Studies were designed to provide some explanation for the unexpectedly large proportion (2%) of parental rat strain peripheral blood lymphocytes that are reactive in the mixed lymphocyte interaction (MLI) to a strong homologous transplantation isoantigen(s) present on cells from an F1 donor. The possibilities considered involve nonspecific activation and multispecific reactivity on the part of the responding cells.

The essential findings of this study were:

(a) In 3-way mixed cultures, lymphocytes obtained from tolerant animals were not "recruited" to proliferate in the presence of cells from normal, isologous donors which were in the process of responding to F1 cells bearing the tolerance-inducing antigens. With the use of chromosome markers and normal and tolerant parental strain donors of different sexes, the responsive cells were identified and proved to be derived from the normal and not the tolerant donor.

(b) The magnitude of the proliferative response is increased additively when potentially reactive cells are exposed to two antigen systems simultaneously. On the other hand, doubling the "gene-dosage" of the genetic determinants of the H isoantigens employed had no effect on the responding cells.

(c) A state of induced immunologic tolerance to one H isoantigen system did not alter the response capacity of cells from such a donor to an alternative antigen system.

(d) Mixed cultures of heterologous cells from human and rat donors displayed a proliferative response which was less than that of homologous mixed cultures from human or rat donors. Prior sensitization of rat donors with human cells, however, greatly increased the mitotic activity of rat lymphocytes stimulated with human cells.

These results suggest that the large number of responsive cells in the MLI do not include a significant number recruited or activated in some nonspecific manner. Rather, they appear to be fully specific in their response capacities so that a given lymphocyte does not react to a multiplicity of different antigens. The degree of proliferation depends on the number of different antigen systems presented to the responding population and not on the number of genetic determinants or "gene dosage" of a given isoantigen system. Finally, on a cell-for-cell basis, the peripheral blood lymphocyte population contains more cells reactive to histocompatibility isoantigens within the species than to heterologous antigens of a different species.

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