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Biomedical subjects

A Singer

Publications and source records attributed to A Singer.

At least 199 records · Page 11Linked to original sources
PubMed1989

Characterization of anti-CD8-resistant cytolytic T lymphocytes induced by multivalent cross-linking of CD8 on precursor cells.

The lytic activity of most CD8+ MHC class I allospecific CTL generated in vitro can be inhibited by anti-CD8 antibodies. Such inhibition has led to hypotheses that CD8/class I interactions normally contribute to the triggering of CTL with low or moderate avidity Ag-specific TCR by providing those CTL with auxiliary binding avidity. However, CD8 has also been proposed to play an active signaling role in T cell activation. We have recently reported that multivalent cross-linking of CD8 on CTL precursors in MLC does appear to mediate activation signals, and induces the generation of CD8+ MHC class I allospecific CTL whose lytic activity cannot be blocked by anti-CD8 antibodies. In our present study, we have further characterized such anti-CD8 uninhibitable effector cells. These CTL are resistant to blocking of their lytic function by anti-Lyt-3 mAb as well as anti-Lyt-2 mAb, but remain sensitive to blocking by anti-LFA-1 mAb, indicating that they do use non-CD8 cell adhesion molecules during target cell recognition and lysis. As a consequence of mAb-induced multivalent CD8 cross-linking during their generation, anti-CD8 uninhibitable CTL significantly reduce their cell surface expression of CD8, which permits their identification and facilitates their purification from heterogeneous MLC populations. Such anti-CD8 uninhibitable effector cells can be maintained as stable CTL lines, in the absence of anti-CD8 mAb after the initial induction period. The in vitro generation of anti-CD8 uninhibitable CTL, which may be highly enriched for cells bearing high affinity TCR, could represent a new experimental approach to studies of TCR gene usage and repertoire, as well as a potentially important strategy for the deliberate generation of high affinity effector cells for adoptive immunotherapy.

Animals↗
PubMed1989

Cell surface comodulation of CD4 and T cell receptor by anti-CD4 monoclonal antibody.

In our study we have used anti-CD4 mAb to investigate the cell surface association between CD4 and the Ag-specific TCR complex on mature peripheral T cells. Anti-CD4 mAb was administered in vivo and in vitro and its effects on CD4 and CD3 cell surface expression were determined. In vivo, anti-CD4 mAb reduced cell surface expression of its ligand, CD4, and secondarily also reduced cell surface expression of CD3/TCR on CD4+ splenic T cells. In vitro, multivalent cross-linking of CD4 by anti-CD4 mAb and either FcR+ cells or anti-Ig mAb also resulted in decreased surface expression of CD4 and specific comodulation of CD3/TCR. The secondary reduction in cell surface CD3/TCR expression induced by CD4 cross-linking could be pharmacologically disrupted by high doses of PMA, indicating that the comodulation of CD3 with CD4 was dependent upon intracellular mediators, possibly including protein kinase C. These results demonstrate that, in the presence of anti-CD4 mAb, CD4 is functionally associated with the CD3/TCR complex, and that this association is dependent upon the activity of intracellular mediators. Such intracellular mediators might induce the coordinate down-modulation of physically unassociated CD4 and CD3/TCR molecules, or, alternatively, might promote a physical interaction between CD4 and CD3/TCR molecules.

Adjuvants, Immunologic↗
PubMed1989

Role of CD4 in thymocyte selection and maturation.

We examined the possible role of CD4 molecules during in vivo and in vitro fetal thymic development. Our results show that fetal thymi treated with intact anti-CD4 mAbs fail to generate CD4 single-positive T cells, while the generation of the other phenotypes remains unchanged. Most importantly, the use of F(ab')2 and Fab anti-CD4 mAb gave identical results, i.e., failure to generate CD4+/CD8- T cells, with no effect on the generation of CD4+/CD8+ T cells. Since F(ab')2 and Fab anti-CD4 fail to deplete CD4+/CD8- in adult mice, these results strongly argue that the absence of CD4+/CD8- T cells is not due to depletion, but rather, is caused by a lack of positive selection, attributable to an obstructed CD4-MHC class II interaction. Furthermore, we also observed an increase in TCR/CD3 expression after anti-CD4 (divalent or monovalent) mAb treatment. The TCR/CD3 upregulation occurs in the double-positive population, and may result from CD4 signaling after mAb engagement, or may be a consequence of the blocked CD4-class II interactions. One proposed model argues that the CD3 upregulation occurs in an effort to compensate for the reduction in avidity or signaling that is normally provided by the interaction of the CD4 accessory molecule and its ligand. As a whole, our findings advocate that CD4 molecules play a decisive role in the differentiation of thymocytes.

Animals↗
PubMed1989

Role of lymphokine-secreting CD8+ T cells in cytotoxic T lymphocyte responses against vaccinia virus.

The present study has examined the relative role of CD4+ and CD8+ Th cells in the generation and reactivation of antivaccinia virus memory CTL responses. We show that mice primed in vivo to vaccinia virus generate in vitro antivaccinia virus memory CTL responses through both CD4+ and CD8+ Th cell pathways, with the CD4+ Th pathway being the more prominent of the two. In addition, we show that vaccinia virus-specific CD8+ Th cell function is mediated through production of lymphokines, including IL-2, and that the CD8+ Th cell component in the CTL response is labile, decreasing progressively with increasing time after in vivo priming. Thus, this study demonstrates the existence of two phenotypically distinct Th cell pathways in the generation of antivirus CTL responses.

Animals↗
PubMed1989

Inhibition of allorecognition by an H-2Kb-derived peptide is evidence for a T-cell binding region on a major histocompatibility complex molecule.

The class I and class II major histocompatibility complex (MHC) antigens are polymorphic cell-surface glycoproteins that present antigenic peptides to T lymphocytes in the generation of immune responses. While much is known about the recognition and processing of antigens, the nature of T-cell recognition sites on MHC molecules is poorly understood. Both structural and functional studies have suggested that the two major alpha-helical regions of the class I MHC molecule not only define the site for binding of antigenic peptide but also provide potential sites for interaction of the MHC molecule with the T-cell receptor. A peptide derived from one of these regions on the H-2Kb molecule, peptide Kb163-174, was previously shown to specifically inhibit the stimulation of an alloreactive T-cell hybridoma. To further investigate the role of this region in the recognition of H-2Kb, the effects of peptide Kb163-174 on allospecific T-cell lines and clones were studied. When peptide Kb163-174 was cocultured with either an H-2Kbm10 anti-H-2Kb cytotoxic T-lymphocyte (CTL) clone or a CTL line, this peptide inhibited lysis of H-2Kb targets. Pretreatment experiments showed that the blockade was due to interaction of the peptide with the effector T cells. Surprisingly, peptide Kb163-174 also inhibited lysis of H-2Kb targets by H-2Kbm1-, H-2Kbm3-, H-2Kbm6, and H-2Kbm8-anti-H-2Kb CTLs. These CTLs, which identify multiple antigenic sites on H-2Kb in the alpha 1 and alpha 2 domains, are not directed against amino acid residues 163-174 of H-2Kb. In addition, peptide Kb163-174 specifically blocked lysis of only H-2Kb and not H-2Ld targets by a single bulk CTL culture that was alloreactive on both H-2Kb and H-2Ld. These results indicate that peptide Kb163-174 interferes with T-cell receptor engagement of a contact site on the H-2Kb molecule. Thus, amino acid residues 163-174 define a site used by many alloreactive T cells to engage the H-2Kb molecule.

Amino Acid Sequence↗
PubMed1989

The effect of the Vietnam War on numbers of medical school applicants.

Among the little-noticed but far-reaching side effects of the Vietnam War was its impact on the higher education system. This often-unpopular war, coupled with the military draft and student deferment policies, led many young men to enter educational institutions of all types. Beginning around 1964, there was a surge of enrollments and degrees granted in higher education that began to abate only after the draft ended in 1973. The leading edge of the post-World War II "baby-boom" also became of college age in the mid-1960s and undoubtedly contributed to elevated levels of enrollments and degrees in higher education. But the Vietnam War had an impact over and above the purely demographic, as can be seen when population effects are factored out. This effect largely explains why the numbers of bachelor's degrees and doctorates (Ph.D. degrees and equivalent) granted to men suddenly stopped increasing in 1974 even though the relevant population groups continued to grow throughout the 1970s. The patterns of enrollments and degrees attained by women are quite different from the men's patterns, and they serve to reinforce the evidence of a draft effect. Students in health professions schools of all types were given special consideration under the deferment policies established by the Selective Service System, leading to rapid increases in applications to medical, dental, and other health professions schools during the period 1968-1974. Since then, the health professions schools have had quite similar experiences with applications--those from men have generally declined while those from women have generally increased. Also, career choices are shifting.(ABSTRACT TRUNCATED AT 250 WORDS)

Career Choice↗
PubMed1989

Regional cerebral blood flow measurements in the diagnosis of dementia.

The Xenon-133 regional cerebral blood flow technique (rCBF) was used to assess cortical perfusion in a group of 15 elderly patients (mean age = 79.1, SD = 8.7) with a probable diagnosis of Dementia of the Alzheimer type (DAT). Nine had mild DAT and six were in the moderate stages of DAT. These patients were compared with 15 age and sex matched normal elderly controls (mean age = 75.1, SD = 5.6). RCBF was measured in each patient and control at rest with eyes closed. The DAT patients had significantly lower mean global CBF than normal controls (t = -4.63, p less than 0.0001). In addition, a further 15 normal elderly subjects aged 60 to 92 were assessed and combined with the original 15 to allow calculation of a normal range of rCBF for elderly individuals. Seventy-three per cent of the DAT patients fell below the lower limit of the normal range (39.3 - 59.3 ISI units). These results show the possible usefulness of rCBF as an aid in the diagnosis of early DAT.

Aged↗
PubMed1989

An explanation for the problem of false-negative cervical smears.

False-negative cervical cytology due to sampling error is a well-recognized problem. Forty-seven women with histologically proven cervical intraepithelial neoplasia (CIN) were studied. All had two cervical smears performed at a mean interval of 3 months. At the time of the second smear, cervicography, colposcopy and biopsy were performed. The area of acetowhite cervical lesions and of the total visible atypical transformation zone (ATZ) were measured from the cervical photographs. The 17 women in whom one or both smears showed no dyskaryosis were found to have a significantly smaller proportion of their ATZ affected by CIN. It is suggested that this finding can account for the sampling error which causes false-negative cervical cytology. New screening techniques, such as cervicography, may offer a method of detecting and assessing these relatively smaller cervical lesions.

Biopsy↗
PubMed1989

Cytological status and lesion size: a further dimension in cervical intraepithelial neoplasia.

Quantitative histological study of 84 laser cone biopsies showed a highly significant correlation between the grade of a cervical smear and the size of the lesion for all grades of cervical intraepithelial neoplasia (CIN) (CIN I P = 0.004; CIN II P = 0.0001; CIN III P = 0.003; total CIN P less than 0.0001); 10 of 34 (29%) of women with CIN III and mild dyskaryosis or less had significantly smaller lesions than 23 of 36 (63%) of women with CIN III and moderate or severe dyskaryosis. Repeat cytology identified as severe dyskaryosis all those with large CIN III lesions. Lesion size has been neglected in studies of the natural history of CIN and in the assessment of cytological screening, but offers an explanation for the apparent discrepancies between cytological, colposcopic and histological assessment of progression of CIN.

Biopsy↗
PubMed1989

Dynamic MR imaging of the liver with Gd-DTPA: initial clinical results.

Gd-DTPA was evaluated as a hepatic contrast agent for MR imaging. Twenty-six consecutive patients referred for suspected masses in the liver were studied at 1.5 T. Fourteen patients had hepatic metastases and one patient each had cholangiocarcinoma and multicentric hepatocellular carcinoma. Four patients had cavernous hemangiomas and the remainder had other benign lesions. Diagnoses were proved by biopsy, sonography, or radionuclide scintigraphy in 23 cases and by autopsy in one case. Precontrast scans were obtained by using standard pulse sequences. In addition, breath-hold scans were obtained before and after bolus administration of 0.1 mmol/kg Gd-DTPA by using a multislice T1-weighted gradient-echo pulse sequence with an ultrashort echo time. Mean lesion-liver signal difference/noise increased by 50% (p less than .01) in the immediate postcontrast phase. In two of 26 cases, multiple additional lesions as small as 3 mm were detected after contrast administration that were not seen before contrast administration. In no case was lesion-liver contrast worsened on scans obtained immediately after administration of contrast material. However, on delayed scans, detection of lesions worsened in some cases because of equilibration of contrast material between liver and lesion. These initial clinical results suggest that enhancement with Gd-DTPA is a practical method for improving lesion-liver contrast and has the potential to improve the accuracy of MR imaging in the liver. However, optimized fast imaging techniques are required for best results.

Contrast Media↗
PubMed1989

Possible cofactors in the etiology of cervical intraepithelial neoplasia. An immunopathologic study.

Previous work in our department demonstrated a reduction in the numbers of Langerhans' cells in cervical epithelium showing histologic changes of human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN). In conjunction with a localized reversal of the T4:T8 ratio of T-lymphocytes, that finding provides evidence of the association of epithelial immunosuppression with both HPV infection and CIN. To investigate whether that phenomenon occurs primarily because of HPV alone or might be caused by a cofactor (e.g., cigarette smoking, oral contraceptive use, chlamydial infection), we performed a study of the effect of those cofactors on the immune defenses of the cervical epithelium. In a study of Langerhans' cells we showed that infection with HPV type 16 and current cigarette smoking both exert effects that cause a reduction in those cells. That diminution of the major antigen-presenting cells in cervical epithelium may constitute a mechanism that explains the observed role of those agents in the etiology of cervical neoplasia.

Antigens, CD1↗
PubMed1989

The P300 event-related potential and regional cerebral blood flow in patients with Alzheimer's disease.

A number of studies have reported that an abnormal delay in the latency of the P300 event-related potential (ERP) is characteristic of the majority of patients with a dementing process. Another body of research suggests regional cerebral blood flow (rCBF) is significantly reduced in Alzheimer's disease (AD). No previous study has compared the effectiveness of these 2 measures in identifying the same patients with AD. Furthermore, most of the studies on which the above findings are based examined patients in the moderate to severe stages of the disorder. In this study we examined P300 latency and rCBF in 10 patients with mild to moderate Alzheimer's disease, and compared their responses with those of normal subjects of similar age. The P300 component was not evident in 2 of the patients: the remaining 8 had a latency within normal limits for their age. On the other hand, 8 of the patients had abnormally reduced rCBF. These results suggest rCBF measures may be useful for identifying AD in its early stages.

Aged↗
PubMed1988

Induction of anti-CD8 resistant cytotoxic T lymphocytes by anti-CD8 antibodies. Functional evidence for T cell signaling induced by multi-valent cross-linking of CD8 on precursor cells.

The effector function of most MHC class I allospecific CTL is inhibited by anti-CD8 mAb. In the present study, we report the surprising observation that multi-valent cross-linking of CD8 molecules on precursor cells by specific antibody actively induces the generation of CD8+ class I allospecific CTL whose lytic function is resistant to anti-CD8 antibody inhibition, and actively induces down-modulation of cell surface CD8 expression on these cells. In marked contrast, bi-valent cross-linking of CD8 inhibits the generation of CD8+ CTL from precursor cells and fails to induce down-modulation of cell surface CD8 expression. These results demonstrate that CD8 can transduce net positive signals, but only when the molecule is extensively cross-linked.

Animals↗