Medical genetics / edited by Victor A. McKusick and Robert Claiborne.

Date:
[1973]
Catalogue details

Licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

Credit: Medical genetics / edited by Victor A. McKusick and Robert Claiborne. Source: Wellcome Collection.

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    BACH AND BACH an МНС difference. Bailey was able to localize the mutation as being on the H-2K side; and in skin grafting experiments, there was mutual rejec¬ tion of grafts between the congenie animals in a manner consonant with a major transplantation barrier. Work¬ ing with Chary and Snell, Bailey then tried to produce antisera to the anti¬ gens responsible for rejection. But no serologically identifiable antigens could be detected. When we learned of this phenom¬ enon — rejection without serologic dif¬ ference — we asked Bailey if he would let us study these mice in the м l с system. Essentially the question being asked of the system was whether, de¬ spite the fact that the В cells of the mouse failed to produce antibodies to the skin graft, the T cells in the cul¬ ture would respond by being stimu¬ lated. And indeed, we did find stim¬ ulation in both directions, the first firm evidence that differences other than those detectable serologically could lead to mlc activation. We called these ld differences, obviously because they were definable by activ¬ ity in T lymphocytes. In terms of chromosomal location, it could be said at this point that the mutation that accounted for separa¬ tion of the s d and l d genes was to the left of the Ss. We could not tell whether it was within the Ir region, between Ir and H-2K, or even to the left of H-2K, that is outside of the H-2 locus. If the last were true, there was a possibility that we were still dealing with differences at the H-2K locus not detectable by our methodol¬ ogy. The opportunity to test this pos¬ sibility came in experiments with Klein of Ann Arbor. In these investi¬ gations, the mouse strains used were BIO.A (2R) and BIO.A (4R). These strains have a significant advantage in that they are both derived from the same Fj^ heterozygote between two parental strains, so that the exact мне differences can be mapped. Re¬ combinants vwthin the мне are read¬ ily recoverable. Stimpfling and other workers were able to recover sequen¬ tially recombinants between Ss and D and between two of the Ir genes. The segment between these two recombi¬ nants could then be isolated with assurance that it would include differ¬ ences only for part of the Ir region ( that closest to Ss ), going to the right on the chromosome but not including H-2D. It thus appears that differences are in the middle of the мне, and that in terms of s » the animals are identical. The 2R and 4R mice did not reject Degree of Stimulation Composite presentation of 17 MLC experiments - in each of which the cells of a poten¬ tial recipient are tested with stimulating cells from 13 to 20 different potential unrelated donors - indicates that there is a very great variation (more than 60-fold) between the weakest stimulating mixture, i.e., the best recipient-donor combination, and the strong¬ est stimulating mixture. In each experiment the average stimulation of the 15 to 20 different mixtures is equated to 1, and the stimulation in each of the individual mix¬ tures is plotted as a fraction of the average for that experiment. skin grafts from each other. But it was the mixed leukocyte culture stud¬ ies that produced the remarkable results. In most мье experiments, whether in unrelated humans or in¬ bred mice, one finds that if cells stim¬ ulate in one direction, they will also stimulate in the opposite direction. But here, we found that 4R cells re¬ sponded to 2R stimulation, but 2R cells essentially were unresponsive to 4R cells. In the light of the mutual tolerance of skin grafts, these mlc results suggested to some that per¬ haps the mixed leukocyte culture is a very elegant in vitro model with no relevance to the allograft response. We were, understandably I think, reluctant to accept this proposition. Instead, with Klein, we decided to look at another parameter of the homograft reaction, one which inci¬ dentally Simonsen, among others, had always equated with mlc — the graft- vs-host reaction. Klein injected 2R lymphocytes into 4R animals, and then 4R cells into 2R animals. In the first instance, there was no response, but in the second he was able to ob¬ serve a very strong reaction which was unmistakably graft vs host. In short, there was complete correlation with the mlc observations. There appears to be a region of the мне between the two serologically defined loci and separable from them by recombina¬ tion, closely associated with and per¬ haps identical to the Ir region, the phenotypic products of which lead to mlc activation and to graft-vs-host reactions. These phenotypic products are lymphocytically but not serologi¬ cally definable. The one obvious question that arises from this is, if there are ld differences that lead to T cell activa¬ tion in the form of graft-vs-host reac¬ tions, why do they not also lead to allograft rejection via host-vs-graft reactions? So as not to arouse expectations unduly, let us begin by stating that we are not yet able to provide a def¬ inite answer to the question. However, there are some intriguing pieces of evidence that are important in them¬ selves and that provide a springboard for some interesting hypotheses and speculations. First, there has been the most elegant family study in man by Eijsvoogel and his colleagues show¬ ing that with cells from siblings one 192