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Biomedical subjects

S Shaw

Publications and source records attributed to S Shaw.

At least 397 records · Page 22Linked to original sources
PubMed1984

Primary in vitro generation of cytotoxic cells specific for human minor histocompatibility antigens between HLA-identical siblings.

A limiting dilution culture system was developed for the primary in vitro detection of human minor histocompatibility antigens by cytotoxic T lymphocytes (CTL). CTL were generated in primary in vitro culture between two HLA-identical sibling pairs and propagated as stable CTL lines. Population and family studies indicate that these CTL lines recognize minor histocompatibility antigens in an HLA-restricted manner. The antigen recognized by one CTL line is detected on six (out of 37) HLA-B7-positive donors but not on 32 HLA-B7-negative donors. The cytotoxicity of this CTL line is mediated by T3+, T8+ effector cells. The antigen detected by this CTL population is different from all known human minor histocompatibility antigens. The data of this study, like those in the mouse system, suggest that a suppressor cell is diluted out in a limiting dilution culture, which allows the activation of the CTL precursors.

Cytotoxicity Tests, Immunologic↗
PubMed1983

A novel HLA-D/DR-like antigen specific for human B lymphoid cells. Biochemical evidence for similarity to but nonidentity with known HLA-D/DR antigens.

The polymorphic human B cell-specific antigen, 33.1, detected by a murine monoclonal antibody, was compared by genetics and structural analysis with known human Ia antigens from a panel of DR homozygous Epstein-Barr virus-transformed B lymphoblastoid cell lines. Cells homozygous for DR 1, 2, 4, 5, and w6 were positive, while cells that are DR3,3 or DR7,7 usually failed to express this antigen. Mutant DR null, DC/MB-positive cells were 33.1 positive while DR null, DC/MB-negative cells failed to express this antigen, suggesting the segregation of 33.1 with the DC antigen. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis revealed that 33.1 alpha and beta chains were of lower molecular weights than the DR alpha and beta chains isolated from the same cell line. Partial N-terminal amino acid sequence analyses were carried out for the heavy and light chains of the 33.1 antigen radiolabeled with [3H] phenylalanine. The results of these analyses, in conjunction with previous data on tissue distribution, indicate that the 33.1 antigen is a non-DR but Ia-like antigen closely related to the previously defined I-A homologues, DC and DS.

Amino Acid Sequence↗
PubMed1983

In vitro generation of cytotoxic cells specific for human minor histocompatibility antigens by lymphocytes from a normal donor potentially primed during pregnancy.

A normal female donor (H9) is described, whose cells generate strong cytotoxicity against a human minor histocompatibility antigen in vitro. These cytotoxic T lymphocytes are generated after secondary restimulation with cells from an HLA-A, -B, -C, and -DR-matched donor and are HLA restricted (HLA-B7). No other donor could be identified whose cells responded to this antigen. The two children of donor H9 are virtually HLA identical to her and one of the children expresses the relevant minor histocompatibility antigen. These data suggest that priming in vivo during pregnancy has facilitated cytotoxic T cell response to human minor histocompatibility antigens in vitro.

Cytotoxicity, Immunologic↗
PubMed1983

SB-restricted presentation of influenza and herpes simplex virus antigens to human T-lymphocyte clones.

The HLA-D region of the human major histocompatibility complex (MHC) has been shown to be homologous to the murine I region in terms of both structure and function. Both regions encode class II MHC molecules which restrict T-lymphocyte interactions with antigen-presenting cells. We have recently described the MHC restriction and antigen specificities of human T-lymphocyte clones directed at strain A influenza virus. The majority of T-lymphocyte clones recognized antigen in the context of cell surface interaction products encoded by HLA-D/DR genes. However, a few clones recognized antigen presented by cells histoincompatible for D/DR antigens. We report here that some of these clones recognized viral antigens in association with antigens encoded by genes identical with or closely linked to the recently described secondary B-cell (SB) locus of the MHC. This is the first report that SB-restricted antigen recognition may form an integral part of normal, human immune responses.

Antigens, Viral↗
PubMed1983

Mapping SB in relation to HLA and GLO1 using cells from first-cousin marriage offspring.

A newly defined leukocyte antigen system, the secondary B-cell (SB) system, was shown to be linked to HLA. The SB marker has been investigated in lymphocyte donors presumed to be genetically homozygous for HLA-A through HLA-D/DR by virtue of descent from a first-cousin marriage and of phenotypic homozygosity for these HLA markers. Of 19 donors, 3 were found to be heterozygous for SB. Studies of the families of these three donors could not distinguish with certainty whether the heterozygosity resulted from SB/DR recombination or from "pseudohomozygosity" for HLA-A through -D/DR by inheritance of two genetically unrelated but similar haplotypes. However, our data favored the occurrence of SB/DR recombination with a meiotic distance perhaps as large as 3.3 cMorgan. Recombinations were identified which mapped SB between HLA-B and GLO1. These studies demonstrate the usefulness of cells from first-cousin marriage offspring in mapping a polymorphic genetic system.

B-Lymphocytes↗
PubMed1983

Homogeneity of the HLA-linked SB2 and SB3 specificities demonstrated by cloned alloreactive T cells.

The HLA-linked "SB" antigens comprise a new segregant series of B-cell alloantigens mapping between HLA-DR and glyoxylase. They can be detected by secondary proliferative responses of lymphocytes primed against HLA-A, B, C, DR, MB- and MT-compatible stimulators. To asses genetic complexity of the SB-gene region, alloreactive cloned T-cell lines were derived from four reagents detecting specificities designated SB2 and SB3. In two families, products detected by seven different clones segregated with the HLA haplotypes bearing the SB2 or SB3 specificities as recognized by the uncloned reagents. There were no indications that the cloned cells differed from the oligoclonal reagents in their fine specificity. In contrast to previous results with an SB4-associated specificity, in population studies of 25 SB2-positive and 23 SB3-positive donors, no evidence could be found for subtypes of either specificity. Thus, even at the level of recognition by cloned T-cells, both SB2 and SB3 appear to be remarkably homogeneous in the population.

Clone Cells↗
PubMed1983

Depressed hepatic glutathione and increased diene conjugates in alcoholic liver disease. Evidence of lipid peroxidation.

The role of lipid peroxidation in the pathogenesis of alcoholic liver disease has been a subject of controversy. In order to study this question we measured hepatic glutathione and diene conjugates in liver biopsies from 16 alcoholics with different stages of liver injury and 8 nonalcoholics with liver disease. Patients with alcoholic liver disease were found to have decreased hepatic glutathione compared to patients with liver disease unrelated to alcohol (22.1 +/- 2.5 vs 33.5 +/- 4.6 nmol/mg protein, P less than 0.05). The decrease in glutathione was accompanied by an increase in diene conjugates in hepatic lipids (3.37 +/- 0.14 vs 2.26 +/- 0.21 OD at 232 nm/mg lipid, P less than 0.001). The changes were present in all stages of alcoholic liver damage including fatty liver but unrelated to nutritional status in these patients. They support the concept that lipid peroxidation may be an important mechanism in the pathogenesis of alcoholic liver disease.

Alkadienes↗
PubMed1983

Comparison of animal and vegetable protein sources in the dietary management of hepatic encephalopathy.

Theoretical considerations based on amino acid metabolism in patients with hepatic encephalopathy as well as some limited patient studies had led to the proposal that dietary protein derived from a vegetable source may be better tolerated and more efficacious in such patients. However, studies in normal humans have revealed that vegetable protein is not as nitrogen sparing as animal protein. This prompted us to study under metabolic ward conditions the effects of vegetable and animal protein sources in patients with hepatic encephalopathy with respect to mental status, nitrogen balance, and plasma amino acids. No significant differences regarding any of the parameters studied was observed in relationship to the source of dietary protein, but compliance to the regimen was more difficult with the vegetable protein diet.

Amino Acids↗
PubMed1983

Plasma amino acids in the alcoholic: nutritional aspects.

Plasma amino acid abnormalities are frequently reported in alcoholics, with the most common abnormalities being those of depressed branched chain amino acids (BCAA) and increased aromatic amino acids. The depression in branched chain amino acids is due to multiple factors including portal-systemic shunting, hyperinsulinemia, hyperglucagonemia (all due to advanced liver disease) as well as dietary deficiency. alpha-Amino-n-butyric acid is a nonessential amino acid derived primarily from the catabolism of methionine, threonine, and serine. Increased levels due to chronic alcohol consumption may reflect altered glutathione metabolism and lipid peroxidation due to alcohol and may be used empirically as a biochemical marker of heavy drinking. The high levels of aromatic amino acids such as tyrosine and tryptophan as well as their breakdown products may be due to impaired hepatic metabolism and appear to play a role in the pathogenesis of hepatic encephalopathy. The effects of high levels of aromatic amino acids may be potentiated by depressed BCAA; these normally compete with each other for CNS transport. Alterations in these amino acids may have implications for nutritional requirements for amino acids in these patients as well as therapeutic approaches.

Alcoholism↗
PubMed1983

Defective in vitro production of influenza virus-specific cytotoxic T lymphocytes in ataxia-telangiectasia.

Peripheral blood mononuclear cells (PBMC) from patients with ataxia-telangiectasia (A-T) were studied for their capacity to proliferate and to generate influenza virus-specific cytotoxic T lymphocytes (CTL) after in vitro stimulation with influenza A/Hong Kong (A/HK (H3N2)) virus. PBMC from 11 patients proliferated poorly to A/HK and 10 of the 11 patients failed to exhibit significant CTL effector activity when tested on influenza A/HK virus-infected autologous target cells. In contrast, PBMC from each of 18 simultaneously studied, unrelated normal individuals proliferated to A/HK and generated influenza-immune CTL. In each of the 10 A-T patients, deficient CTL activity was shown to be due to a lack of generation of CTL and not to target cell resistance to lysis, because the virtually infected target cells of the patients were lysed by parental influenza-immune CTL. Determinations of T cell numbers and existing serum antibody titers to H3N2 influenza virus suggest this nonresponsiveness cannot be simply explained by a lack of T cells or the absence of exposure to type A (H3N2) influenza virus. Studies in which CTL were generated in A-T plasmas and during co-culture of PBMC from an A-T patient and an MHC-matched sibling failed to demonstrate either plasma or cellular suppression as a mechanism for the lack of CTL production in A-T patients. This immune defect in the production of cytotoxic effector T cells may be a cause of the increased frequency of infections and neoplasms observed in A-T patients.

Adolescent↗
PubMed1983

Possible involvement of the T4 molecule in T cell recognition of class II HLA antigens: evidence from studies of proliferative responses to SB antigens.

The T4 molecule has been identified as a marker of human T cell differentiation, but the function of this molecule remains to be defined. We have investigated its possible functional involvement in T cell proliferative responses to class II HLA antigens encoded by the recently described SB locus. The responses of SB-primed cells (specific for each of four different SB antigens) were studied with the use of two proliferation-inducing stimuli, SB antigen or TCGF. The proliferative responses to both stimuli were found to be mediated by T4+, T8- cells. Monoclonal antibodies against some epitopes on the T4 molecule (OKT4A and OKT4B) substantially blocked antigen-stimulated proliferative responses; antibodies against other epitopes of the T4 molecule (OKT4, T4C, T4D) blocked less well. Inhibition of SB-specific proliferation by antibodies to the T4 molecule was maximal only when the antibodies were incubated with the responder cells before the addition of stimulator cells. Proliferative responses of SB-primed cells stimulated with TCGF alone were not inhibited by any of the OKT4-related antibodies, but were completely inhibited by the anti-Tac monoclonal antibody, which reacts with the TCGF receptor. These results lend further support for the hypothesis that the T4 molecule is involved in T cell recognition of and/or activation by class II HLA antigens. We suggest that 1) the T4 molecule binds a nonpolymorphic epitope on class II HLA molecules, and 2) this interaction may facilitate, but not be an obligate requirement for, T cell activation by class II antigens.

Adult↗
PubMed1983

Possible involvement of the OKT4 molecule in T-cell recognition of class II HLA antigens.

The possible functional involvement of the T4 molecule in T-cell recognition of and/or activation by the class II HLA antigens SB was investigated. SB antigens are encoded by the SB gene that (1) maps between GLO and HLA-DR; and (2) codes for Ia-like molecules that are similar to but distinct from HLA-DR molecules. Both cytotoxic T lymphocyte (CTL) and proliferative responses to SB antigens were found to be mediated by OKT4+, OKT8- cells. SB-specific cytotoxicity and proliferation were analyzed in the presence of a series of monoclonal antibodies (OKT4, 4A, 4B, 4C, and 4D) that react with distinct epitopes on the OKT4 molecule. SB1-, SB3-, and SB4-specific CTL were partially inhibited by OKT4A and 4B, but not by OKT4, 4C, and 4D. SB2-specific CTL were not substantially inhibited by any of the OKT4-related antibodies. SB-specific proliferative responses to SB1, 2, 3, and 4 were strongly blocked by OKT4A and 4B but not by OKT4, 4C, and 4D. Proliferative responses of SB-primed cells stimulated with TCGF-containing supernatants alone were not inhibited by any of the OKT4-related antibodies, but were completely inhibited by the anti-Tac monoclonal, which reacts with the TCGF receptor. These results indicate that: (1) the T4 marker may be expressed on most T cells, regardless of their function, that recognize allogeneic Ia or self-Ia plus foreign antigens; and (2) the T4 molecule may be involved in T-cell recognition of and/or activation by class II HLA antigens.

Adult↗
PubMed1982

Phosphoribosyl pyrophosphate synthetase and glutathione reductase in erythrocytes from hyperuricaemic and gout patients.

The enzymic activities of erythrocyte phosphoribosyl pyrophosphate synthetase (EC 2.7.6.1) and glutathione reductase (EC 1.6.4.2) have been measured in 54 primary gout patients, 35 individuals having hyperuricaemia and 51 healthy controls. Statistical analyses have shown a significant increase (p less than 0.01) in the enzymic activity of erythrocyte PRPP synthetase in both the hyperuricaemic and gout groups compared with the controls. No correlation between activity and age was found in any of the three clinical groups. A significant decrease (p congruent to 0.01) was found in the enzymic activity of red cell glutathione reductase in the gout group compared with the other two groups. The biochemical significance of the changes in enzymic activities of the two enzymes in primary gout is discussed.

Erythrocytes↗
PubMed1982

Alpha and beta chains of SB and DR antigens are structurally distinct.

Limited amino-terminal amino acid sequences of the HLA-controlled SB and DR antigens from the cell line PREISS (DR4/4, SB3/4) show differences in both the alpha and beta chain sequences of the two molecules. SB antigens, like DR antigens, appear to be homologues of the murine I-E antigens.

Amino Acid Sequence↗
PubMed1982

Possible involvement of the OKT4 molecule in T cell recognition of class II HLA antigens. Evidence from studies of cytotoxic T lymphocytes specific for SB antigens.

A recently described HLA gene, SB, which maps between GLO and HLA-DR, codes for Ia-like molecules that are similar to but distinct from HLA-DR molecules. Cytotoxic T lymphocytes (CTL) specific for SB1, SB2, SB3, and SB4 were compared with HLA-A2-specific CTL with respect to their surface expression of the T cell differentiation antigens OKT3, OKT4, and OKT8. All CTL activity was eliminated by treatment with OKT3 and C'. The SB-specific cytotoxicity was eliminated by OKT4 plus C' but not by OKT8 plus C'. In contrast, HLA-A2-specific killing was completely susceptible to treatment with OKT8 plus C' but not with OKT4 plus C'. Cytotoxicity was analyzed in the presence of OKT8 and a series of monoclonal antibodies (OKT4A, 4B, 4C, and 4D) that react with distinct epitopes on the OKT4 molecule. SB1-, SB3-, and SB4-specific CTL were partially inhibited by OKT4A and 4B (45-75%), whereas HLA-A2-specific CTL were partially inhibited by OKT8 (48-63%) but not by OKT4. SB2-specific CTL were not inhibited (less than 26%) by OKT8 or by any of the OKT4-related antibodies. These results suggest that the OKT4 marker may be expressed on most T cells that recognize allogeneic Ia or self Ia plus foreign antigens; OKT4+ cells do not appear to be functionally homogeneous in that they can act both as helper/inducer and cytotoxic cells. Models are proposed for the functional involvement of the OKT4 molecule in T cell-Ia antigen interactions.

Antibodies, Monoclonal↗