Biomedical subjects
Publications and source records attributed to H Noreen.
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.
We have histocompatibility (HLA) genotyped 24 families with two or more juvenile, insulin-dependent, ketosis-prone diabetic siblings. This criterion for family selection was used to obtain a homogeneous form of diabetes within a sibship, because diabetes appears to be a genetically heterogeneous disease. 58 diabetic and 53 nondiabetic sibs and 40 parents were studied. 55% of the diabetic pairs were concordant for both HLA haplotypes (expected 25%), 40% were concordant for one haplotype (expected 50%), and 5% were discordant for both haplotypes (expected 25%). These values are significantly different from the expected values (P < 0.001). On the other hand, the inheritance of haplotypes among the nondiabetic sibs in these families was not significantly different from the expected mendelian segregation. When comparing 20 pairs of HLA identical (sharing two haplotypes) with 15 pairs of haploidential (sharing one haplotype) diabetic sibs for the intrapair difference in age of onset of disease, we found that the HLA identical sibs were significantly more concordant for age of onset (3.9 yr difference) than the haploidential (7.3 yr difference) (P < 0.05). The same type of analysis for the difference in seasonal incidence in months revealed that the HLA indentical sibs were more concordant (1.8 mo difference) than the haploidentical sibs (3.2 mo difference) (P < 0.025). Furthermore, the HLA identical diabetic sibs were more likely to develop diabetes in the winter months (78%) than the haploidentical diabetic sibs (21%). No particular HLA haplotype or antigen seemed to be associated with any particular clinical feature. These data are compatible with the theory of genetic heterogeneity of juvenile, insulin-dependent diabetes. It is suggested that there are one or more diabetes response genes in the HLA region playing an important role in the pathogenesis of juvenile, insulin-dependent diabetes in the families studied here. It is, however, possible that other genes, not associated with the HLA complex, may play an etiologic role in some cases of juvenile, insulin-dependent diabetes, resulting in lack of association between HLA and some forms of diabetes.
From June, 1970, to January, 1975, 399 first transplants were performed at the University of Minnesota. Of these 399, 52 had performed antibodies against HLA antigens. When the results of transplantation to these recipients were compared with the results of transplantation to a recipient group matched for age, sex, presence of diabetes, time of transplant, and donor type, no differences were observed. Similarly, no differences were observed when either group of transplant recipients were compared with all first transplant recipients during this period of time. When the results were controlled for diabetes, related or cadaver donation, or degree of presensitization, no differences were observed. Four patients developed hyperacute rejection during this period of time. All four were found to have antibodies to the donor on retrospective analysis utilizing the most sensitive antiglobulin technique. In addition, 65 donor:recipient pairs negative by standard National Institutes of Health and cross-matching techniques proved to have positive prospective cross-matches utilizing the new antiglobulin technique. The correlation between the presence of anti-HL-A antibodies and negative antidonor cross-match and early kidney loss cannot be confirmed at a single institution. The results suggest that a highly sensitive antiglobulin cross-matching technique utilizing sera drawn just prior to the scheduled transplant and cross-matching utilizing the sera bearing the greatest number of anti-HL-A antibodies will eliminate correlation between anti-HL-A antibodies and early graft rejection in the presence of a negative cross-match.
Whenever the results are compared within a given time period, within a given age group, within the nondiabetic population, and within groups receiving high or low doses of ALG, the advantages of well-matched kidneys continually and significantly demonstrate themselves. Tissue matching failed to improve survival and function only in diabetic patients who frequently die of problems unrelated to rejection. The results thus demonstrate an overall clear superiority in patient survival and transplant function of the better-matched kidneys.
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To gain further insight into the genetic determinants of diabetic small vessel disease, we studied 22 HLA antigens in 110 juvenile-onset, insulin-dependent diabetics with terminal glomerulosclerosis and retinopathy, who were being prepared for kidney transplant. HLA antigens were comtemporarily determined in non-diabetic kidney transplant recipients and healthy controls. The frequency of antigens A1 and B8 were significantly higher in diabetics than in controls (P less than .02 and .011), but the frequency of BW15 was normal. The data are compatible with the concept that juvenile diabetes with microangiopathy is one of the HLA-B8 associated disorders.
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Bidirectional strong stimulation in one-way mixed lymphocyte cultures (MLC) is reported between an HL-A recombinant and sibling, apparently differing only at the LA or first locus HL-A. The strong MLC reaction may represent a second strong MLR-S locus associated with the LA or first locus HL-A. Alternative explanations are discussed. A second example of a recombinant HL-A haplotype transmitted to progeny is also reported.
Fifty-seven members of a family that spanned three generations were studied for antigen E and ragweed skin sensitivity and HL-A antigens. There was significant association between the haplotype HL-A 2-12 and antigen E skin hypersensitivity (F = .22 to .26) in this family. The map order is first locus of HL-A, second locus of HL-A, and IrE. These determinants are considered to be part of the linkage group HL-1.
Transplantation of immediately vascularized grafts across species barriers in which preformed cytotoxic antibodies exist, otherwise known as discordant combinations, has uniformly resulted in hyperacute rejection. We studied how well plasma exchange and perfusion through organs removes preformed immunoglobulin M cytotoxic antibodies and prolongs survival of a porcine heart heterotopically transplanted into a rhesus monkey. With the use of plasma exchange or absorption of antibodies by porcine kidney perfusion with or without immunosuppression, graft survival was prolonged, although antibody-mediated rejection ultimately occurred. In one case in which plasma exchange, kidney perfusion, and immunosuppression were combined, a functioning pig heart survived in a rhesus monkey for 8 days without evidence of rejection. The animal was killed on day 8 according to protocol because of a wound dehiscence. With this animal we were able to demonstrate that circulating antibodies against graft endothelium had bound to the graft endothelium without inducing rejection, a process referred to as accommodation. In this case, despite the presence of antiendothelial antibodies, complement did not appear to be activated, and fibrin thrombi did not form. Although we have achieved this rejection-free survival only in one animal, this case suggests that it may be possible to maintain xenotransplants in discordant species without rejection if preformed antibodies are appropriately lowered or altered during the initial period of graft implantation.