Neurological Manifestations of COVID-19 Feature T Cell Exhaustion and Dedifferentiated Monocytes in Cerebrospinal Fluid

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The time course of cross-talk during the simultaneous specification of bimanual movement amplitudes

 We investigated the time course of the amplitude specification of rapid bimanual reversal movements (lateral displacements on two digitizers). To this end we used the timed-response paradigm in which the response has to be initiated synchronously with an auditory signal. Information about the required amplitudes was presented at various times before the synchronization signal. Consistent with previous results, the progression of amplitude specification was reflected in the dependence of the amplitudes of the reversal movements on the time interval between amplitude information and synchronization signal. Same or different amplitudes for the hands were used to examine cross-talk at the programming level of the two-level model of intermanual interference. The results indicate the existence of cross-talk in particular at short intervals between information about amplitude and movement initiation. This is consistent with the notion that cross-talk between concurrent processes of amplitude specification is transient and vanishes as the time available for motor programming increases. Received: 28 August 1996 / Accepted: 10 July 1997     

Detection of perforin and granzyme A mRNA in infiltrating cells during infection of mice with lymphocytic choriomeningitis virus

The analysis of gene expression in cytotoxic T cells by in situ hybridization of serial liver and brain sections from mice infected with lymphocytic choriomeningitis virus (LCMV) and immunostaining with T cell marker- and virus-specific antibodies revealed a close histological association of infiltrating lymphocytes expressing the perforin and granzyme A genes with virally infected cells. Maximal frequency of perforin and granzyme A mRNA-containing cells on liver sections preceded by about 2 days maximal LCMV-specific cytotoxicity of the lymphoid liver infiltrating cells. These results are most consistent with an involvement of perforin and granzyme A in cell-mediated cytotoxicity in vivo.     

Chronic pneumonia despite adaptive immune response to Mycobacterium bovis BCG in MyD88-deficient mice

To assess the role of Toll-like receptor (TLR) signalling in host response to mycobacterial infection, mice deficient in the TLR adaptor molecule myeloid differentiation factor 88 (MyD88) were infected with the vaccine strain Mycobacterium bovis (BCG), and the immune response and bacterial burden were investigated. Macrophages and dendritic cells from MyD88-deficient mice stimulated in vitro with BCG mycobacterial antigens produced very low levels of proinflammatory cytokines, while the expression of costimulatory molecules such as CD40 and CD86 was preserved. Upon systemic infection with BCG (2 x 10(6) CFU i.v.) MyD88-deficient mice developed confluent chronic pneumonia with two log higher CFU than wild-type mice. Interestingly, the infection was controlled in liver and spleen and there was efficient systemic T-cell priming with high IFNgamma production by CD4+ splenic T cells in MyD88-deficient mice. Lung infiltrating cells showed IFNgamma production by pulmonary CD4+ T cells upon specific restimulation, and a reduced capacity to produce nitric oxide and IL-10. In summary, despite the dramatic reduction of the innate immune response, MyD88-deficient mice were able to mount an efficient T-cell response to mycobacterial antigens, which was however insufficient to control infection in the lung, resulting in chronic pneumonia in MyD88-deficient mice.     

Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance

Therapeutic application of broadly reactive anti-T cell antibodies can lead not only to potent immunosuppression but also to profound and long-lived T cell depletion. We reasoned that a strategy that almost exclusively targets activated cytopathic donor reactive T cells and spares immunoregulatory networks might prove to be an exceptionally potent and highly selective means of producing long-term engraftment and tolerance. Herein we show that the combined administration of rapamycin and agonist IL-2- and antagonist IL-15-related cytolytic fusion proteins provides for long-term engraftment/tolerance in exceptionally stringent allotransplant models by (1) limiting the early expansion of activated T cells, (2) preserving and even exaggerating their subsequent apoptotic clearance, and (3) further amplifying the depletion of these activated T cells by antibody-dependent mechanisms, while (4) preserving CD4+CD25+ T cell-dependent immunoregulatory networks.     

Kinetic fluorescence RT-PCR is highly sensitive for detection of germ-cell-tumor-specific transcripts in peripheral blood

The aim of our study was to determine whether conventional staging in patients with testicular germ-cell-tumors (GCT) could be supplemented by quantification of beta-human choriogonadotropin mRNA levels in peripheral blood using kinetic fluorescence RT-PCR. Blood samples from 41 patients with GCT of different clinical stages (CS) were pre-therapeutically examined by kinetic fluorescence RT-PCR with the LightCycler for beta-human chorionic gonadotropin (beta-HCG) mRNA expression levels. The controls comprised of samples taken from patients 3 months after treatment, from patients with inflammatory testicular diseases or non-germ-cell-tumors and from healthy males (n=66). Six positive results [cut-off level: normalized beta-HCG mRNA (Nbeta-HCG) >400 relative gene expression (RGE)] were found in controls (specificity 90.9%, 95% CI: 76.9-97.3%). The overall ratio of positive PCR results in the group of GCT patients was 82.92% (34/41) (CS I 18/23, CS IIa-b 6/7, CS >IIb 10/11) (sensitivity 82.9%, 95% CI: 65.1-91.2%). The average Nbeta-HCG level in patients with clinical stage I tumors was 63772.0+/-125720.5 (mean +/- standard deviation) relative gene expression (RGE), 35076.0+/-52253.5 RGE in those with CS IIa-b tumors and 87298.3+/-120895.3 RGE in those with CS >IIb tumors. Kinetic fluorescence RT-PCR for tumor-specific gene products is, in contrast to qualitative RT-PCR, a promising approach to improve conventional staging in clinical low-stage testicular germ-cell-tumors. With high specificity, its sensitivity is higher than that of the corresponding serum tumor marker (82.92% vs 48.72%).