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Biomedical subjects

M S Pollack

Publications and source records attributed to M S Pollack.

At least 37 records · Page 2Linked to original sources
PubMed1991

DNA amplification for DQ typing as an adjunct to serological prenatal HLA typing for the identification of potential donors for umbilical cord blood transplantation.

It has recently been demonstrated that umbilical cord blood from genotypically human leukocyte antigen (HLA)-matched donors can provide sufficient numbers of progenitor cells for hematopoietic reconstitution. This technique has been successfully applied in the treatment of two children affected with Fanconi anemia (FA). Fetal cells from the potential sibling donors were first tested to determine that the fetus was not affected with FA. Unaffected fetal cells were then tested for HLA type. Cord blood from compatible donors can be harvested at birth and used immediately or frozen for subsequent use in hematopoietic reconstitution. We now show that fetal cell DNA amplification and hybridization for DQ typing can be an important adjunct procedure to verify serologically determined HLA class II types and/or to establish class II haplotype identity with the affected sibling.

Blood Transfusion↗
PubMed1991

Tight linkage of the gene for spinocerebellar ataxia to D6S89 on the short arm of chromosome 6 in a kindred for which close linkage to both HLA and F13A1 is excluded.

A locus for an autosomal dominant form of spinocerebellar ataxia (SCA1) has been assigned to the short arm of chromosome 6 on the basis of linkage to the major histocompatibility system (HLA). In this study of a five-generation American black family, close linkage between the disease locus and both HLA and the coagulation factor XIIIA (F13A1) locus was excluded, and lod scores for all locations of the disease locus between HLA and F13A1 were less than -1.4. These results suggest that the locus causing spinocerebellar ataxia in this family is not in this region. However, the disease locus was found to be closely linked to a microsatellite polymorphism, D6S89, which is between HLA and F13A1. The maximum lod score for SCA1 and D6S89 is 4.90 at a recombination fraction of 0, both in males and in females. These data show that exclusion of close linkage to the HLA complex and F13A1 in a kindred with spinocerebellar ataxia does not rule out the possibility that the disease locus in that family is on 6p. Accordingly, all families segregating a dominantly inherited ataxia should be evaluated for linkage to D6S89, to determine whether the locus causing the disease is SCA1.

Adolescent↗
PubMed1990

HLA-D region genes associated with autoantibody responses to histidyl-transfer RNA synthetase (Jo-1) and other translation-related factors in myositis.

Myositis has been associated with HLA-B8 and DR3, especially in white patients with polymyositis and serum anti-Jo-1 antibodies. Twenty-eight patients with myositis and serum translation-related autoantibodies anti-Jo-1, anti-PL-7, anti-PL-12, anti-KJ, and anti-SRP were studied for HLA class II specificities by Southern blotting with HLA-DR beta, DQ beta, and DQ alpha probes. The association of HLA-DR3 (DRw17) with anti-Jo-1 antibodies in white myositis patients was confirmed (P = 0.003, relative risk 8.9). However, HLA-DRw52 haplotypes, regardless of subtype, were present in all of the white and black patients with serum anti-Jo-1 and other translation-related autoantibodies. Moreover, one anti-Jo-1 positive patient had HLA-DRw8, an HLA-DRw52 haplotype on which the DR beta 3 gene has been partially deleted. No HLA-DQ specificity or allele was common to all patients. The HLA-DR3, DR5, DRw6, and DRw8 haplotypes, which bear the HLA-DRw52 specificity, share the most homology in the DR beta 1 first hypervariable region at amino acid positions 9-13. Thus, this DR beta 1 region appears to be the most likely candidate "epitope" for translation-related autoimmune responses in inflammatory myositis.

Alleles↗
PubMed1990

Autoimmune T cell recognition of human acetylcholine receptor: the sites of T cell recognition in myasthenia gravis on the extracellular part of the alpha subunit.

Autoimmune T cell lines were prepared from peripheral blood lymphocytes of five myasthenia gravis patients by passage in vitro with an equimolar mixture of 18 overlapping synthetic peptides corresponding to the entire extracellular region (residues alpha 1-210) of the alpha subunit of human acetylcholine receptor (AChR). The proliferative responses of the human AChR-specific T cell lines to each of the individual peptides were determined. It was found that the profiles of the peptides recognized by the T cells were different among the five T cell lines, consistent with genetic control operating at the recognition site level. However, other regulatory influences may play important roles in the triggering of the autoimmune responses. These results suggest that the pathogenesis of this autoimmune disease is variable at the cellular-molecular level.

Animals↗
PubMed1990

Prenatal identification of potential donors for umbilical cord blood transplantation for Fanconi anemia.

Reported here are studies of Fanconi anemia fetal cells that led to the first use of umbilical cord blood for hematopoietic reconstitution in a clinical trial. Prenatal diagnosis and HLA typing were performed in fetuses at risk for Fanconi anemia (FA) to identify, prior to birth, those that were unaffected with the syndrome and were HLA-identical to affected siblings. Umbilical cord blood was harvested at the delivery of these infants; assays of progenitor cells indicated the presence of colony-forming units-granulocyte-macrophage (CFU-GM) in numbers similar to those of bone marrow CFU-GM that are associated with successful engraftment in HLA-matched allogeneic bone marrow transplantation. The possibility that umbilical cord blood from a single individual can be used as an alternative to bone marrow for hematopoietic reconstitution has now been demonstrated by the successful engraftment of two patients with FA. Progenitor cell assays of umbilical cord blood collected at the birth of a child affected with FA, who had been misdiagnosed on the basis of chorionic villus sampling (CVS) studies, indicated a profound deficiency in colony formation, consistent with previously reported abnormalities in the growth of FA cells in vitro. These results suggest that the hematopoietic disorder in FA is related to an underlying problem with cell proliferation.

Blood Cell Count↗
PubMed1989

Relationship of hypergammaglobulinemia, circulating immune complexes, and histocompatibility antigen profiles in patients with cystic fibrosis.

Among patients with cystic fibrosis (CF), those in the subset who develop hypergammaglobulinemia and circulating immune complexes often have relatively severe disease and a decreased likelihood of survival. Because Fc receptors have an important role in the removal of immune complexes and because defective Fc receptor function has been associated with inheritance of the histocompatibility antigens HLA DR2 and HLA DR3, we postulated that HLA DR2 and/or HLA DR3 might be genetic markers for this subset of patients with CF. However, in a group of 20 carefully documented patients with CF, we found no association of HLA DR2 or HLA DR3 with serum immunoglobulin, immune complex levels, or evidence of rapidly progressive disease.

Adolescent↗
PubMed1988

Spinocerebellar ataxia: variable age of onset and linkage to human leukocyte antigen in a large kindred.

We studied a seven-generation kindred with autosomal dominant spinocerebellar ataxia (SCA) to assess linkage relationships to multiple human leukocyte antigen (HLA) loci on the short arm of chromosome 6. Age at onset, clinical features, and course of the disease are described. Although the mean age of onset was 34 years in this family, in 6 of 41 affected individuals onset was below 15 years of age and was accompanied by the unique clinical features of mental retardation and rapid progression of disease. Linkage studies were performed on 93 individuals, and the results show strong evidence for linkage of the SCA locus to the HLA loci. A maximum logarithm of the odds score of 5.83 was found at a recombination fraction of 0.12. This is the first documentation of childhood onset in the HLA-linked form of SCA.

Adult↗
PubMed1988

The detection of conventional class I and class II I-E homologue major histocompatibility complex molecules on feline cells.

The presence on feline cells of class I and class II I-E type major histocompatibility complex (MHC) homologues was demonstrated using cross-reacting monoclonal antibodies (mAb). The feline class I antigen homologues were detected with both immunofluorescent and biochemical techniques, using the anti-human class I mAb W6/32. The class I antigens were detected on in vitro cultured feline fibroblasts and lymphoid cells, but not on fresh lymphoid cells, apparently as a result of the association of bovine beta-2 microglobulin with feline class I heavy chains which generated the determinant(s) recognized by mAb W6/32. Class II I-E-like molecules could be detected with immunofluorescent techniques using the species cross-reactive anti-mouse I-E antibody 40D only when peripheral blood mononuclear cells were activated, for example, with the mitogens staphylococcus enterotoxin A or lipopolysaccharide. The predominant expression of I-A-like molecules by resting class II-positive feline cells could explain some of the functional difference we have seen in comparison with those of most other mammalian species.

Animals↗
PubMed1988

The HuT series of 'carcinogen-transformed' human fibroblast cell lines are derived from the human fibrosarcoma cell line 8387.

In 1977 Kakunaga reported the carcinogen-induced transformation of the diploid human fibroblast cell line KD into focus-forming, morphologically altered cells. Cell lines were developed from 15 individual foci. These exhibited an infinite lifespan in culture and all those that were tested (7/7) formed malignant tumors (sarcomas) in athymic mice. The existing cell lines, designated HuT-11 to HuT-14, have been studied intensively during the past decade as examples of human fibroblasts malignantly transformed by treatment with a chemical carcinogen, 4-nitroquinoline-1-oxide. Recently, in comparing the HuT-11, HuT-12 and HuT-14 cell lines with KD cells, McCormick and Maher (Mutat. Res., 199, 273-291, 1988) found evidence that the malignant cells could not have been derived from the latter. But, this did not rule out the possibility that as the target cells for his original study of carcinogen-induced transformation, Kakunaga had inadvertently used cells from some other, unidentified normal individual. Since the donor of such cells would not be known and the original cell line was not available, it would be impossible to determine the degree of identity between such a target cell line and the HuT cell lines. However, in the course of examining methods for such testing, we recently became aware that the isozyme pattern of these HuT cell lines was identical to that of the human fibrosarcoma-derived cell line 8387 established in 1966. We here report that the HuT cell lines and the 8387 cell line also exhibit an identical series of HLA determinants and identical restriction fragment length polymorphisms (RFLPs). Assuming that each of these three assays measures independently inherited characteristics, the chance that an unrelated donor of the fibroblasts that gave rise to the HuT cell lines happened to possess characteristics identical to those of the patient whose fibrosarcoma gave rise to the 8387 cell line is 1 x 10(-8). Therefore, we conclude that 8387 cells are the source of the malignant cells designated HuT from Kakunaga's original transformation experiment. Additional RFLP analysis, using a probe made from M13 bacteriophage DNA which detects a hyperpolymorphic 'minisatellite' pattern in human DNA, also showed that DNA from HuT-14 cells and from 8387 cells exhibit identical banding patterns, indicating that the cell lines were taken from the same individual. The latter banding patterns differed from that observed with DNA from KD cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Gamma interferon induces detectable serological and functional expression of DR and DP but not DQ antigens on cultured amniotic fluid cells.

Cultured amniotic fluid cells, which are used for HLA typing studies for the prenatal diagnosis of HLA linked diseases and for prenatal determination of paternity, usually contain mixtures of fibroblastic and epithelioid cells. Cells of both types lack constitutive expression of HLA class II antigens, but these can be induced by pretreatment with gamma interferon. Both serological and functional studies indicate that detectable levels of DR and DP but not DQ antigens can be thereby induced. DR and DP cannot, however, be induced on chorionic villus cells.

Amniotic Fluid↗
PubMed1988

Uniparental disomy as a mechanism for human genetic disease.

A female with cystic fibrosis and short stature was investigated for molecular or cytogenetic abnormalities that might explain the combined phenotype. Analysis with polymorphic DNA markers indicated that the father did not contribute alleles to the propositus for markers near the CF locus or for centromeric markers on chromosome 7. High-resolution cytogenetic analysis was normal, and the result could not be explained on the basis of nonpaternity or a submicroscopic deletion. All of the data indicate that the propositus inherited two identical copies of maternal sequences for much or all of chromosome 7. The occurrence of uniparental disomy could be explained by models postulating postfertilization error, gamete complementation, monosomic conception with subsequent chromosome gain, or trisomic conception followed by chromosome loss. Uniparental disomy in an individual with a normal chromosome analysis is a novel mechanism for the occurrence of human genetic disease.

Adolescent↗
PubMed1987

Insulin-specific human T cells. Epitope specificity, major histocompatibility complex restriction, and alloreactivity to a diabetes-associated haplotype.

T cells from an insulin-treated diabetic (ML, HLA DR1, w6) were stimulated in vitro with insulin, cloned at limiting dilution, and examined for their fine specificity and genetic restriction. T cell lines (TCL) derived from beef insulin stimulation were highly specific for epitopes on beef insulin, whereas pork insulin stimulation generated T cells that recognized determinants shared with beef insulin. Included among TCL reactive with pork insulin is one line (P2/9) that is autoreactive with human insulin. Antigen-presenting cells of known HLA type and monoclonal antibodies directed at class II major histocompatibility complex antigens were used to confirm the role of HLA-DR in restricting the response of insulin immune T cells. No preference or determinant selection within the donor's haplotypes was identified because either DR1 or DRw6 antigen-presenting cells could present the A loop of beef insulin. A TCL that recognized the A loop of beef insulin in association with DR1 was also alloreactive to HLA DR3, or a molecule closely linked to it, in the absence of insulin. A second T cell clone with insulin specificity and alloreactivity was also derived by allo stimulation of the donor's cells with DR3+ cells. When tested with a series of DR3+ stimulator cells, the alloreactivity was directed at diabetes-associated haplotypes. These data show that the T cell repertoire for insulin of a single diabetic donor encompasses that of multiple inbred animal strains and includes fine specificity for one to two amino acids, recognition of autologous insulin, and cross-reactivity with an allogeneic major histocompatibility complex antigen.

Animals↗
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↗