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 Genetics of histocompatibility in one family were elucidated, in a collaborative study with R. Ceppellini, D. B. Amos, and associates, by identifying antigens of parents and six children. By careful analysis it was possible to identify antigen groups associated with the two paternal alleles (a,b) and the two maternal alleles (c,d) and to show that all patterns found in the children can be formed by various combinations of one pa¬ ternal and one maternal allele. To illustrate: the father is positive for antigen 3, mother and siblings A through E are negative. Sibling F is also positive. If antigen is arbi¬ trarily assigned to allele a of the father, F has inherited that allele. The father is also positive for antigen 10, for which the mother is negative. In this case, however, siblings A-E are positive and F negative. Antigen 10 is therefore assigned to allele b of the father, and allele b to siblings A-E. Only one possible combination —a/с-was not found. this hypothesis has come through a quite different approach to transplant matching, one that may turn out to possess extensive practical applica¬ tions. This technique seeks to obtain a physiologic measure of histocom¬ patibility without attempting to de¬ fine the antigens involved. Some years ago it was noted that w^hen leukocytes from two unrelated individuals are mixed together in tis¬ sue culture they stimulate one an¬ other to enlarge and divide. Further experiments showed that a mixed leukocyte culture of cells from identi¬ cal tv\dns produces no stimulation and that in related individuals stimula¬ tion averages below normal. These and other findings suggested that the M L с could provide a useful measure of histocompatibility in man; this sup¬ position was strengthened by the clas¬ sical finding that peripheral blood lymphocytes can be used to sensitize individuals to skin grafts from other individuals, indicating that they are among the cells that carry histocom¬ patibility antigens. They are, more¬ over, known to be involved in the pro¬ cess of graft rejection. In addition, it was soon demonstrated that skin grafts between siblings whose cells did not stimulate in mlc survived longer than grafts between stimulat¬ ing siblings. There were, however, a number of weaknesses in the original mlc method, notably the fact that it was impossible to differentiate the stimu¬ lus exerted on individual A's leuko¬ cytes by individual B's (which would presumably reflect A's potential re¬ sponse to a graft from B) from that exerted in the opposite direction (which would prefigure B's response to a graft from A). In 1966, we and our associates at the University of Wisconsin were able to develop a technique for measuring one-way stimulation. Cells from a potential donor are inactivated with the drug mitomycin С (an experimental anti¬ neoplastic compound), which pre¬ vents them from responding to stimu¬ lation but leaves intact the ability to stimulate other leukocytes from the recipient; the latter respond by in¬ creasing their synthesis of dna, which can be measured through the cells' incorporation of isotopically labeled thymidine. As a control, the uptake of labeled material in this sys¬ tem, AB,„ (a active, в inactivated), is compared with that produced in the autogeneic A Aji system. In some cases, notably those of siblings whose cells do not stimulate each other, we introduce a further control by stimulating A's cells with inactivated cells from an¬ other individual (ax,„) and by stim¬ ulating these latter with inactivated В cells (xB„j). By furnishing control levels for both A's response capacity and B's stimulus capacity, this final step helps exclude variations due to technical problems. Our hypothesis that the one-way MLC technique for measuring leuko¬ cyte compatibility in vitro would prove to be a good prognosticator of histocompatibilty in vivo has in the main been borne out, but with certain notable exceptions. Both the suppor¬ tive evidence and the exceptions are, we believe, of great importance in our understanding of the biology of histo¬ compatibility. A number of studies presented to the 1972 International Transplanta¬ tion Conference very specifically ad¬ dressed themselves to the question of whether one-way mlc studies done prior to transplantation were predic¬ tive of subsequent graft survival. For example, van Rood, Koch, and their colleagues from Leyden showed that one could predict the relative survival times of skin grafts from two differ¬ ent donors on the basis of м l с stim¬ ulation with a very high level of sta¬ tistical confidence. Similarly, Kountz of San Francisco demonstrated the re¬ liability of M L с predictions in rela¬ tionship to clinical kidney transplants between unrelated donor-recipient pairs. Hamburger and his colleagues in Paris have for years presented data consistent with the validity of м l с prognostication. Evidence that the major histocom- 190