摘要：

The question of self-nonself discriminatiosn by the immune system is still awaiting a complete solution. The problem was recognized a long time ago and Owen's observation 1 (1945) in dizygotic cattle twins, which were chimeric with regard to their blood cells, indicated that self tolerance was acquired rather than inherited. Ideas by Burnet 2 (1957) which were reinforced by Lederberg 3 (1963) had a simple -- possibly too simple -- solution to the problem of self tolerance: it was argued that clones of lymphocytes, each bearing a distinct antigen receptor, went through an early phase in development where contact with antigen was lethal rather than inducing effector function. Thus, tolerance to self was thought to be due to the elimination of self reactive clones early during their development. This concept had two weaknesses in explaining all self-tolerance. First, it was difficult to imagine that all self antigens could reach developing lymphocytes in primary lymphoid organs. Second, considering the enormous diversity of antigen receptors themselves, it was difficult to see how deletion of lymphocytes induced by diverse receptors on other lymphocytes would leave anything substantial behind fit to deal with foreign antigens. 4 Possible solutions to these considerations were first, that clonal deletion was not the only mechanism of tolerance and second, that tolerance induction required a certain threshold amount of antigen which probably was not reached by most idiotypic antigen-receptor sequences. The main question was clearly not whether clonal deletion was the only way to achieve tolerance, but whether clonal deletion existed at all as central tolerance mechanism possibly aided by some additional mechanisms responsible for silencing already matured lymphocytes which had escaped clonal deletion simply because they did not encounter their self antigen early in development.

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