Competitive control of the self-renewing T cell repertoire

We develop a mathematical model for the self-renewing part of the T cell repertoire. Assuming that self-renewing T cells have to be stimulated by immunogenic MHC-peptide complexes presented on the surfaces of antigen-presenting cells, we derive a model of T cell growth in which competition for MHC-peptide complexes limits T cell clone sizes and regulates the total number of self-renewing T cells in the animal. We show that for a sufficient diversity and/or degree of cross-reactivity, the total T cell number hardly depends upon the diversity of the T cell repertoire or the diversity of the set of presented peptides. Conversely, for repertoires of lower diversity and/or cross-reactivity, steady-state total T cell numbers may be limited by the diversity of the T cells. This provides a possible explanation for the limited repertoire expansion in some, but not all, mouse T cell re-constitution experiments. We suggest that the competitive interactions described by our model underlie the normal T cells numbers observed in transgenic mice, germ-free mice and various knockout mice.      

Immunotopographic assessment of lymphoid and plasma cell malignancies in the bone marrow

To determine the utility of tissue section immunochemistry in the evaluation of bone marrow involved by lymphoid and plasma cell malignancies, snap-frozen, undecalcified bone marrow core and aspirate samples from 23 patients with these disorders were studied with a battery of monoclonal antibodies. With techniques that preserve architecture, difficult diagnostic cases characterized by core but not aspirate involvement, or the reverse, were resolved. By means of an extensive battery of monoclonal antibodies applied to serial sections, complex tumor cell phenotypes were established in all 23 cases. In addition to the identification of straightforward monoclonal surface immunoglobulin expression in small cleaved cell lymphomas (four cases), the battery approach added immunologic certainty in malignancies with unusual or difficult phenotypes: peripheral T-cell lymphomas with idiosyncratic antigen expression, and chronic lymphocytic leukemias and small cell lymphomas with faint surface immunoglobulin expression (four cases). For the chronic lymphocytic leukemias and the small cell lymphomas, the combined IgD+, B2+, B1+, Ia+, Leu-1+ phenotype taken as a whole had greater utility than any isolated marker. The acute lymphocytic leukemias and the myelomas studied demonstrate the wide range of B-cell antigens that must be detected to account for the variety of B-cell neoplasms encountered. Additionally, the previously undescribed phenotypic subset of CALLA+ myelomas, which is of prognostic relevance, was identified. Marrow frozen section immunotyping is a major asset in the evaluation of patients with lymphoma, leukemia, and myeloma when special care is accorded to tissue handling and to treatment of endogenous peroxidase/pseudoperoxidase and interstitial immunoglobulin.     

Lack of influence of glucagon on glucose homeostasis after prolonged exercise in rats

Summary The significance of glucagon for post-exercise glucose homeostasis has been studied in rats fasted overnight. Immediately after exhaustive swimming either rabbit-antiglucagon serum or normal rabbit serum was injected by cardiac puncture. Cardiac blood and samples of liver and muscle tissue were collected before exercise and repeatedly during a 120 min recovery period after exercise. During the post-exercise period plasma glucagon concentrations decreased but remained above pre-exercise values in rats treated with normal serum, while rats treated with antiglucagon serum had excess antibody in plasma throughout. Nevertheless, all other parameters measured showed similar changes in the two groups. Thus after exercise the grossly diminished hepatic glycogen concentrations remained constant, while the decreased blood glucose concentrations were partially restored. Simultaneously concentrations in blood and serum of the main gluconeogenic substrates, lactate, pyruvate, alanine and glycerol declined markedly. During the post-exercise period NEFA concentrations in serum and plasma insulin concentrations remained increased and decreased, respectively, while plasma catecholamines did not differ from basal values. Muscle glycogen concentrations decreased slightly. These findings suggest that in the recovery period after exhaustive exercise the increased glucagon concentrations in plasma do not influence gluconeogenesis.     

Localization of a gene for otosclerosis to chromosome 15q25-q26

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi- generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease- causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.      

Ultrastructure of canine type II pneumocytes during hypothermic ischemia of the lung: a study by means of conventional and energy filtering transmission electron microscopy and stereology

Alterations in pulmonary surfactant have been reported to be associated with ischemia/reperfusion injury in experimental and clinical lung transplantation. It is unknown whether these alterations are due to damage to surfactant synthesizing type II pneumocytes during hypothermic ischemic storage. The aim of the present study was to examine the effects of hypothermic ischemic storage of the lung on canine type II pneumocytes by means of conventional (CTEM) and energy filtering TEM (EFTEM) and stereology. The lungs of 18 dogs were fixed for TEM immediately after cardiac arrest (6 double lungs) and after storage in Tutofusin at 4 degrees C for 20 min, 4 hr, 8 hr, and 12 hr (6 single lungs, respectively). Using a systematic uniform random sampling scheme, type II pneumocytes were analyzed qualitatively and stereologically. The relative phosphorus content of cell organelles, especially the surfactant containing lamellar bodies, was investigated by EFTEM. By CTEM, no major qualitative alterations could be observed in type II pneumocytes of the experimental groups. Stereologically, no significant changes in the volume densities or the volume-to-surface ratios of type II pneumocytes and their lamellar bodies were found. By EFTEM, the highest intracellular phosphorus signals were recorded over lamellar bodies in all experimental groups. No changes in the phosphorus signals were observed during ischemia. These results indicate that the ultrastructure of canine type II pneumocytes and their lamellar bodies is not affected by hypothermic ischemia of the lung up to 12 hr. Structural preservation of intracellular surfactant is possible during prolonged ischemic lung storage.     

Persistent infection of human lymphoid and myeloid cell lines with herpes simplex virus.

Herpes simplex virus (HSV) type 1 replicated and persisted in human T, B, and myeloid cell lines with different patterns of viral replication and various effects on cell growth. T cell line CEM supported the replication of HSV for over 400 days without detectable differences in cell growth as compared with uninfected cells. HSV persisted in B cell line NC37 and myeloid cell line K562 for up to 222 and 374 days, respectively, but led to a significant decrease in the number of viable cells by 7 weeks of infection. The average number of cells producing infectious virus was very low in these cell lines (range, 0.5 to 2.7+) compared with a larger proportion of cells exhibiting HSV antigens by immunofluorescence (range, 24 to 58%). In contrast, null cell line LAZ 221 failed to replicate HSV even though the viral infection led to a cessation of cell growth.     

Serum-induced chronic pancreatitis

Summary Clinical research into patients with idiopathic chronic pancreatitis points to a possible immunopathogenetic process in a number of cases.In order to examine the behaviour between the exocrine pancreas under the influence of anti-rat-pancreas immune serum produced in rabbits, a 1.00 ml immune serum is administered once a week over a maximum 26 week period into Wistar-rats by intraperitoneal injection. By electrone-microscopy a much reduced production of enzymes apparently takes place, though to differing extent. There is also destruction of the basal membrane of acinocytes; the production of interstitial oedema, the new formation of collagen fibres and the proliferation of connective tissue cells. Under a conventional light microscope the first changes become noticeable after 8-12 weeks of study. These take the form of localised cell decay, deterioration and lysis of acinocytes; and an increasing non-specific inflammation. There is also the new formation of connective tissue. After 20–26 weeks the exocrine pancreas is characterised by reduction of parenchyma, acino-ductal metaplasia, chronic inflammatory infiltrates of differing density, fibrous and irregular calibres of the smaller and larger ducts.The findings are almost identical to the structural changes of chronic idiopathic pancreatitis in human beings. The results support the view of an immuno-pathologic aetiology for human chronic idiopathic pancreatitis.Supported by Deutsche Forschungsgemeinschaft