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Unlabelled: The incidence and significance of a donor-specific human leukocyte antigen antibody response to massive fresh-frozen human bone allograft implantation is not established. This study was a prospective, multicenter study of a cohort of consecutive patients who self-randomized themselves into two groups based on their alloantibody response to allograft bone transplant. The study hypothesis was that donor-directed antibodies are an independent risk factor influencing incorporation of massive frozen bone allografts. Pretransplant and posttransplant human leukocyte antigen alloantibody analysis was performed and correlated to determine pre-existing and graft-induced antibodies. The surgical outcomes of the two groups of patients were compared to determine the relationship between alloantibody response and bone graft incorporation. Preliminary results revealed that donor-specific human leukocyte antigen sensitization occurred in 17 of 32 (53%) of previously nonsensitized patients. A survival analysis of time to healing based on human leukocyte antigen status showed no evidence of an association between human leukocyte antigen status and time to healing. Longer followup in additional patients will be required to determine if this sensitization is correlated with an alteration in the time to union or with the quality or type of bone graft incorporation., Level of Evidence: Therapeutic study, Level II. See the Guidelines for Authors for a complete description of levels of evidence.

To determine whether recipient HLA phenotypes are correlated with an increased or decreased risk of alloantibody sensitization in end-stage renal disease (ESRD) candidates for first or repeat kidney transplantation; we analyzed 19440 kidney allograft recipients consisting of 13,216 Caucasians and 6224 non-Caucasians transplanted between 10/87 and 11/98 at South-Eastern Organ Procurement Foundation (SEOPF) member institutions. Relative risk values and 95% confidence limits were obtained using Wolfe's method. Logistic regression was used to adjust for covariates that influence sensitization, i.e. ethnicity, gender, age, pregnancies, transfusions, primary/repeat transplant and living versus cadaver donor. Univariate analysis of the entire cohort indicated that nine HLA allelotypes (DR1,4,7; B8,12,40; A1,2,11) were associated with a significantly reduced risk of sensitization, and five allelotypes (B42,B53; A 10,19,36) were associated with an increased risk of PRA responses. Corrected for the number of statistical comparisons, recipients with DR1, DR4, A1 or A2 were 15% less likely to be sensitized per allelotype. Recipients with B42, B53 or A36 were at increased risk of preformed antibodies, after correction of the P value, for an average of 38% increased risk per allelotype. In the multivariate analysis, HLA phenotypes identified as independent risk factors associated with protection against sensitization were DR1,4,7; B12(44,45); and A1,2, with an average reduced risk of 9% per allelotype. The only independent susceptibility allelotype was A36 with an increased risk of 29%. The A10 (25,26,34,66) group reached borderline significance. We also looked for HLA-DR,-B,-A combinations that could potentially represent protective or at risk haplotypes/genotypes. Stepwise logistic regression identified five combinations associated with protection: DR1-B35-A3; DR1-B35-A2; DR1-B44-A2; DR4-B44-A2; DR7-B57-A1 (RR range 0.83-0.63) with 27% average reduced risk per combination. Phenotype combinations associated with an increased risk of sensitization were: DR2-B44-A2; DR2B53-A2; DR3-B8-A1: DR3-B42-A30; DR6-B42-A30; DR11-B53-A30 (RR range 2.76-1.48) with an average increased risk of 70% per combination. This study provides strong evidence that HLA-linked genes influence the anti-HLA PRA response. The magnitude of the altered PRA response risk in DR-B-A combinations was approximately twice that of the allelotypes at individual loci. HLA-DR genes seemed to contribute most of the altered risk. The correlations between DR types and PRA responsiveness are consistent with the DR types previously regarded as predictors of kidney graft survival. The magnitude of increased PRA risk attributable to an allelotype or combination was approximately twice that associated with a decreased risk. We conclude that some HLA class II-linked genes modulate the PRA response in a clinically significant manner. This immune response gene (Ir) regulation probably operates through polymorphic HLA molecules in their physiologic roles of antigen processing and presentation to helper T cells.

Twenty percent of patients initiating Medicare-supported end-stage renal disease (ESRD) therapy in the United States have chronic glomerulonephritis-induced ESRD. IgA nephropathy (IgAN) and focal and segmental glomerulosclerosis (FSGS) likely account for many of these incident dialysis cases, although patients presenting with advanced renal insufficiency may not receive renal biopsies. To determine whether HLA phenotype associations existed in the subset of IgAN and FSGS patients who develop ESRD, we analyzed HLA frequencies by race in patients with these etiologies of ESRD entered in the South Eastern Organ Procurement Foundation (SEOPF) database. Serologically determined HLA frequencies from 605 renal transplant recipients with ESRD due to FSGS and 196 renal transplant recipients with ESRD due to IgAN were compared with those of 4,506 race-matched cadaveric kidney-donor controls. Race-specific odds ratios (ORs) were calculated and fitted into a log-linear model to determine associations between the HLA system and ESRD due to IgAN and FSGS. Values reported were considered significant (P < 0.05) after Bonferroni correction for multiple comparisons. HLA-B27 and HLA-DR1 frequencies were increased and HLA-DR2 frequency was decreased in African-American and white IgAN-induced ESRD cases compared with race-matched controls (race-combined OR of 2.10, 1.89, and 0.57, respectively; all P < or = 0.004). HLA frequency differences were not observed in FSGS-induced ESRD patients compared with controls. The results of this study indicate that HLA-B27 and HLA-DR1 are positively associated and HLA-DR2 is negatively associated with IgAN-induced ESRD in patients of both races.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic lupus erythematosus (SLE) has higher incidence and mortality rates in addition to a greater risk for nephropathy in African Americans (blacks), compared with whites. We analyzed the South-Eastern Organ Procurement Foundation (SEOPF) database from 1982 through 1986 to determine if variation in human leukocyte antigen (HLA) frequencies, beyond those normally present between the races, were associated with lupus nephritis (LN). HLA antigen frequencies in 271 black and 230 white renal transplant recipients with LN as the cause of end-stage renal disease (ESRD) were compared with 4,506 race-matched cadaveric kidney donor controls. Odds ratios (ORs) and chi-square values were computed to assess the prevalence of each HLA phenotype among the cases versus the controls separately for blacks and whites. HLA-B8 and -DR2 frequencies were increased, and HLA-DR4 frequency was decreased in cases of both races compared with race-matched controls (race-combined ORs, 1.68, 1.46, and 0.49, respectively; all P < 0.01). Race-specific analyses showed that HLA-DR6 was decreased in black cases versus black controls (OR, 0.48; P < 0.001) and HLA-DR3 was increased in white cases versus white controls (OR, 1.88; P < 0.001). HLA-B8 and DR2 are positively associated and HLA-DR4 is negatively associated with LN in patients of both races. HLA-DR3 and -DR6 demonstrate race-specificity in LN and place whites at a disadvantage relative to blacks. It is likely that non-HLA-mediated genetic factors and/or environmental factors contribute to the increased risk of nephritis observed in black patients with SLE.(ABSTRACT TRUNCATED AT 250 WORDS)

Black patients with insulin-dependent diabetes mellitus are at increased risk for the development of diabetic nephropathy compared with white patients. To determine if genetic differences associated with the HLA system account for racial variation in insulin-dependent diabetes mellitus-induced nephropathy, serologically defined HLA phenotypes from renal transplant recipients and donors in the South-Eastern Organ Procurement Foundation database from 1982 to 1986 were analyzed. Renal transplant recipients (N = 1,531) with insulin-dependent diabetes mellitus-induced renal failure as the cause of ESRD (patients) were compared with 4,506 race-matched, nondiabetic cadaveric kidney donors (controls). Log-linear models were used to assess the relationship between insulin-dependent diabetes mellitus-induced renal failure and prevalence of each HLA phenotype. Bonferroni adjustments of P values were used to correct for multiple comparisons. A comparison of HLA frequencies in patients with insulin-dependent diabetes mellitus-induced renal failure demonstrated the presence of racial differences beyond those normally present between the black and white populations. Blacks, compared with whites, had increased frequencies of HLA-B62 (odds ratio [OR] black:white, 6.13:1.97; P < 0.02) and HLA-DR9 (OR black:white, 4.82:1.57; P < 0.008) and decreased frequencies of HLA-A1 (OR white:black, 1.56:0.8; P < 0.008) and HLA-DR3 (OR white:black, 4.9:2.82; P < 0.004). These results suggest that differences in HLA frequency may account, in part, for the observed racial variation in incidence of diabetic nephropathy. In addition, several antigens in positive and negative association with diabetic nephropathy were identified within each race.

Black patients with hypertension are six times more likely to develop end-stage renal disease than are their white counterparts. To determine if genetic differences associated with the Human Leukocyte Antigen (HLA) system account for racial variation in hypertensive renal failure, we examined antigenic frequencies from a large renal transplant registry. Human Leukocyte Antigen phenotypes from cadaveric renal transplant recipients and donors in the South Eastern Organ Procurement Foundation database from 1982 to 1986 were analyzed. One thousand six hundred four renal transplant recipients with hypertensive renal failure as the cause of end stage renal disease (cases) were compared with 4506 race-matched cadaveric kidney donors (controls). Log-linear models were used to assess the relationship between hypertensive renal failure and prevalence of each HLA phenotype. Bonferroni adjustments of P values were used to correct for multiple comparisons. Comparison of HLA frequencies between blacks and whites with hypertensive renal failure demonstrated that blacks had an increased frequency of HLA-DR3 beyond that normally known to exist between black and white populations. Black cases compared to black controls had an 8.6% increase in HLA-DR3 frequency contrasted with a 1.6% decrease in the frequency of this antigen between white cases and white controls. This absolute 10.2% difference between the races was significant (P = .02) because the control black and white populations had nearly identical frequencies for this antigen. White cases compared to white controls had lower HLA-A1 and B8 frequencies (21.2% v 30.6%, P = .0005 and 13.7% v 22.3%, P = .001, respectively) and a greater HLA-B35 frequency (20.7% v 14.2%, P = .02).(ABSTRACT TRUNCATED AT 250 WORDS)

Five hundred and thirty-seven cases of disputed paternity in North Carolina were tested for five erythrocyte polymorphisms, HLA antigens, or both. The data were analyzed to evaluate the ability of the tests to exclude the alleged father or to include the alleged father as the biological father. Incompatibility between the phenotypes of the alleged father, and those of the mother and child, were found in 40.6% of black males and 30.3% of white males (P less than 0.005). The rates of exclusion appeared to vary between countries in which the cases originated, although the significance of the differences could not be determined because of the small sample size. Using a Bayesian approach and 0.5 as the prior probability of paternity, we calculated the posterior probability of paternity for HLA and five erythrocyte systems combined as well as for HLA and erythrocyte systems separately. The probability of paternity values based on the combined HLA and RBC tests exceeded 95% in 299 of the 345 nonexcluded cases as compared to only 218 cases based on HLA tests alone and 36 cases based on erythrocyte tests alone. We conclude that in approximately 10% of paternity cases in the population served by this laboratory, the information obtained is inconclusive. To resolve these cases, additional polymorphisms and/or a panel of genetic tests systems which can provide greater than 95% probability of exclusion is required.

Five years of experience with cell exchanges between laboratories comprising the Southeastern Organ Procurement Foundation (SEOPF) were analyzed in order to evaluate progress in HLA typing proficiency. The results of the analysis of 15 cell exchanges involving a total of 60 cells indicate that the average detection rate was 95% or greater for HLA-A1, 2, 3, 9, 10, 11, 28, and 29; B7, 8, 12, 13, 14, 15, 17, 27, and 40. HLA-A locus antigens were detected more often (85.8%) than B locus antigens (80.9%). False negative results were more frequent than false positive antigen assignments. Errors in antigen assignments tended to be nonrandomly distributed for certain antigens belonging to cross-reacting groups but usually were randomly distributed for well defined antigens. During the period of the study, SEOPF laboratories demonstrated improved proficiency in the identification of most HLA-A, B, and C provisional (w) specificities. The results demonstrate the benefits of interlaboratory proficiency testing and indicate that cell exchanges can be carried out successfully on a regional basis.

As HLA testing is becoming a major vehicle for parentage determination with non-excluded, alleged fathers being compared to their racial peers, it is important to ensure that the population data used accurately reflect the genetic profile of the region from which the alleged fathers are drawn. This paper presents data on the HLA profile of Black and White residents of North Carolina. Significant differences were observed for certain antigens when the North Carolina data were compared to nationally derived population tables. Differences were observed for B7 (increase) and Bw16 (decrease) in Whites and A10 (decrease), B7 (increase) and Bw42 (decrease) in Blacks. Internal controls comparing the testing from the two participating centers showed complete agreement for White persons, but a significant difference for B5 between the two Black populations.

Seventy-nine Caucasians with acute myelogenous leukemia (AML) were genotyped to determine whether AML, the induction of remission or patient survival were associated with particular HLA phenotypes or haplotypes. HLA-B17 and B27 were increased in AML patients over 40 years of age. Combined analysis of four independent studies indicates that HLA-B17 is significantly but weakly associated with AML, relative risk = 1.48 (.01 less than P less than .025). The A1, B17 and Aw24, Bw35 haplotypes occurred more frequently in the AML group as compared to racial and geographic controls (uncorrected P = 0.0068 and 0.0098, respectively Fisher's Exact Test). Induction of remission occurred less frequently in patients with the B17 phenotype as compared to patients lacking this antigen (P = 0.047). Patient survival was associated with remission status (P = 0.002) but was not significantly associated with particular HLA phenotypes or haplotypes. These results indicate that a gene or genes in the HLA-B region of the major histocompatibility complex can influence susceptibility to AML and also the response to chemotherapy.

Several investigators have reported that subdivisions of HLA-B44, which are not defined by available cytotoxic antisera, can be detected by cytotoxic T lymphocytes. The present study was designed to evaluate two sera which appear to recognize a specificity on some HLA-B44 and B45 positive cells and to determine whether the specificity is correlated with one of the B44 subgroups which are defined by cell-mediated lympholysis. Serum BG1359, eluted from a placenta and serum Cutchember (a gift from Dr. Wilma Bias), were tested on a 23-member B44 positive cell panel. The panel was typed independently with CTLQ1/M3 (specificity 44.1) and CTLM3/Q1 (specificity 44.2). Cells classified as 44.2 usually typed positive with serums 1359 and Cutchember, whereas 44.1 cells usually were negative with these sera in the Amos modified cytotoxicity technique. In the 4th American workshop data, serologic reactivity correlated with B44 (r = 0.87 and 0.75) and B45 (r = 0.32 and 0.34) for serums 1359 and Cutchember, respectively. In a North Carolina population study (N = 155), specificity 1359 was detected in 37 of 53 (70%) of B44 positive individuals and in 5 of 6 B45 positive individuals. In three informative families, the 1359 private specificity segregated with B44 haplotypes. The 44.2 subgroup is in positive linkage disequilibrium with C4 and DR7 and possibly with A23, A26, and A29, whereas the 44.1 subgroup seems to be in disequilibrium with A2, Cw5, DR4, and DRw6.

Five multigenerational kindreds with familial hypertension were typed for human leukocyte antigen (HLA) and blood group antigens to investigate genetic factors that influence variability in blood pressure. Pedigree analysis revealed that children of matings in which both parents were hypertensive had a significantly greater risk of hypertension than children of matings in which one parent or neither parent was hypertensive. Blood types N and MN were abnormally distributed among hypertensive as compared with normotensive members of white but not black families. The distribution of ABO and Rh types was not significantly different between hypertensive and normotensive siblings. When all possible pairings of siblings were examined for HLA haplotype sharing, abnormal distributions were observed among hypertensive sib pairs whereas the expected mendelian segregation was observed among hypertensive-normotensive sib pairs and normotensive-normotensive sib pairs. These results suggest the genetic factors controlling variation in blood pressure may include loci in the region of the MN locus on chromosome 4 and, possibly, the major histocompatibility complex on chromosome 6.

Fifty mouse monoclonal antibodies (mAb) specific for HLA class I epitopes were compared for their reactivity against two closely related nonhuman primate species, pigtailed macaques (Macaca nemestrina, Mn) and longtailed macaques (M. fascicularis, Mfl), which diverged from the hominoids 23-40 million years ago. An analysis of Nei's genetic identity (I) and distance (D) based on reactivity of all class I-specific mAb showed, as expected, that the macaques are more closely related to each other (I = 0.959) than to man (I = 0.782 for Mn and 0.859 for Mfl). However, there were clear differences in genetic similarity with respect to certain epitopes. Macaques were most different from each other and from man in expression of heterologous epitopes recognized by the mouse that are not polymorphic among humans. In contrast, the most polymorphic epitopes unique to single HLA alleles, so-called private epitopes, were present in all the species, and neither macaque species could be distinguished from humans, suggesting that certain class I private epitopes may be highly conserved in evolution.

Data collected prospectively on 3811 cadaver renal transplants performed between June 1977 and July 1982 by the 42 member institutions of the South-Eastern Organ Procurement Foundation (SEOPF) were analyzed to determine whether donor-recipient compatibility based on public rather than private HLA-A,-B specificities influenced the beneficial effect of HLA matching on outcome. HLA compatibility was calculated considering match and mismatch based on common private or various public (crossreactive group, [CREG]) specificities. Donor-recipient compatibility using certain CREG assignments provided an equivalent means of stratifying graft outcome by the degree of HLA-A,-B match or mismatch, and other CREGs assignments did not. Multivariate Cox regression analysis of donor-recipient compatibility based on certain public antigens showed as high an association (P less than 10(-5) between good matching and decreased graft rejection as did matching for private antigens alone. Patient stratification by HLA match provided a stronger association with graft outcome than by HLA mismatch, irrespective of whether private or public antigens were considered. The likelihood of finding a better match was significantly increased using CREG assignments, and patients with at least one matched private antigen had equivalent or better graft survival when additional public antigens were matched. These findings indicate that with conventional immunosuppressive therapy: (1) matching of private or public HLA-A,-B antigens plays a highly significant role in decreasing renal allograft rejection; (2) matching based on certain public antigens can provide the same or a better association with outcome as private antigens; and (3) the association (crossreactivity) of various HLA specificities can be defined on a functional basis in terms of graft survival.

One hundred and seventy-four unrelated white patients with biopsied and clinically diagnosed sarcoidosis and a reference population of 97 were tested for HLA antigens. Selected comparisons showed a statistically significant association of HLA-B8 with the sarcoidosis group (28.9%) when compared to the reference group (15.5%).