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Biomedical subjects

S D Miller

Publications and source records attributed to S D Miller.

At least 217 records · Page 12Linked to original sources
PubMed1984

Suppressor T cell circuits in contact sensitivity. II. Induction and characterization of an efferent-acting, antigen-specific, H-2-restricted, monoclonal T cell hybrid-derived suppressor factor specific for DNFB contact hypersensitivity.

This report defines a methodology for the production and characterization of an antigen-specific, monoclonal T cell hybrid-derived suppressor T cell factor (TsF) that suppresses the passive transfer of 2,4-dinitrofluorobenzene (DNFB) contact hypersensitivity. Fusion of T cells from BALB/c (H-2d) mice tolerized with syngeneic DNP-spleen cells to BW 5147 thymoma cells resulted in several hybrids that constitutively produce a soluble regulatory molecule. One of these hybrids, 26.10.2, was subsequently cloned, and its soluble factor was characterized with respect to its antigen specificity, biochemical nature, MHC restriction pattern, and identity of its target cell. 26.10.2 TsF suppresses the passive transfer of delayed-type hypersensitivity (DTH) mediated by DNP- but not trinitrochlorobenzene- or oxazalone-primed DTH T cells (TDH) after a 1 hr incubation at 37 degrees C. In contrast, 26.10.2 TsF had no suppressive effect on secondary in vitro DNP-specific T cell proliferative responses. 26.10.2 TsF therefore represents an antigen-specific factor with effector (efferent-acting) function. The monoclonal TsF was shown to consist of a two-chain, disulfide-bonded molecule, and to bear a receptor(s) specific for DNP and determinants encoded by the I region of the H-2 complex. Effector suppressive activity of 26.10.2 TsF was restricted by Class I H-2Dd determinants. One cellular target of this monoclonal factor was shown to be the DNP-specific TDH cell, because DNFB-primed lymph node cells from cyclophosphamide-pretreated donors (lacking Ts-auxiliary (Ts-aux) cells) were efficiently suppressed. The TsF appears to focus on passively bound, TDH receptor-associated, DNP-Class I determinants, as suggested by the observation that freshly prepared, but not overnight cultured, DNP-specific TDH cells were susceptible to suppression.

Animals↗
PubMed1983

Antibiotic-associated diarrhoea and pseudomembranous colitis caused by Clostridium difficile. A review of 40 cases.

We found antibiotic-associated diarrhoea (AAD) and pseudomembranous colitis caused by Clostridium difficile in 19% of patients with diarrhoea related to antibiotic therapy or with diarrhoea for which no other cause could be found. Ampicillin, cephalosporins and co-trimoxazole appear to be the agents most commonly associated with this complication. The clinical presentation of AAD falls into two categories: (i) an early-onset type characterized by severe diarrhoea with watery stools which may contain mucus; and (ii) a late-onset variety characterized by chronic, persistent diarrhoea with bulky stools. A definitive diagnosis was made in all cases by the detection of the cytotoxin of Cl. difficile in patients' stools using tissue culture assay. Discontinuation of the implicated agent when possible together with a 14-day course of oral vancomycin effected a cure in 90% of patients. The remaining 10% were successfully treated with a similar course of oral bacitracin.

Adult↗
PubMed1983

A comparative evaluation of drug combinations used in the treatment of pulmonary tuberculosis.

A retrospective analysis was undertaken of the hospital records of 185 patients admitted for the first time for treatment of pulmonary tuberculosis. The time to sputum conversion was used to evaluate the efficacy of short-course antituberculosis therapy and to determine the effect of including rifampicin (RMP) in various chemotherapeutic combinations. RMP per se was not found to be a significant variable in the drug combinations studied. The combination of RMP and pyrazinamide, however, showed greater efficacy in achieving earlier sputum conversion. The therapeutic advantage of using these two drugs in combination should be more readily appreciated.

Antitubercular Agents↗
PubMed1983

Streptococcus milleri causing infection in man.

We describe the microbiological and morphological characteristics of 151 strains of Streptococcus milleri isolated during the course of routine bacteriological investigations. Although these strains formed a fairly heterogeneous group, several constant features were identified which typify the species. Strept. milleri emerged as a major cause of pyogenic infection, clinical disease being characterized by localized collections of pus in almost every organ system. Bacteraemia due to Strept. milleri was a significant indicator of the presence of an occult abscess. Endocarditis was rare. The penicillins or erythromycin remain the drugs of choice for treating infections caused by this organism.

Bacteriological Techniques↗
PubMed1983

Unresponsiveness in hapten-specific cytotoxic lymphocytes. III. Influence of H-2 and non-H-2 gene loci on the in vitro trinitrophenyl-specific CTL response following either acute or chronic in vivo treatment with trinitrobenzene sulfonic acid.

The regulation of the in vitro generation of cytotoxic T lymphocytes (CTLs) directed against hapten-modified syngeneic cells has been investigated. The results indicate that acute intravenous pretreatment with water-soluble hapten, trinitrobenzene sulfonic acid (TNBS), can either positively or negatively affect the in vitro generation of trinitrophenyl (TNP)-specific CTLs. In general, mice bearing the H-2d haplotype are most likely to develop a reduced in vitro response pattern following a single acute in vivo TNBS treatment, wheras mice bearing the H-2k or H-2b haplotypes display either unchanged or augmented in vitro response patterns. We have shown that, in addition to the influences of H-2 genes, non-H-2 genes can also influence the in vitro hapten-specific CTL response following intravenous pretreatment with water-soluble hapten. Further, in two (H-2k X H-2d) F1 combinations between an H-2k strain displaying an unchanged in vitro response pattern following acute in vivo TNBS treatment and an H-2d strain displaying a reduced in vitro response pattern following similar treatment, it was observed that a single in vivo TNBS pretreatment did not induce the unresponsive state when F1-TNP stimulator cells were used. These results suggest that the mechanisms responsible for the reduced in vitro response pattern are not dominant within the F1 environment. However, when TNP-modified parental stimulators are used, a split-response pattern is observed in cells from TNBS-treated F1 mice which reflect the response patterns of the respective parents. These latter results again emphasize the influence of gene loci on the in vitro response patterns following acute TNBS treatment. In contrast to the significant influence of H-2 and non-H-2 genes on the in vitro TNP-specific response following acute in vivo TNBS treatment, these genes do not appear to significantly influence the in vitro TNP-specific response pattern following chronic TNBS treatment. Chronic TNBS treatment renders all strains tested specifically unresponsive.

Animals↗
PubMed1983

T-cell responses induced by the parenteral injection of antigen-modified syngeneic cells. II. Mechanisms, specificity, and cellular analysis of 2,4,6-trinitrophenol (TNP)-specific cytolytic response priming by intravenous versus subcutaneous injection with TNP-modified syngeneic cells.

We have examined the underlying mechanisms accounting for the enhanced in vitro TNP-specific cytotoxic T-lymphocyte (CTL) response following the parenteral injection of syngeneic hapten-modified lymphoid cells. Augmented CTL activity noted following parenteral injection (iv vs sc) of 2,4,6-trinitrophenol-modified syngeneic spleen cells (TNP-SC) is most apparent when limiting numbers of TNP-modified stimulator cells are used in the in vitro sensitization phase. Enhanced CTL responses seen following sc and iv priming is due to distinct mechanisms. Spleen and lymph node (LN) cells from sc primed mice were found to contain significant levels of radioresistant helper activity upon coculture with either viable normal spleen cells in bulk culture or with thymocytes as the source of precursor CTLs in a limiting dilution assay. The helper activity was found to be mediated by a Lyt 1+2- T cells. In addition, Lyt 2-depleted spleen and LN cells from sc primed BALB/c mice could restore the ability of tolerant spleen cells from 2,4,6-trinitrobenzenesulfonic acid (TNBS)-injected BALB/c mice to generate TNP-specific CTLs. Conversely, Lyt 2-depleted spleen and LN cells from iv primed mice provided no measurable helper activity either in bulk culture or in the limiting dilution assay and did not restore the ability of TNBS-tolerant BALB/c spleen cells to generate TNP-specific CTLs. CTL priming via the iv route was found to be completely antigen specific as iv injection of either 2,4-dinitrophenol (DNP)- or fluorescein isothiocyanatel (FITC)-modified cells caused no enhanced CTL activity. Priming via the sc route exhibited a unique specificity pattern as it was shown that sc injection of both TNP-SC and DNP-SC, but not FITC-SC, resulted in enhanced TNP-specific CTL responses. CTL T-helper (Th)-cell induction via the sc route was correlated with (1) the presence of H-2 I region determinants on the inducer cells as the sc injection of TNP-modified erythrocytes led to no enhanced CTL responses or CTL Th activity (while iv injection of TNP-erythrocytes did lead to enhanced CTL responses without detectable helper activity) and (2) the detection of both hapten-specific T-cell proliferation and Interleukin 2 (IL-2) production upon restimulation in culture. We conclude that the sc injection of TNP-SC leads preferentially to an increase of specific Lyt 1+ helper activity, while iv injection leads preferentially to an apparent expansion of Lyt 2+ prelytic effector CTLs.

Animals↗
PubMed1983

T cell responses induced by the parenteral injection of antigen-modified syngeneic cells. I. Induction, characterization, and regulation of antigen-specific T helper cells involved in delayed-type hypersensitivity responses.

This report presents evidence for the role of antigen-specific helper T cells in augmenting the in vivo development of delayed-type hypersensitivity (DTH) responses to both hapten and protein antigens. The role of these helper T cells in the in vivo induction and regulation of DTH responses was investigated. Mice were primed subcutaneously with optimal numbers (3 X 10(7)) of either protein antigen- or TNP-modified syngeneic spleen cells. Primed spleen or lymph node cells, but not thymocytes or unprimed cells, were found to significantly augment the DTH response of syngeneic recipients injected subcutaneously with suboptimal numbers (1 to 2 X 10(6)) of antigen-modified syngeneic cells. Primed spleen or lymph node cells augmented both in vivo ear swelling reactions and in vitro antigen-induced T cell proliferative responses in recipient animals. The helper effect was found to be mediated by a population of radioresistant, Thy-1+, Lyt-1+2-, I-A+ cells, a phenotype identical to that of antigen-specific Tprlf cells found in primed lymph nodes. In contrast, effector TDH cells were found to be Thy-1+, Lyt-1+2-, I-A- cells. Splenic T cells from TNP-primed mice augmented TNP-specific DTH responses, but not DTH to irrelevant protein antigens, and vice versa. Helper T cell induction correlated with the presence of H-2 I-region determinants on the inducer cells, because antigen-modified spleen cells were the most efficient inducers, modified thymocytes were less efficient, and modified erythrocytes were ineffective. Mapping studies also indicated that I-region identity between the antigen-modified spleen cell immunogen and the Th donors was both necessary and sufficient for DTH Th cell induction. In addition, functional helper T cell activity could be both specifically tolerized and suppressed by the transfer or suppressor T cells raised by the i.v. injection of antigen-modified syngeneic cells.

Animals↗
PubMed1983

Clonal abortion of bone marrow T cell precursors: T cells acquire specific antigen reactivity prethymically.

Lethally irradiated (900 R) mice were reconstituted with bone marrow cells from syngeneic donors that had been tolerized 2 to 3 wk earlier to either DNP or TNP compounds. Five weeks after reconstitution, these animals were tested for their ability to mount a delayed hypersensitivity (DH) response to the tolerizing haptens. Recipient mice were specifically tolerant to the hapten that was used to induce tolerance in the marrow donor. Mixing experiments in which mice were reconstituted with marrow from DNP-tolerant and TNP-tolerant donors showed no indication of active suppression or effective antigen carry-over in this system. This observation held true even in experiments in which mice were reconstituted with a mixture of marrow from tolerant and normal donors at a ratio of 5:1. Thus the reduced responsiveness in recipient mice seemed to be due to the functional elimination of hapten-responsive T cell precursor (pre-T) clones. Recipient unresponsiveness was also shown to be MHC restricted. Maintenance of unresponsiveness appeared to be due to the restricted access of regenerating pre-T cell clones to the maturational influence of the recipient's thymus.

Animals↗
PubMed1982

Gain/loss of poly(Glu50Tyr50)/poly(Glu60Ala30Tyr10) responsiveness in the bm12 mutant strain.

The development of inbred strains of mutant mice has proven useful in ascribing specific gene functions to particular genetic loci within the regions and subregions of the H-2 complex. The B6.C-H-2bm12 (bm12) strain is of particular interest in that, compared to parental C57Bl/6Kh (B6) mice, it bears a presumptive single gene mutation altering the Ab beta chain encoded by the I-A subregion. Our data show that bm12 mice have gained the ability to respond to poly(Glu50Tyr50)(GT) and have lost the ability to make plaque-forming cell or delayed-type hypersensitivity responses to the closely related copolymer, poly(Glu60Ala30Tyr10)(GAT), although retaining the ability to mount a GAT-specific T cell proliferative response. This is in sharp contrast to the parental B6 strain, which is a GT nonresponder and a GAT responder. Thus, this study is the first to report the establishment of responder status as a consequence of mutation. Possible mechanisms accounting for the gain/loss of GT/GAT responsiveness in the context of a two-step helper T cell model are discussed.

Animals↗
PubMed1982

Suppressor T cell circuits in contact sensitivity. I. Two mechanistically distinct waves of suppressor T cells occur in mice tolerized with syngeneic DNP-modified lymphoid cells.

Suppressor T cells induced by the i.v. injection of syngeneic DNP-LC were studied at varying times after tolerization. It was found that 7 days after tolerization both the spleen and lymph nodes of tolerant mice contained Ts active in suppressing the efferent (effector) phase of the contact sensitivity response (Ts-eff). At 14 days after tolerization, however, only the spleen showed significant suppressive activity that was active on the afferent (induction) phase of the contact sensitivity response. This second wave of afferent suppression was shown to be mediated by an antigen-specific, Ia-positive T cell (Ts-aff). Ts-aff could also be induced in normal, but not in CY-pretreated mice transfused with lymphoid cells containing primed Ts-eff, provided an appropriate induction period was allowed. Also the activity of Ts-aff, but not of Ts-eff, could be eliminated by treatment with anti-DNP antibody (i.e., idiotype) and C. Thus, Ts-aff appears not to be a maturation stage of Ts-eff. It was also shown that Ts-eff and Ts-aff interacted in an antagonistic fashion; cotransfer of these populations along with DNFB-immune TDH cells neutralized the efferent suppressive activity of Ts-eff for the immune cells, allowing successful passive transfer of immunity. The exact role of this antagonistic interaction is not clear, but it may play a part in maintaining the balance of suppression in the intact animal. The data are discussed in terms of a cellular network in immune suppression and are compared and contrasted to other suppressor systems in which network interactions have been described.

Animals↗
PubMed1982

Inhibition of specific immune responses by feeding protein antigens. V. Induction of the tolerant state in the absence of specific suppressor T cells.

The effect of CY pretreatment on the ability of OVA feeding to induce both tolerance and active suppression was examined in mice. CY-pretreated, OVA fed mice were fully unresponsive in both OVA-specific DTH and antibody responses, but, in contrast to untreated OVA-fed mice, did not transfer suppression to normal recipients via splenic lymphocytes. Restoration of Ts activity in CY-pretreated mice was accomplished by reconstitution with normal T cells before antigen feeding, indicating that the CY effect was at the Ts precursor level. In addition, it was found that certain OVA-specific immune parameters (DTH and splenic PFC responses) in recipient mice were susceptible to suppression by transfer of spleen cells from OVA-fed donors, whereas other measures (antigen-induced T cell proliferation and serum antibody titers) were not. The data suggest that CY-sensitive Ts are not necessary for either induction or maintenance of specific tolerance after OVA feeding.

Animals↗
PubMed1981

Unresponsiveness in hapten-specific cytotoxic T lymphocytes. I. Characteristics of tolerance induction in adult mice.

These experiments concern the regulation of cytotoxic T lymphocytes (CTL). Here we describe the induction of unresponsiveness in TNP-specific cytotoxic cells generated in vitro. Previous work has shown that i.v. injection of water-soluble TNP (TNBS) prevents in vivo generation of TNP-specific CTL in C3H/HeN mice. In contrast, this report shows that the in vitro generation of TNP-specific CTL from similarly treated C3H/HeN mice is not inhibited. Nevertheless, unresponsiveness in CTL can be induced with TNBS. This unresponsiveness appears to be H-2 linked, since 3 strains of H-2d mice (BALB/c, DBA/2J, and B10.D2) were rendered unresponsive after a single injection of TNBS, whereas 3 strains of H-2k mice (C58/J, C3H/HeN, and CBA/J) were not. This CTL unresponsiveness is antigen specific in both induction and expression. The unresponsiveness is reversed by pretreatment with cyclophosphamide but not by adult thymectomy. Furthermore, the addition of supernatants from Con A-stimulated spleen cells to cultures containing the unresponsive responder cells enhanced the generation of cytotoxic activity. These results suggest that a) the ability to induce TNP-specific CTL unresponsiveness is linked to H-2 loci, b) a regulatory network is involved in the unresponsiveness, which is sensitive to cyclophosphamide but resistant to adult thymectomy, and c) at least 1 level of regulation involves amplifying T cells.

Animals↗
PubMed1980

Induction of tolerance to 1-fluoro-2,4-dinitrobenzene contact sensitivity with hapten-modified lymphoid cells. II. Selective tolerance in F1 mice of T cell subsets recognizing 1-fluoro-2,4-dinitrobenzene associated with parental major histocompatibility complex antigens.

F1 animals were tolerized to 1-fluoro-2,4-dinitrobenzene (DNFB) contact sensitivity with parentally derived, in vitro hapten-modified spleen cells. This tolerant state was found, upon adoptive transfer to naive parental strain recipients, to affect only that T cell subpopulation that recognized the parental haplotype of the cell used as the tolerogen, and did not inhibit the ability of the remaining T cell subset to confer immunity. This demonstrates that this tolerant state involves the inactivation of a cell required for the expression of contact sensitivity by recognizing DNFB in association with self major histocompatibility complex gene products.

Animals↗