Biomedical subjects
Publications and source records attributed to H Noreen.
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The functional survival rates of kidney grafts from zero-HLA haplotype-matched sibling pairs are similar to one-haplotype-matched pairs and superior to cadaver grafts. From January 1980 to March 1988, 318 primary renal transplants from sibling donors (151 matched for two, 130 for one, and 37 for zero HLA haplotypes), and 352 cadaver graft transplants were performed at the University of Minnesota. The renal graft survival rates at two years were 94%, 91%, and 94% for the 2, 1, and 0-haplotype pairs versus 75% for cadaver graft recipients (P less than 0.04). When analyzed across the different immunosuppression protocols the same trends held up, similar graft functional survivals for 1- and 0-haplotype-matched pairs both being superior to cadaver graft recipients. The graft functional survival rates at two years of recipients of 0-haplotype-matched sibling donor grafts (n = 37) was 94% versus 80% for recipients of cadaver donor grafts matched for greater than or equal to 4 HLA antigens. In addition, for recipients of 0-haplotype-matched grafts, hospital stay was shorter, fewer patients required dialysis posttransplant, and, despite a slightly higher incidence of rejection episodes (51% versus 40%, P = ns), the creatinine values one year posttransplant were significantly lower (1.5 mg/dl versus 1.9 mg/dl, P less than 0.02) than those of recipients of cadaver grafts matched for greater than or equal to 4 HLA antigens. These data support the use of cadaver grafts for patients not having a willing sibling donor, and the use of all willing sibling donors, whether or not they are a zero-haplotype match, for patients fortunate to have that family commitment.
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DNA restriction fragment length polymorphisms (RFLP) can be easily demonstrated in DNA of cells expressing different DR specificities when class II cDNA probes are used for hybridization. Previous studies of DR4+ homozygous typing cells (HTCs) carrying different Dw subtypes, however, detected no RFLP correlating with subtypes. In contrast, we report here Southern blotting studies of DR2+ HTCs carrying different subtypes which showed RFLP patterns characteristic for each subtype, using both DR beta and DQ beta probes and several restriction enzymes. The RFLP between subtypes of DR2 was, however, appreciably lower than that found between DR specificities.
Insulin-dependent diabetes (IDD) is strongly associated with certain HLA class II (Ia) antigens. The frequency of DR2 is significantly reduced in IDD; among DR2+ patients, the frequency of the subtype specificity Dw2 defined with homozygous typing cells (HTCs) is significantly reduced compared to DR2+ controls, and the specificity LD-MN2, which we have defined using primed lymphocyte typing reagents, is significantly increased. We have studied DNA restriction fragment length polymorphisms (RFLP) of DR2-LD-MN2+ individuals and homozygous typing cells carrying specificities antigenically related to LD-MN2. Using a number of different restriction enzymes, a characteristic pattern of fragments could be defined for DR2-LD-MN2 using both DQ beta and DR beta cDNA probes. This pattern was shared with some but not all of the antigenically related HTCs, and was distinct from that of DR2-Dw2. The RFLP pattern of DR2-LD-MN2 obtained with the DQ beta probe is identical, except for one band, to that of DR1-Dw1, suggesting that at least some part of the DQ region is identical in these two haplotypes. These results indicate that analysis of RFLP patterns can be used to help identify the genetic regions and, eventually, genes most important in the association of HLA and IDD.
B cell crossmatches were performed at cold (4 C) and warm (22 C and 37 C) temperatures on 193 renal allograft recipients with negative T cell crossmatches to their donor; 152 of the patients were also tested for autoantibody to autologous B cells. Fifty-six (29%) had a positive B cell crossmatch (21 cold, 35 warm); 14 were autoantibody positive, 23 autoantibody negative, and 19 were not tested for autoantibody. There were no differences in HLA-A, B, C, or DR antigen disparity between the B cell positive (14, 0 DR mismatch; 25, 1 DR mismatch; 9, 0 DR mismatch) and the B cell negative group (40, 0 DR mismatch; 57, 1 DR mismatch; 13, 2 DR mismatch). Similarly, age, diabetic status, and number and type of pretransplant blood transfusions were comparable between B cell positive and negative groups. Although there were no hyperacute rejections, 2-year actuarial graft survival was significantly lower in the B cell positive group, regardless of donor source, graft number, or temperature of reaction. Patients with a positive B cell crossmatch, presumably due to demonstrable autoantibody, may have better graft survival rates than patients with a positive B cell crossmatch and no autoantibody.
The effects of mismatching for DR antigens on renal allograft survival rates have largely been restricted to analyses of cadaver transplant results. Analyses of HLA matching in recipients of transplants from related donors have focused on the number of haplotypes shared between the recipients without regard to DR, or on the total number of HLA antigens mismatched, or on the degree of MLC responsiveness of the recipient to the donor. Most related donor-recipient pairs sharing only one HLA haplotype will be mismatched for DR at the other haplotype, but because there are a limited number of DR alleles, sharing of DR antigens on the mismatched haplotypes occurs relatively frequently. To determine the influence of mismatching for DR on the fate of renal allografts from related donors, we analyzed the results of 172 kidney transplants from related donors who shared one HLA-ABC haplotype with the recipient. There were 156 primary grafts and 16 retransplants; 147 donor-recipient pairs were satisfactory typed for DR antigens. Because genotyping was not usually done, we performed two analyses under two different assumptions. The first assumption was that individuals expressing less than or equal to 1 DR antigen had null antigens, or were homozygous for DR; the alternative assumption was that blanks were true antigens and individuals with blanks were heterozygous. The first assumption is more likely to be correct, and is the assumption used in most analyses of the effect of DR antigen mismatches on the results of cadaveric transplantation. Under the first assumption, of the 147 related donor-recipient pairs in whom DR typing was satisfactory, 33% were mismatched for 0, 64% for 1, and 3% for 2 DR antigens. The one-year absolute graft survival rates in recipients of kidneys from donors with 0 mismatches for DR was 92% (n = 49); in those with one mismatch for DR it was 82% (n = 94); and from those with two mismatches it was 50% (n = 4). The one-year graft survival rate in 25 donor-recipient pairs in which one or both members could not be satisfactorily DR typed was 76%. Differences in graft survival rates between the 0 and 1 and the 1 and 2 DR-mismatched groups were not statistically significant.(ABSTRACT TRUNCATED AT 400 WORDS)
Cytotoxicity tests with alloantisera were used to study the expression of HLA-D region antigens in HLA-DR-null mutants of a human lymphoblastoid cell line. The initial cell line contained just one copy of the MHC as a haplotype that included DR1 and MB1/MT1. Gamma ray mutagenesis of the single haplotype cells followed by selection with complement and an anti-DR monoclonal antibody were then used to isolate DR-null mutants. Two categories of mutants were identified with a panel of alloantisera. Expressions of DR1 and MB1/MT1 were simultaneously lost in four mutants. Nine mutants still expressed MB1/MT1 but had lost the expression of DR1. The dissociated loss of expression of MB1/MT1 and DR1 antigens is evidence for separate genetic control of these alloantigens. The methods used exemplify a versatile approach for conveniently inducing separations of closely linked loci of the MHC.
We studied the histocompatibility antigens A and B in 300 insulin-dependent diabetics: 200 had proliferative retinopathy and 100 did not. The two groups were matched for known duration of diabetes and other clinical features. In both groups the frequencies of HLA-B8, HLA-B18, and HLA-B8/HLA-B15 were significantly higher, and those of HLA-B7 and HLA-B12 were significantly lower than in healthy controls. The patients with proliferative retinopathy were significantly less often positive for HLA-B7 (X2 = 10.0; Pc < .03) than patients with nonproliferative retinopathy. When both groups were stratified for age at diagnosis, there were additional differences. HLA-B15 was significantly more frequent in the proliferative retinopathy group with age at diagnosis between 15 and 40 years (nonproliferative retinopathy = 16.4%; proliferative retinopathy = 39.4%; X2 = 7.89, Pc < .03; relative risk = 3.32) and HLA-B7 significantly less frequent (nonproliferative retinopathy = 23.6%; proliferative retinopathy = 5.6%; X2 = 8.0, Pc < .03; relative risk = 0.19). These differences in histocompatibility frequencies between patients with and without proliferative retinopathy indicate a genetic contribution to diabetic retinopathy.
We have histocompatibility (HLA) genotyped 28 families with insulin-dependent diabetics in two or more consecutive generations, usually parent and child. This strategy of ascertainment was used to maximize the likelihood of obtaining a homogeneous type of disease within a family, and an autosomal dominant mode of inheritance. 76 diabetics and 169 nondiabetics were studied in these families. The frequencies of the antigens Dw3 and Dw4, and the genotype Dw3/Dw4 among the diabetics are 59, 68, and 30%, respectively, as compared with 15, 12, and 2% in normal controls, and 43, 41, and 10% in the nondiabetic relatives of the diabetics. Dw2 is present in only one diabetic (4%), as compared with 18% in normal controls and 17% in nondiabetic relatives.HLA haplotype concordance was analyzed for sib pairs in relation to the haplotype shared by the affected parent/child pair, and for the diabetic sib pairs within each sibship. The results failed to reveal deviations in the expected HLA haplotype assortment. Assuming an autosomal dominant mode and several penetrance levels, linkage analysis between the HLA and diabetes was performed. The total lod score is 0.37 for a recombination fraction of 0.29 at 50% penetrance. Although the linkage and concordance analysis results are inconclusive, they seem to be different from those reported by us for families with normal parents and two or more diabetic sibs. Because ascertainment biases may have influenced these results in an unquantifiable manner, it is not certain whether the two types of families are genetically different. However, the marked difference in the lod scores for the 50% penetrant autosomal recessive model between the two types of families is compatible with a genetic dissimilarity between them. The high frequency of the Dw3 and Dw4 antigens, the Dw3/Dw4 genotype, and the decreased frequency of Dw2, however, indicate the existence of two or more important diabetic genetic factors associated with the D region of the HLA in these families.
Analysis of 100 patients receiving HLA identical sibling transplants was performed. Excellent graft survival demonstrated in the group attests to the importance of matching serological determined antigens. There seems to be a modest beneficial effect on antilymphoblast globulin in low dosage, but not in high doses. Insulin dependent diabetes mellitus results in a significant negative influence on patient survival and graft function in the male recipient but not in the female. A particularly striking point that emerges is the potential hazard in incorrectly treating for rejection. Rejection occurs very rarely in these patients; in a patient with deteriorating renal function, etiologies other than rejection should be vigorously sought (including transcutaneous biopsy) prior to initiation of rejection therapy.
The effect of HLA matching on the success of cadaver renal allografts was examined utilizing computerized multifactoral analysis in a large single renal transplant center. One hundred ninety-one consecutive cadaver transplant recipients (from January 1968 to August 1975) were followed from 2 1/2 to 9 years. During the period surveyed we had not utilized the tissue typing results in a prospective manner to select recipients. The data presented attest to the beneficial effect of utilizing well matched cadaver grafts. HLA matching of two or more antigens results in significantly superior 2- and 4-year patient survival and graft function compared to results for cadaver kidneys matched for zero and one HLA antigen. The results are not greatly influenced when age, sex, or time of transplant are controlled. The importance of tissue typing is particularly clear if higher doses of antilymphoblast globulin (ALG) are administered. The risk inherent in advancing recipient age is markedly reduced by better transplant matches. Graft function is also superior in the diabetic patients receiving good HLA matches, but there are too few patients to make these results statistically significant.
Forty-one unrelated juvenile, insulin-dependent diabetics have been HLA tissue typed for A, B and Dw anitgens and compared with a normal control population. We have found statistically significant increases in the frequencies of B8, B18, and Dw3, and significant decrements in the frequencies of B7, B12 and Dw2. The log-linear modeling technique was used to study the association of JIDD with Dw3 and B8 antigens. We confirmed that the B8 excess seen in diabetics is secondary to the excess of Dw3. The decrements of B7, B12 and Dw2 could reflect an association of these antigens with a protective factor for the disease, or could be due to an artifact. The latter possibility was excluded for B7 and Dw2 by adjusting for the excess antigen frequencies. These findings suggest that the associations between the HLA and diabetes are compatible with the existence of genes which are concerned with the pathogenesis of the disease and are closely associated with the D locus of the major histocompatibility system.
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The HLA antigen profile of the Bari and Yupa Indians who live in the Motilones Valley on the border between Venezuela and Colombia was studied. Both groups showed very limited polymorphism. HLA--A1, A3, A11, Aw23, A25, A26, A29, Aw30, Aw32, and Aw33, and HLA--B7, B8, B12, B13, B14, B17, B18, Bw22, and B27 were not observed in either population.
Sera obtained from planned immunizations between unrelated donors and recipients, identical or compatible at HLA-A and B, were assessed for their capacity to alter the in vitro response of a test panel of lymphocytes to PHA and a purified streptococcal antigen (PAS). In the case of PHA, no serum effects were apparent. The response to PAS, however, significantly inhibited by two sera. When tested for their complement-dependent cytotoxicity on enriched populations of T and B lymphocytes, none of the sera manifested cytotoxicity against T cells nor did serological inhibition correlate with the capacity to lyze B cells. The data suggest that inhibition of the PSA response is mediated by blocking antibodies specific for a subset of lymphocytes, possibly T cells. While the precise mechanism governing the response to PSA is not known, the data are compatible with the idea that an HLA-linked Ir gene, expressed on a subset of T lymphocytes, controls immune responsiveness to PSA.
A large 81 member, four-generation black family with hereditary angioedema is reported with regards to its clinical course and the association with the histocompatibility system. No mortality was seen related directly to the disease. Assuming that this trait is autosomal dominant it appeared to have no linkage with the histocompatibility system as noted by an estimated recombination rate in males and females of 0.5 and a maximum lod score of 0.0. Further evidence of no linkage is given by the fact that lod scores below -3.0 were observed for values of theta less than 0.5.