The estimation of the number of histocompatibility genes controlling the successful transplantation of normal skin in mice

Abstract

The success or failure of a transplant of tissue from one animal to another depends on the action of a number of independently acting histocompatibility genes which are present in the donor's tissues and absent from those of the host. An estimate of the number of such genes in mice can be made from the proportion of grafts which survive transplantation from either of the two parent strains to members of their $F_{2}$ generation. If n is the number of genes, the proportion of successful grafts $=(\frac{3}{4})^{n}$. Most previous work of this sort has used tumour tissue to provide material for grafting. A normal tissue, such as skin, has several advantages over malignant tissues which may kill the host and are difficult to observe; it is also probably more exacting in its genetic requirements. We have used single 7 mm diameter full-thickness pieces of skin transplanted orthotopically to the side of the chest as test grafts. Taking survival in an autograft-like condition 100 days after grafting as the criterion for judging success or failure, two of 120 A strain and one of 154 CBA strain grafts survived transplantation to $F_{2}$ generation mice. Assuming that each separate antigen is capable of causing breakdown of the graft, these figures imply that certainly not less than fifteen independently segregating genes control the fate of a transplant. But since breakdown of such 'successful' grafts was observed as late as 180 days after grafting, the estimates represent minimal values only. The survival times for the grafts are distributed widely from 10 or 11 days (the normal survival time for interstrain homografts) to more than 100 days. Both frequency distributions (for A and CBA donors) are quite unlike the theoretical distribution for the frequency of occurrence of 0 to 15 homozygous gene pairs in the $F_{2}$ generation. They also differ between themselves and suggest that the alleles in the CBA strain are less potent sources of antigens than those in the A strain. It is not possible to equate numbers of gene differences with survival for any given number of days, but clearly the individual genes have widely differing powers of forming antigens. The process of destruction, once begun, is soon complete and resembles the breakdown process in normal interstrain homografts more closely than it does the slower, vacillating process found in mice that have acquired tolerance to foreign skin by virtue of an inoculation during embryonic life. Second set grafts are usually thrown off more rapidly than the first set but anomalous results occur occasionally. Immunoparalysis was not found even when five sets of grafts were transplanted in succession.