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Genetic control of the response to specific natural-product antigens has been documented in three informative families. Families were selected on the basis of probands with tuberculosarcoidosis, chronic cutaneous moniliasis, and rheumatoid arthritis. An increased incidence of delayed cutaneous unresponsiveness was observed in each family. Positive associations were identified between HL-A haplotypes and immediate cutaneous hypersensitivity responses to 5, 8, and 11 of 23 test antigens in the three respective families. HL-A-associated differences in averaged responses of cutaneous hypersensitivity were excluded. These significant associations are consistent with linkage between HL-A haplotypes and genes responsible for the immune response to various natural-product antigens.

The immunogenicity of the haplotypes in 30 families was measured by survival of skin grafts between selected paired family members. These families were genotyped for HL-A using 57 selected cytotoxic alloantisera defining HL-A 1-12 as well as other nondefined specificities. Mixed leukocyte reactions were also studied in this series and the correlations between the mixed leukocyte reactions with skin graft survival times, individual HL-A specificities, and the number of incompatible HL-A alleles are reported. Comments concerning the interpretation and quantitation of the mixed leukocyte reactions are discussed.

The concept that antigens of a major histocompatibility locus (HL-A), the mixed leukocyte reaction, and the rejection of a graft are expressions of the same genetic region has been generally accepted. WE HAVE PRESENTED EXPERIMENTS THAT CHALLENGE THE ABOVE CONCEPT AND SUGGEST THAT THE REJECTION TIME OF SKIN AND ORGAN TRANSPLANTS IS DEPENDENT ON IMMUNIZATION AGAINST THE PRODUCTS OF TWO, AND POSSIBLY THREE, SEPARATE, BUT CLOSELY LINKED, GENETIC SYSTEMS: HL-A, mixed leukocyte reaction (MLR-S), and hypersensitivity delayed reaction (HDR). The findings presented and discussed here suggest that the HL-A antigens are not the primary factors involved in the cell-mediated component of allotransplantation, and that these antigens and phenotypes of the mixed leukocyte reaction can only be used as a guide in predicting the survival of allografts that are obtained from unrelated donors.

16 patients underwent renal transplantation from a sibling donor who was prospectively determined to be ABO compatible and HL-A identical with the recipient. Unidirectional mixed leukocyte reactions were performed; in each instance, lymphocyte stimulation in either direction was not observed. The plasma creatinine 10-68 months after transplantation in these 16 patients ranged between 0.9 and 1.9 mg/100 ml. The creatinine clearance ranged from 48 to 113 ml/min, and the blood urea nitrogen (BUN) ranged between 12 and 35 mg/100 ml. Urine protein excretion varied from 0.11 to 1.86 g/day. Six patients exhibited no detectable clinical episodes of acute rejection; they were treated with azathioprine alone and each of them demonstrated normal or near normal renal histology when biopsy specimens were obtained more than 6 months after transplantation. Nine patients experienced acute rejection episodes that required the use of steroid therapy. The severity of these rejection episodes was variable; they included a mild reduction in renal function with an immediate steroid-induced restoration of function and eventual discontinuance of steroid therapy to severe reduction in function requiring prolonged and moderate doses of steroids without return to normal renal function. Renal histological observations in this group ranged from mild to marked cellular and structural changes which fit the criteria of the rejection. One patient demonstrated a gradual loss of renal function with heavy proteinuria. Biopsy of this allograft demonstrated the recurrence of original disease, i.e., lobular glomerulonephritis. The marked variability in the clinical course and allograft morphology in these 16 patients could be explained by antigenic differences at non-HL-A loci. The presence of minor histocompatibility loci has been well documented in other mammalian species and they are most certainly present in man. The need for their identification and definition is stressed.

The evidence is reviewed that a single genetic system, the major histocompatibility locus in man, HL-A, determines most of the antigens measured by presently available leukocyte isoantisera, and also controls reactivity in one-way mixed leucocyte culture tests. Studies in 12 families are presented to support this conclusion. Some interesting exceptions to the general typing-MLC tests correlation are presented and discussed.

A single locus with 15 or more alleles controls reactivity in mixed leukocyte culture tests. Genes at this locus also control most of the specificities measured by cytotoxic antiserums to leukocytes. Both of these tests can be used to predict survival of skin grafts. It is proposed that this is the major histocompatibility locus in man.