376 PAUL S. RUSSELL 



portion of the chimera should not, however, be so inactivated 

 unless it had become tolerant of its A-line surroundings which 

 contain several of the antigens that are present in C3H but missing 

 in CBA. The prolonged survival of these C3H grafts may, there- 

 fore, be at least partly explained by a mechanism of graft-versus- 

 host tolerance. 



It must remain entirely speculative as to whether this change 

 reflects the specific deletion of reactive cells by allergic destruction 

 as considered by Gorer and Boyse (1959^), or by some other of the 

 alternatives which have been proposed to account theoretically 

 for immunological tolerance (Medawar, i960). 



The fact that the cytotoxic agent amethopterin appears greatly 

 to hasten this process in some animals is unfortunately not critically 

 helpful in clarifying its mechanism. Although a number of cell 

 types are doubtless injured by this drug (certainly pigment cells) 

 blind destruction of an unselected segment of the lymphoid cell 

 population of the young animal may be expected to do no more 

 than change the relative proportion of graft and host cells. No 

 indication was forthcoming, however, from our cell dosage 

 experiments that very large or very small single doses had any 

 influence on the establishment of a foreign cell population tolerant 

 of the injected host. One must speculate, therefore, that a more 

 particular action of this drug exists and that the function of cells 

 active in homograft reactions of this sort is particularly susceptible 

 to its effects in an unknown way. This additional damaging 

 influence, aflecting the appropriate cells in the presence of antigen 

 excess, must persist long enough either to dispose of a sufficient 

 proportion of the offending cells or to redirect their course of 

 action so that thev become innocuous to the host. This would 

 result in a selective elimination, by one way or another, of 

 immunologically active cells but would still require that tolerance 

 be maintained in the constantly self-replicating cell population, 

 presumably in large measure by virtue of the presence of large 

 quantities of the appropriate antigens. It is a matter of considerable 



