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W Heath

Publications and source records attributed to W Heath.

12 recordsLinked to original sources
PubMed1996

A subclass of dendritic cells regulates the response of naive CD8 T cells by limiting their IL-2 production.

Previous work indicated that a subclass of mouse spleen dendritic cells (DC), those bearing CD8alpha, expresses the Fas ligand and restricts peripheral CD4 T cell responses by initiating Fas-mediated apoptosis. To determine whether a similar regulation applies to CD8 T cells, they were purified from normal or from TCR-transgenic mice, and then cultured with purified splenic CD8+ DC or CD8- DC presenting either alloantigens or the specific Ag for the TCR transgene. In all systems studied, the proliferative response of CD8 T cells was markedly less on stimulation with CD8+ DC compared with conventional CD8- DC. However, the basis of this restricted proliferation in response to CD8+ DC was totally different for CD8 T cells than for CD4 T cells. The reduced proliferation of CD8 T cells occurred later in the response than with CD4 T cells. In contrast with CD4 T cells, the reduced proliferation of CD8 T cells occurred even with T cells from Fas-deficient Ipr mice, or with DC from Fas ligand-deficient gld mice, indicating that Fas-induced apoptosis was not involved. Also, in contrast with CD4 T cells, the reduced proliferation of CD8 T cells was completely reversed by the addition of exogenous IL-2. Furthermore, cultures of CD8 T cells with CD8+ DC were found to be deficient in IL-2 production. Accordingly, although CD8+ DC are very efficient at stimulating CD8 T cells into cell division, they are deficient at stimulating endogenous cytokine production. The implications of these different DC regulatory systems are discussed.

Animals↗
PubMed1995

Intermediate steps in positive selection: differentiation of CD4+8int TCRint thymocytes into CD4-8+TCRhi thymocytes.

The differentiation potential of putative intermediates between CD4+8+ thymocytes and mature T cells has been examined. Such intermediate populations were sorted, in parallel with CD4+8+ thymocytes, from three types of C57BL/6 mice: major histocompatibility complex (MHC) class II-deficient mice, mice transgenic for an alpha/beta T cell receptor (TCR) restricted by class I MHC and normal mice. The sorted populations were then transferred into the thymus of nonirradiated C57BL/Ka mice differing in Thy 1 allotype, and the progeny of the transferred cells were analyzed 2 d later. Surprisingly, with all three types of donor mice, a major proportion of the CD4+8intTCRint-derived progeny were found to be CD4-8+TCRhi cells, thus delineating a new alternative pathway for development of the CD8 lineage. In contrast, the transfer of CD4int8+TCRint thymocytes produced CD4-8+TCRhi cells but no significant proportion of CD4+8-TCRhi cells, suggesting that there is no equivalent alternative pathway for the CD4 lineage. The results negate some of the evidence for a stochastic/selective model of lineage commitment, and point to an asymmetry in the steps leading to CD4-8+ versus CD4+8- T cells.

Animals↗
PubMed1995

Split tolerance in spleen chimeras.

Transferring small doses of T cells to heavily irradiated F1 mice expressing isolated MHC class I or class II differences invariably leads to rapid death from graft-vs-host disease (GVHD). Paradoxically, GVHD is mild or absent when irradiated F1 mice are reconstituted with large doses of unseparated parental strain spleen cells. This applies when bulk populations of B6 spleen cells are transferred to irradiated class II-different (B6 x bm12)F1 mice or class I-different (B6 x bm1)F1 mice. In this study, we examined whether the donor T cells in long-term spleen chimeras become tolerant to host MHC Ags. On the basis of skin-allograft rejection and induction of GVHD on adoptive transfer, the results show that the donor T cells display strong tolerance to host antigens; this applies to CD4+ cells in class II-different chimeras and to CD8+ cells in class I-different chimeras. In marked contrast to the profound tolerance seen by these in vivo parameters, little or no tolerance is observed in standard in vitro assays. The results illustrate that typical in vitro tests for alloreactivity are an imprecise guide to physiologic tolerance of T cells in vivo.

Animals↗
PubMed1992

Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation.

In the present study, we have measured protein kinase C (PKC) specific activities and total diacylglycerol (DAG) level in the aorta and heart of rats, which showed that after 2 weeks of streptozotocin (STZ)-induced diabetes, membranous PKC specific activity and total DAG content were increased significantly by 88% and 40% in the aorta and by 21% and 72% in the heart, respectively. Hyperglycemia was identified as being a causal factor since elevated glucose levels increased DAG levels in cultured aortic endothelial and smooth muscle cells. Analysis by immunoblotting revealed that only alpha and beta II PKC isoenzymes are detected in these two tissues and vascular cells among those studied. In STZ-induced diabetic rats, beta II isoenzyme is preferentially increased in both aorta and heart, whereas PKC alpha did not change significantly. The increases in membranous PKC specific activity and DAG level are observed in both spontaneous diabetes-prone diabetic BB rats as well as in STZ-induced diabetic BB and Sprague-Dawley rats, which persisted for up to 5 weeks. After 2 weeks of diabetes without treatment, the normalization of blood glucose levels for up to 3 weeks with islet cell transplants in STZ-induced diabetic BB rats reversed the biochemical changes only in the heart, but not in the aorta. These results suggest that PKC activity and DAG level may be persistently activated in the macrovascular tissues from diabetic animals and indicate a possible role for these biochemical parameters in the development of diabetic chronic vascular complications.

Animals↗
PubMed1992

Does interleukin-2 abrogate peripheral immunologic self-tolerance in vivo?

Transgenic mice that constitutively expressed murine IL-2 in islet beta cells (RIP-IL-2 mice) had pancreatitis from birth which resolved into a peri- and intra-islet infiltrate in adult animals. In spite of the impressive infiltration, these mice did not develop autoimmunity to islet antigens. Neither was autoimmunity found to extrathymic H-2Kb molecules known to induce tolerance by a peripheral mechanism, when IL-2 and H-2Kb were coexpressed in the beta cells. Apparently, IL-2 can only act on activated T cells and is unable to reverse tolerance in T cells that have been made unresponsive through inappropriate antigen presentation in our system.

Animals↗
PubMed1991

The T cell receptor V alpha 11 gene family. Analysis of allelic sequence polymorphism and demonstration of J alpha region-dependent recognition by allele-specific antibodies.

Allelic polymorphism in TCR loci may play an important role in shaping the T cell repertoire and in disease susceptibility. We have used a combination of antibody and sequence analysis to investigate polymorphism in the murine V alpha 11 family. Two different antibodies have been analyzed that recognize particular V alpha 11 family members of the V alpha b and V alpha d haplotypes. One antibody shows J alpha dependency, suggesting a conformational element to the epitope. Investigation of the anti-V alpha 11 staining pattern on different mouse strains indicates that there is a marked influence of MHC haplotype on V alpha 11 selection and that V alpha 11 is preferentially expressed on CD4+ cells. Sequence analysis of V alpha 11 genes from the V alpha a, V alpha b, and V alpha d haplotypes shows two potential regions for the haplotype-specific epitopes. The relatedness of the different V alpha 11 family members from different haplotypes suggests that the V alpha 11.1/11.2 gene duplication is relatively recent, but that V alpha 11.3 separated much earlier. Differences between V alpha 11.3 and V alpha 11.1/11.2 are concentrated in the putative complementarity determining regions (CDR), whereas differences between alleles are not clearly clustered. However, the V alpha 11.1a and V alpha 11.1d alleles differ from V alpha 11.1b and V alpha 11.2b in CDR1. A V alpha 11.2-expressing anti-cytochrome c T cell has the same V-J junction as a V alpha 11.1-bearing cell with a similar fine specificity, indicating that V alpha 11.1b and V alpha 11.2b do not contribute different Ag specificities.

Alleles↗
PubMed1990

Substitutions at the P2' site of gag p17-p24 affect cleavage efficiency by HIV-1 protease.

Heptapeptide substrates containing a single amino acid substitution at the p2' position of the gag p17-p24 junction (S-Q-N-Y-P-X-V where X = G, A, L, I, F, and W) were compared as substrates for HIV-1 protease. Binding of the Ile-, Leu-, and Ala- containing peptides was about equal although hydrolysis was 20-fold lower for the Ala and Leu peptides compared to Ile. Insertion of Gly or Phe at the p2' position resulted in significantly lower cleavage of the peptide while a Trp-containing peptide was not cleaved. These data suggest that a relatively small hydrophobic amino acid is important for hydrolysis and binding at this site. Structure-activity studies such as those described here may be useful in the design of specific inhibitors for HIV-1 protease.

Amino Acid Sequence↗
PubMed1987

Felodipine compared to prazosin as additional therapy to a beta-blocking drug.

Felodipine was compared with prazosin in patients with essential hypertension whose blood pressure was not controlled by a beta-blocking drug. One hundred patients with a supine diastolic blood pressure greater than or equal to mm Hg after 4 weeks or more on a beta-blocking drug and placebo were randomly assigned to felodipine or prazosin tablets. The drugs were titrated at 2-week intervals if diastolic BP was greater than or equal to 90 mm Hg. Titration steps of felodipine were 5, 10, 20 mg b.i.d. and of prazosin were 1, 2, 4 mg b.i.d. The fall in blood pressure with felodipine 32/21 mm Hg was greater than the fall with prazosin 16/12 mm Hg (p less than 0.001); 36 patients achieved a diastolic blood pressure of less than 90 mm Hg with felodipine, which was a significantly greater number than the 20 patients who obtained such a level with prazosin (p less than 0.01). Both drugs were well tolerated, but more patients complained of vascular type side effects (flushing, peripheral edema) with felodipine than with prazosin. There was significant weight gain with prazosin but not with felodipine. Felodipine was shown to be a well-tolerated, effective antihypertensive agent when used with a beta-blocking drug and to be suitable for people with hypertension who fail to be controlled with a beta-blocking drug.

Adrenergic beta-Antagonists↗
PubMed1985

In vivo and in vitro analyses of the immunogenicity of B16 melanoma cells.

In vitro grown B16, an H-2b melanoma cell line, was found to kill B10 (H-2b), B10.BR (H-2k), CBA (H-2k), and BALB/c (H-2d) but not B10.D2 (H-2d) mice. BALB/c mice could be protected against a lethal dose of B16 by co-administration of H-2b spleen or peritoneal exudate cells, suggesting B16 was susceptible to an immune response but unable to induce it. However, evidence for the immunogenicity of B16 tumour in vivo was shown in two ways--(i) by immunization with irradiated B16 before lethal tumour challenge, and (ii) by demonstration of specific immunity in BALB/c mice which survived a low dose of viable B16 tumour. The resistance of most B10.D2 mice to doses of B16 tumour which were lethal to four other strains of mice was also compatible with the immunogenicity of B16 in vivo. By contrast, B16 was unable to induce a primary Tc-cell response in vitro but was able to induce a secondary response. The significance of these results for theories of T cell immunity to foreign tissue and for improving immunogenicity of tumours is discussed.

Animals↗