The most immediate requirement of research relating to dominant immunological tolerance is to clarify its significance relative to other mechanisms for the functioning of the immune system. A similar imperative applies in relation to all of the other mechanisms that have heen claimed to mediate tolerance. Several decades of research on immunological tolerance have abundantly indicated what can happen: it is necessary now to identify what most commonly does happen and the circumstances predisposing to this. In attempting a synthesis that could explain the significance of the apparently diverse mechanisms that have heen demonstrated to account for self tolerance, I propose to a. ssume., as a first principle, that all represent aspects of one integrated system. It appears inherently implausihle to me that fragments of a numher of altemative ways of ensuring self tolerance would remain operative and independently functioning. My second assumption is that examination of the evolutionary development of immunological tolerance is required to attain an understanding of the significance of the processes that are responsible for self tolerance in mammals.

The confidence with which immunological tolerance of self could he regarded as understood has steadily diminished as experimental data relating to it has proliferated. One suspects that the first major confusion about the nature of immunological tolerance arose hecause of the temporal proximity between the prediction of induc-