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.
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.
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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.
HLA-A, B, C and DRw typing was performed on peripheral blood lymphocytes of 17 adults with the diagnosis of chronic active hepatitis made by liver biopsy as the only criterion for study. An increase in the frequency of HLA-DRw4 (71 vs. 24%, p less than 0.005) was observed, but there was no increased frequency of HLA-A1, B8 or any other HLA locus specificity.
Linkage analysis between the major histocompatibility system (HLA) and juvenile, insulin-dependent diabetes, assuming an autosomal recessive mode and 50% penetrance was performed on 21 juvenile, insulin-dependent diabetic multiplex families (two or more diabetics per sibship) with phenotypically normal parents. The total lod score was the highest (3.98) at a recombination fraction of 13%. For a penetrance of 100%, the highest total lod score was 2.92 at a recombination fraction of 18%. These results are compatible with the existence of linkage between an autosomal recessive diabetic gene with 50% penetrance and the HLA in some of the families studied. Our ascertainment strategy would be expected to increase the likelihood of selecting for genetically homogenous diabetes and against sporadic forms of the disease. Thus, our findings may apply only to a small proportion of all cases of juvenile, insulin-dependent diabetes.
HLA haplotypes in a kindred with a maturity-onset type of hyperglycemia in the young (MOHY) were studied. All diabetics had mild hyperglycemia of early onset, and the inheritance pattern suggested an autosomal dominant trait. Eight of 11 subjects with hyperglycemia shared haplotype A3, Bw15. When only this haplotype was considered, there appeared to be a significant association with hyperglycemia chi2 = 6.36). However, since both haplotypes in the proband could be associated with hyperglycemia (both proband's parents had hyperglycemia), the data for both haplotypes were combined, and analysis for an association between both haplotypes and hyperglycemia was not significant (chi2 = 2.53). Linkage between a diabetes gene causing MOHY and the HLA, evaluated by lod score analysis, was suggested, but the values were not significant.
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One hundred fifteen consecutive patients received first transplants from cadaver donors at the University of Minnesota between January 1, 1968, and May 31, 1973. All patients have been followed for at least two years. The two-year survival rate is 70 per cent and the two-year transplant function rate is 58 per cent. Considerable improvement in both patient survival and transplant function has been noted since 1971. The success of transplantation appears to depend to a large degree on the age of the transplant recipient, the number of HLA antigens matched between donor and recipient, and the dose of antilymphoblast globulin (ALG) administered to the recipient during the first two weeks after transplantation. Each of these factors appears to be important even when the other factors are controlled, and when patients with diabetes, suffering technical failure or hyperacute rejection, are excluded. The results utilizing well-matched cadaver kidneys plus large doses of ALG appear to be equivalent to those obtained with the use of mismatched kidneys from relatives, but further analysis will be required to draw a definite conclusion. Patients receiving poorly-matched cadaver kidneys do far less well than patients receiving mismatched related grafts, however, even when ALG is utilized.
From January 1, 1968 to May 31, 1973, 100 patients received first kidney transplants from sibling donors. All recipients have been followed for at least two years and several as long as 7.5 years. One hundred per cent follow-up information is available. The absolute two-year patient survival is 85% and the absolute two-year kidney function survival is 76%. Patients with diabetes (especially males) have less success following transplantation than do patients without diabetes. When diabetic patients are excluded, older patients appear to do slightly less well than younger patients. Patients with phenotypically identical HL-A matches with the donor do better than patients without such matches. In the nondiabetic technically perfect transplant recepient, better than 90% long-term transplant function can be expectedwith no kidney losses after the first few months. In contrast, the less well-matched transplant demonstrated both an increased early rejection rate and a high rate of loss after the third to fifth year. Increasing doses of anti-lymphoblast globulin (ALG) had beneficial results in HL-A mismatched sibling transplants, but were slightly detrimental in phenotypically identical HL-A donor-recipient pairs because of an increased rate of infection. The results are compared with the results of transplants from other related donors and from cadavers performed during the same period.