Mechanisms of neonatal transplantation tolerance.

Although our analysis is very incomplete, our data indicate that a complete explanation of tolerance induced neonatally to H-2 encoded alloantigens will include elements of clonal deletion and active suppression. Background genes not encoded in H-2 play an important role in determining the extent to which clonal reduction occurs. In mice of B10 background genotype, extensive elimination of clones capable of recognizing class I and class II antigens is accomplished. Tolerance to class I alloantigens alone seems to be maintained almost exclusively by this mechanism. In B10 background mice tolerant of class II antigens alone or in consort with class I alloantigens, peripherally maintained (post-thymic) active suppression exists, that is dependent upon donor I-J expression, and is superimposed on clonal reduction. As a consequence, the activities of class II alloantigen-specific cells appear to be reduced to background, a level insufficient to activate specific effector precursors, even in the presence of relevant alloantigens. Donor alloantigens expressed on chimeric cells that exist among central (bone marrow, thymus) and peripheral (spleen, lymph nodes) lymphoid cells are undoubtedly crucial both to the process of ongoing clonal elimination as well as of active suppression. The role of clonal reduction in the maintenance of class II alone tolerance in mice of A/J background is more obscure. If the class II alloreactive cells that provide helper/inducer activity are identical to the cells that provide effector function (cytotoxic T cells, TDTH cells), then clonal reduction seems not to occur. Instead, class II tolerogen reactive cells remain within the peripheral lymphoid tissues of the tolerant mice, but appear to be incapable of differentiating beyond the initial steps of antigen-driven activation. We know little about the process by which such cells could be placed under these differentiation strictures, nor why they are retained within the tolerant animal's lymphoid mass. However, the absence of detectable chimerism in alloclass II tolerant animals of A/J background may offer an important clue to solving this mystery.