FACTORS WHICH HAVE A SIGNIFICANT EFFECT ON THE SURVIVAL OF HUMAN SKIN GRAFTS

Abstract

SUMMARY Survival of 436 ABO-compatible skin grafts exchanged in 97 Caucasian families was prolonged if donor and recipient were genotypically, as compared with phenotypically, HLA identical. Among skin grafts between haploidentical family members, a mismatch at the A locus was equivalent to a mismatch at the B locus. Skin grafted from child to mother survived longer than did skin grafted between other family members, other variables being equivalent. A highly significant positive correlation was found between the age of recipient and skin graft survival. In addition, a significant interaction was found between the relationship of donor and recipient and degree of antigen match. Genetic factors contribute significantly to the survival of grafted tissues and organs in experimental animals and in man. In particular, prolonged graft survival is associated with compatibility for a genetic complex, usually referred to as the major histocompatibility system. The major histocompatibility complex, called HLA in man and H-2 in mouse, includes a number of distinguishable genes, each of which may contribute by one mechanism or another to graft survival or rejection. By exchanging grafts between congenic strains of mice, it has been possible to measure directly the effect of incompatibility for segments of the H-2 complex on graft survival (13). Such direct measurements cannot be made in man since a human equivalent of congenic strains does not exist. Two individuals, whether related or unrelated, may differ for several genes which influence graft survival in addition to the genetic factor(s) in question. Therefore, in man the effect of single genes or chromosome segments must be measured indirectly and evaluated by statistical methods. Attempts have been made in the past to measure the relative strength of incompatibilities. The earliest attempts were through the third man test, in which a recipient (the third man) was sensitized by receiving leukocytes (10) or a skin graft (19) from a given subject and was then tested by receiving grafts from a donor panel. Donors whose skin was rejected as second-set or white grafts were considered to share antigens, absent from the third man, with the original donor. Although it was possible to show antigenic variation in this way, no information was obtained about specific antigens. The next step was to type for the then identified HLA-related specificities and match in such a way that the sensitizing donor possessed a specificity absent from the third man. Test grafts were then placed on the recipient from two or more donors possessing and two or more lacking the specificity in question (controls). Sensitization was by injection of leukocytes or platelets, or by skin graft. In almost every case skin from the antigen-positive donors was rejected in an accelerated fashion, and control grafts were usually rejected as first-set grafts 3 or 4 days later. Unfortunately, the sophistication of antigen definition was low and the validity of some of the data (e.g., with platelet immunization) seems rather doubtful. In any event the tests did not show that some specificities were consistently more immunogenic than others. Skin grafts between “matched” and “mismatched” donor-recipient pairs did not show any consistent differences (30); although from a consideration of variations in length of survival of skin grafts and of the survival and function of kidney grafts, there are great differences between pairs matched for one HLA haplotype. The relevance of the HLA system to transplant survival, however, is beyond question. Grafts from HLA-identical siblings are consistently better accepted than are grafts from siblings, parents, or others, clearly mismatched for one or more haplotype. In this study, we have attempted to evaluate the relative importance of matching for HLA antigens per se and the effects of other variables on the survival of skin grafted to nonimmunosuppressed normal, healthy family members. Our results suggest that matching for HLA antigens themselves, or consequently, for factors in significant linkage disequilibrium with them, significantly prolongs skin graft survival. Other significant factors are the familial relationship of graft donor and recipient and age of recipient. Our data demonstrate the importance of multivariate analysis in assessing the significance of individual variables on skin graft survival.