangement the first clear point is 

 that the reaction is not an immediate one. Much as in the typical 

 host-versus-graft reaction there is a period of several days before 

 disease is manifest. Thereafter it is generally agreed (de Vries and 

 Vos, 1959; Gorer and Boyse, 1959.1) that the reaction rapidly 

 embarks on a complex chain of pathological events. Widespread 

 derangement of the cellular machinery of response to foreign 

 substances may well allow the entry of pathogenic organisms in 

 some cases. An outstanding cause of debilit)'- in the animals of the 

 present study must have been hepatic damage. Our observations 

 here reaffirmed the possible importance of the large macrophage 

 or histiocyte as a possible operative cell in the production of the 

 disease (see Gorer and Boyse, 1959^). 



The facts that specific treatments directed toward destroying the 

 cells bearing donor-strain antigens can retrieve some animals from 

 an otherwise inevitable death when begun as late as the fifth day 

 of life, and that animals which survive this treatment are not 

 tolerant of donor-strain skin, indicate that an appreciable share of 

 the irreversible damaging effects of these cells takes place after the 



