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This paper reports tests of two hypotheses that have been proposed to account for the enhanced growth of tumor homografts in the presence of antiserum reactive with the graft (immunological enhancement). According to the first hypothesis, enhancement is due to some "physiological" alteration in the tumor, induced by its contact with antiserum, which insures its survival despite the hostile response of the host. According to the second hypothesis, antiserum alters the response of the host. By blocking the development of the cellular type of immunity, which is the main agent in graft destruction, it permits the graft to survive. To test hypothesis 1, strain A tumor SaI was passed from A's, and from enhanced B10.D2's, into untreated B10.D2's. The per cent of deaths was essentially the same in both groups (48 and 44 per cent, respectively); there was no evidence that passage through enhanced B10.D2's altered the capacity of the tumor to grow in the foreign strain. Several other groups of mice included in the experiment all confirmed this conclusion. The experiment failed to confirm hypothesis 1. In the tests of hypothesis 2, the effect of isoantiserum on immune responses of both the humoral and cellular type was measured. When antiserum was given together with foreign strain lymphoid cells (antigen), almost no additional antibody was manufactured; in contrast with this, controls receiving foreign cells only produced red cell agglutinating antibody in high titer. The effect of antiserum on the development of immunity of the cellular type was tested by the method of Winn. In this assay, presumptively immune node cells, in various dilutions, are mixed with tumor cells and injected into appropriate mice. Immunity is indicated by inhibited tumor growth. Antiserum given at the same time as a tumor homograft greatly depressed the immunity of the cells expressed from the draining nodes. At 6 days after the graft, the level of immunity of cells from treated mice was 1/24th to 1/32nd that of cells from controls receiving tumor alone. The same sort of depressing effect was noted when the immunizing tissue was foreign thymus or embryo. Antiserum given 1 or more days after the immunizing tissue also resulted in a lower level of cellular immunity (but the assay used in this case was a less critical one). These results provide an adequate explanation of the phenomenon of immunological enhancement, at least as it occurs in the particular test system used in these experiments. Since it is cellular immunity rather than humoral antibody that inhibits the growth of most grafts (transplantable leukemias are an exception), the depression of this immunity by antibody is favorable to the growth of a homograft.

Eleven strains of mice bearing recombinant H-2 chromosomes derived from known crossover events between known H-2 types were immunized with a series of branched, multichain, synthetic polypeptide antigens [(T,G)-A--L, (H,G)-A--L, and (Phe,G)-A--L]. Results with nine of the eleven H-2 recombinants indicated that the gene(s) controlling immune response to these synthetic polypeptides (Ir-1) is on the centromeric or H-2K part of the recombinant H-2 chromosome. Results with two of the eleven recombinant H-2 chromosomes indicated that Ir-1 was on the telomeric or H-2D part of the recombinant H-2 chromosome. Both of these recombinants were derived from crossovers between the H-2K locus and the Ss-Slp locus near the center of the H-2 region. One of these recombinants, H-2(y), was derived from a known single crossover event. These results indicate that Ir-1 lies near the center of the H-2 region between the H-2K locus and the Ss-Slp locus. The results of a four-point linkage test were consistent with these results. In 484 offspring of a cross designed to detect recombinants between H-2 and Ir-1, only two putative recombinants were detected. Both of these recombinants were confirmed by progeny testing. Extensive analysis of one of them has shown that the crossover event occurred within the H-2 region. (Testing of the second recombinant is currently under way.) Thus, in the linkage test, recombinants between H-2 and Ir-1 are in fact intra-H-2 crossovers. These results permit assignment of Ir-1 to a position between the H-2K locus and the Ss-Slp locus.

The cell-mediated lympholytic capability of mouse spleen cells stimulated in mixed lymphocyte culture is related to the major histocompatibility complex genotype on target lymphocytes. The strain combinations AQR-B10. T(6R) and B10.A(4R)-B10.A(2R) that result in significant mixed lymphocyte culture activation do not mediate cell-mediated lympholysis on sensitizing target lymphocytes; serologically defined regions (H-2K and H-2D) are identical within each combination. H-2K or H-2D region disparity alone does not cause cell-mediated lympholysis. However after mixed lymphocyte culture activation as seen with B10.A-B10.T(6R), a target cell bearing only an H-2K region difference from the effector cell is sensitive to cell-mediated lympholysis. Likewise an H-2D region difference is an adequate target after mixed lymphocyte culture activation of the effector cell in the combination B10.A(2R)-B10.D2.