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E Mickelson

Publications and source records attributed to E Mickelson.

At least 37 records · Page 2Linked to original sources
PubMed1989

Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma.

We analyzed the relevance of HLA compatibility to sustained marrow engraftment in 269 patients with hematologic neoplasms who underwent bone marrow transplantations. Each patient received marrow from a family member who shared one HLA haplotype with the patient but differed to a variable degree for the HLA-A, B, and D antigens of the haplotype not shared. These 269 patients were compared with 930 patients who received marrow from siblings with identical HLA genotypes. All patients were treated with cyclophosphamide and total-body irradiation followed by the infusion of unmodified donor marrow cells. The rate of graft failure was 12.3 percent among the recipients of marrow from a donor with only one identical haplotype, as compared with 2.0 percent among recipients of marrow from a sibling with the same HLA genotype (both haplotypes inherited from the same parents) (P less than 0.0001). The incidence of graft failure correlated with the degree of donor HLA incompatibility. Graft failure occurred in 3 of 43 transplants (7 percent) from donors who were phenotypically HLA-matched with their recipient (haplotypes similar, but not inherited from the same parents), in 11 of 121 donors (9 percent) incompatible for one HLA locus, in 18 of 86 (21 percent) incompatible for two loci, and in 1 of 19 (5 percent) incompatible for three loci (P = 0.028). In a multivariate binary logistic regression analysis, independent risk factors associated with graft failure were donor incompatibility for HLA-B and D (relative risk = 2.1; 95 percent confidence interval, 1.7 to 2.5; P = 0.0004) and a positive crossmatch for anti-donor lymphocytotoxic antibody (relative risk = 2.3; 95 percent confidence interval, 1.8 to 2.8; P = 0.0038). Residual host lymphocytes were detected in 11 of 14 patients with graft failure, suggesting that the mechanism for graft failure could be host-mediated immune rejection. We conclude that donor HLA incompatibility and prior alloimmunization are significant risk factors for graft failure, and that a more effective immunosuppressive regimen than those currently used is needed for consistent achievement of sustained engraftment of marrow transplanted from donors who are not HLA-identical siblings.

Adolescent↗
PubMed1988

Analysis of HLA-DP allelic sequence polymorphism using the in vitro enzymatic DNA amplification of DP-alpha and DP-beta loci.

Allelic sequence variation of the HLA DP-alpha and DP-beta genes has been analyzed in a panel of 34 DP-typed cell lines. The polymorphic second exon of these genes was specifically amplified in vitro by the polymerase chain reaction method, using the thermostable DNA polymerase of Thermus, aquaticus. The analysis of M13 clones containing the amplified DP-beta sequences revealed a total of 14 allelic variants. In general, specific allelic DP-beta sequences were associated with each of the defined DPw1-w6 types, with beta allele subtypes revealed for the DPw2 and DPw4 specificities. An additional six DP-beta alleles which did not correlate with any of the T cell-defined specificities (DP "blanks") were also identified. Only the two previously characterized alleles of DP-alpha were detected. These observations suggest that the T cell-defined DP specificities are determined by polymorphic residues on the beta-chain. The sequence polymorphisms in DP-beta are clustered in a few specific regions, and can be detected using sequence-specific oligonucleotide probes and polymerase chain reaction amplified DNA in a rapid dot-blot format. This approach provides a simple and informative method of DP typing. The DP-beta sequences derived from four DP-typed celiac disease patients were compared with the distribution of DP-beta alleles in control individuals.

Alleles↗
PubMed1988

A specific nucleotide sequence defines a functional T-cell recognition epitope shared by diverse HLA-DR specificities.

An oligonucleotide probe that distinguishes the HLA-DR4, Dw14 allele from other HLA-DR4-associated class II genes was used to identify a common nucleotide sequence shared between the DR beta 1 locus encoding HLA-DR1 (Dw1), Dw16, and DRw10 haplotypes. The presence of this nucleotide sequence correlated with the ability of these haplotypes to stimulate an alloreactive proliferative T-cell clone (clone 14B) raised against a Dw14+ stimulator cell. Alleles of DR beta 1 that differ by one specific nucleotide variation at codon 71 neither hybridize to the Dw14-specific oligonucleotide nor stimulate clone 14B. These data demonstrate the presence of a shared epitope present on serologically distinct DR alleles that is recognized as a specific allodeterminant by a single T-cell clone.

Base Sequence↗
PubMed1988

Analysis of DR and DQ gene products of the DR4 haplotype in patients with IDDM: possible involvement of more than one locus.

Fifteen DR4-bearing haplotypes from twelve patients with insulin-dependent diabetes mellitus (IDDM) were analyzed serologically, cellularly, and biochemically. The HLA-Dw composition of these DR4-positive haplotypes was Dw4 (46%), Dw14 (22%), and Dw10 (33%). The biochemical analysis by two-dimensional electrophoresis (2D-PAGE) of the DR beta chains showed that each Dw specificity is characterized by a specific DR4 beta chain that appears to be identical in normal and diabetic individuals. Analysis of DQ beta chains in the DR4-bearing haplotypes revealed that certain Dw specificities such as Dw4 are characterized by the presence of either the DQw7 (formerly DQw3.1) or DQw8 (formerly DQw3.2) alleles, which generate the Dw4.1 or Dw4.2 subtypes, respectively. Others such as Dw14 and Dw10 are characterized by the presence of the DQw8 allele. In our sample of 12 patients the Dw4.2 (Dw4, DR4 beta I-4 DQw8) and Dw10 (Dw10, DR4 beta I-1, DQw8) subtypes were predominant. It is concluded that individual DR beta and DQ beta gene products from the DR4-bearing haplotype of IDDM patients are identical to those of normal control subjects and that Dw14 as well as Dw10 are involved in disease susceptibility. We suggest that disease susceptibility may be influenced by more than one locus within the HLA-D region.

Diabetes Mellitus, Type 1↗
PubMed1987

Differential presentation of HLA-DR, DQ, and DP restriction elements by interferon-gamma-treated dermal fibroblasts.

IFN-gamma has been reported to induce expression of HLA class II (DR, DQ, DP) antigens on cultured human dermal fibroblasts (FB) by stimulating the de novo transcription of the alpha and beta chain genes of HLA-DR, -DQ, and -DP in these cells. We examined the relative nominal and alloantigen-presentation capacity of each HLA class II gene product on FB by using CD4-positive, TNP-specific T cell clones restricted by determinants on DR, DQ, or DP molecules, as well as allospecific, CD4-positive T cell clones recognizing DR-, DQ-, or DP-lymphocyte activating determinants. After IFN-gamma exposure, FB strains used for antigen presentation displayed a high percentage of DR-positive cells and a much smaller percentage of DP-positive cells, but no detectable DQ-positive cells by immunofluorescent techniques. FB stimulator cells supported proliferative responses of two DR-allospecific T cell clones and one TNP-specific, DR-restricted clone, but not another TNP-specific, DR-restricted clone. Despite only modest DP expression, FB stimulated both a TNP-specific, DP-restricted clone and a DP-allospecific T cell line. However, IFN-gamma treated FB failed to stimulate a TNP-specific, DQ-restricted clone and a DQ-allospecific clone. Our data indicate that IFN-gamma differentially regulates expression of functional class II lymphocyte activating determinants on FB antigen-presenting cells and that FB may fail to support DQ-directed T cell responses due to insufficient expression of DQ molecules on the FB cell surface. However, the quantity of DR or DP expressed on FB did not directly correlate with their ability to support T cell responses, indicating that additional factors, such as differences in T cell clone activation requirements, contribute to the capacity of FB to present class II allo- and antigen-restricting epitopes.

Antigen-Presenting Cells↗
PubMed1987

HLA-DP and HLA-DO genes in presumptive HLA-identical siblings: structural and functional identification of allelic variation.

We analyzed HLA class II genomic polymorphisms in three families in which bone marrow transplantation was performed between individuals presumed to be HLA identical, but in which unexplained mixed lymphocyte culture reactivity was observed. These families were characterized by classical HLA serology, MLC, and DP typing. In each family, a pair of "HLA-identical" siblings demonstrated a small proliferative response in bidirectional MLC. Southern blotting analysis performed with cDNA probes for DQ alpha, DP alpha, and DP beta identified DP genomic differences in each case. Hybridization of Bgl II-digested genomic DNA with a DP alpha cDNA probe revealed three prominent polymorphic fragments (7.7, 5.8, and 3.7 kb), which discriminated between presumptive identical siblings and indicated crossover events within HLA. Similarly, hybridization of SstI-digested genomic DNA with a DP beta cDNA probe, although resulting in a more complex pattern, identified DP genomic disparity between the presumed HLA identical siblings. Hybridization of SstI-digested DNA from two families with evidence of DP recombination was performed by using an oligonucleotide probe specific for the newly described HLA class II gene DO beta. Two major polymorphic fragments, at 6.2 and 3.3 kb, segregated in these families and localized the crossovers flanking the DO beta gene between the DQ and DP loci. The contribution of the antigenic differences marked by these HLA DP and DO DNA polymorphisms to allorecognition in MLR and in graft-vs-host disease are discussed.

Alleles↗
PubMed1987

HLA-Dw clusters associated with DR4 in Israeli Jews and the definition of a new DR4 associated Dw subtype: Dw"SHA".

A homozygous typing cell (HTC), that identifies a newly defined HLA-Dw determinant Dw"SHA," is described. The donor of the HTC was a Yeminite Jew and an offspring of first cousin marriage. This cell is not included in the known DR4-associated specificity clusters Dw4,Dw10,Dw13,Dw14,Dw15, or the provisional cluster Dw"KT2." Dw"SHA" was shown to segregate with DR4 positive haplotypes in family analysis, and in a population study was present in three of 43 unrelated DR4 positive individuals. This new Dw determinant was detected in Israeli Jews of Yemenite origin bearing the haplotype HLA-Bw41,DR4,DQw3. This indicates that Bw41,DR4,DQw3,Dw"SHA" may represent a typical allele combination in Yemenite Jews. Among 43 DR4 haplotypes in Israeli Jews, Dw10 had the highest antigen frequency (41.8%), whereas in American Caucasoids and in Japanese, Dw4 and Dw15 were most frequent, 44% and 40.5%, respectively.

Asian People↗
PubMed1986

The HLA system in Inupiat and Central Yupik Alaskan Eskimos.

We have studied HLA antigen profiles of the Inupiaq and Yupik-speaking peoples, two of the four Eskimo linguistic groups residing in Alaska. A relatively restricted polymorphism of HLA-A and -B locus antigens was noted. Only 35% of A locus specificities and 37% of B locus specificities tested for were detected in each population. The most common A locus alleles were A2, A24, and A28; the most common B locus alleles were B51(5), B27, B35, Bw60(40), Bw61(40), and Bw62(15). The antigens Cw3 (75 and 69%) and DR4 (81 and 67%) were found in high frequency in both groups. HLA-DR1, DR2, and DR7 were detected infrequently, while DR3 was not detected at all. DR4 was frequently associated in both Inupiats and Yupiks with Dw4, a specificity that was thought to occur only in Caucasian populations. A statistically significant difference between Inupiats and Yupiks was found for polymorphism at the A locus, but no significant differences were found for polymorphisms at the B, C, D, or DR loci. Analysis of HLA linkage disequilibrium revealed the presence of several novel haplotypes not previously described in other populations, suggesting that the selective factors responsible for positive associations observed in these Native Alaskans were probably distinct.

Alaska↗
PubMed1986

The HLA system in the Korean population.

The frequencies of HLA-A, B, C, DR, and DQ antigens, HLA-D (HTC-defined) haplotypes, and the HLA-linked genetic markers glyoxalase I (GLO), factor B (Bf), C2 and C4 were studied in 162 healthy unrelated Koreans. Antigens A2, A24, A26, B44, B51, Bw62, B35, Cw1, Cw3, DR2, DR4, DRw6, DR7, and DRw8 were observed at frequencies of 15% or greater, and GLO-2, BfS, C4A*3, C2C, C4A*4, C4B*1, and C4B*2 were also frequently observed. The antigens A23, A25, B18, Bw42, Bw47, and B21 were not observed at all. HLA-DR4 was the most common class II antigen and was associated with a series of HLA-D-defined haplotypes including Dw4, Dw10, Dw13, and Dw15. The HLA-DRw6, DR2,Dw8, and DRw8 haplotypes were also found frequently. DR2 haplotypes were either Dw2 or Dw12, while all DRw8 haplotypes tested corresponded to the DB7 or Dw "8.3" specificity that has been described in other Oriental populations. Significant linkage disequilibrium was found between the alleles A2,Cw1; A30,B13; A30,Cw6; A30,DR7; Cw1,Bw22; Cw5,B12; Cw6,B13; Cw6,DR7; B7,DR1; B12,Dw6; B12,DR7; B12,Dw7; B13,DR7, B17,DR3; Bw22,C4B*6; DRw6,BfF; and C4A*4,C4B*2. A comparison of gene frequencies and commonly observed haplotypes between Koreans, Chinese, Japanese, and Caucasians showed that while Koreans share several characteristics in common with other Oriental populations, there are allelic frequencies and haplotypes in Koreans that are distinct.

Complement C2↗
PubMed1986

HLA-DQ heterogeneity among HLA-DRw11(5) haplotypes.

Class II molecular variation among a panel of ten HLA-DRw11(5) homozygous cell lines (HCL) was investigated by analysis of restriction fragment length polymorphisms in genomic DNA. Hybridization of Bgl II, Hind III, and Taq I digested cellular DNA with DQ alpha and DQ beta cDNA probes identified a clustering of characteristic polymorphisms. Considerable diversity was observed between the HLA-DRw11(5), DQw3 positive haplotypes studied, as well as compared to a DRw11(5), DQw1 positive haplotype. In contrast to the observed DQ genomic variability, hybridization with a DR beta probe revealed relatively limited diversity. The molecular heterogeneity seen by genomic restriction fragment analysis illustrates the presence of genomic polymorphisms, particularly within HLA-DQ-related genes among a family of DRw11(5)-related haplotypes.

B-Lymphocytes↗
PubMed1986

Bone marrow transplantation experience for children with aplastic anemia.

From May 1971 through December 1981, 81 children (22 months to 17 years of age) received allogeneic bone marrow grafts for severe aplastic anemia. All donors were HLA-identical family members. Fifty-seven of the 81 (70%) are still alive. Twenty-three untransfused patients were conditioned with cyclophosphamide, 50 mg/kg/d, for four days, and 19 (83%) have survived from 5 to 12 years. All 58 transfused patients were conditioned with cyclophosphamide, 50 mg/kg/d, for four days, 11 received additional immunosuppression, and 19 received posttransplantation donor buffy coat cells. Thirty-eight (65%) have survived from 3 to 13 years (P = .1). In a multivariate analysis, the only factor significantly associated with increased survival among patients with sustained grafts was the absence of significant graft v host disease (P less than .0001). The factors significantly related to increased rejection were low bone marrow cell dose (P less than .05) and positive relative response in mixed leukocyte culture (P less than .0001), but the addition of buffy coat cells did not significantly influence graft rejection. The development of grades II to IV acute graft v host disease was associated with random donor platelet refractoriness (P less than .05) and donor/recipient sex differences (P less than .05). Patients at highest risk for chronic graft v host disease were those patients who developed significant acute graft v host disease (P less than .01) and who received buffy coat infusions (P less than .025). All patients who were untransfused had a negative relative response and were not refractory to random donor platelets.

Acute Disease↗
PubMed1986

Decreased incidence of marrow graft rejection in patients with severe aplastic anemia: changing impact of risk factors.

Patients with severe aplastic anemia were conditioned with cyclophosphamide (200 mg/kg) and given marrow grafts from HLA-identical family members. Among 233 patients transplanted, 225 survived greater than or equal to 14 days and could be evaluated for engraftment. Forty-four of the 225 rejected their graft; 33 of these died and 11 survive. One hundred eighty-one patients had sustained engraftment; of these, 46 died and 135 survived. Binary logistic regression analyses revealed five risk factors for graft rejection: year of transplant, a large number of platelet transfusions, a positive relative response in mixed leukocyte culture, a low marrow cell dose, and omission of donor buffy coat cell infusion for transfused patients. These data show that patients transplanted recently had a lower likelihood of graft rejection than did patients transplanted in earlier years. Conceivably, this was related to changes in transfusion practices, but other factors as yet unidentified are likely to be involved. The data confirm that the largest possible number of marrow cells should be transplanted. Although the difference in the incidence of graft rejection between untransfused and transfused patients was not significant, it should be noted that transfused patients were given buffy coat cells. Because the addition of buffy coat cells results in a higher incidence of chronic graft-v-host disease (GVHD), it is still desirable to transplant patients with marrow alone early in their course before they have been transfused.

Anemia, Aplastic↗
PubMed1985

Alloreactive T cell responses between HLA-identical siblings. Detection of anti-minor histocompatibility T cell clones induced in vivo.

Cytotoxic T cell (CTL) clones were isolated from the peripheral blood of a patient 13 days following marrow transplantation from her HLA-identical brother. Nineteen of the clones were specifically reactive with host--but not donor--cells, but one clone was reactive with donor but not host cells. Family studies using the 19 clones showed reactivity patterns consistent with three non-HLA, minor histocompatibility antigens (minor-HA). The frequency of reactivity on a large panel of unrelated cells indicated a relatively limited degree of polymorphism. Each of the clones was restricted in its activity by a class I epitope common to HLA-B7, B27, and B40. These data demonstrate that by clonal analysis it is possible to identify in vivo antidonor and antihost alloreactive CTL clones directed against HLA determinants following marrow transplantation.

Antibodies, Monoclonal↗
PubMed1984

The HLA-DR4 family of haplotypes consists of series of distinct DR and DS molecules.

Among DR4-associated HLA-D antigens, distinct and consistent structural variations were found for the products of two human "Ia-like" loci, DR and DS. Analysis of neuraminidase-treated immunoprecipitated DR molecules from 15 HLA-DR4-associated HLA-D homozygous B-lymphoblastoid cell lines by two dimensional polyacrylamide gel electrophoresis identified five distinct DR beta chains. In addition, gel analysis of immunoprecipitated DS molecules identified three distinct DS beta chains. Altogether, five distinct DR4 haplotypes were defined according to the observed structural diversity of the DR and DS beta chains. These gene products presumably contribute the dominant polymorphisms recognized by T cells in mixed lymphocyte reaction (MLR). Thus, these studies indicate that the serologic specificity known as HLA-DR4 is not a single haplotype, but a determinant present on products of individual loci arrayed into distinctly different haplotypes. These findings suggest that distinct products of individual loci, rather than conventional HLA specificities defined by alloimmune sera, may represent the genetic markers relevant to HLA-D/DR associated diseases.

Antibodies, Monoclonal↗
PubMed1984

Multiple Ia-like molecules characterize HLA-DR2-associated haplotypes which differ in HLA-D.

Two-dimensional gel electrophoresis of immunoprecipitated human Ia-like molecules was used to investigate the structural relationship between HLA-D and HLA-DR2. Eight different lymphoblastoid lines derived from HLA-DR2-associated homozygous typing cells, representing five distinct HLA-D clusters, were compared. Two or three distinct beta chain molecules from DR-like loci were identified in the DR2 homozygous cell lines studied. Furthermore, one of these molecules was present in all lines tested, while the others were highly variable. The electrophoretic mobility of these variable DR-like molecules correlated very well with HLA-D typing studies, suggesting that the HLA-DR specificity and the HLA-D specificity on these DR2 cells may be present on separate, but related, molecules.

Alleles↗