Analysis of the age-related refractoriness of T-lymphocyte reactivity in humans.

Aged individuals could be divided into two groups according to their T-lymphocyte transformation values. The relationship between the PHA (phytohemagglutinin) stimulation indices and spontaneous thymidine incorporation; the PHA dose-response type distribution and the relative number of resting T lymphocytes was similar to the control group in aged subjects of seemingly intact T lymphocyte transformation values. However, their B cell compartment was found to be reduced. On the other hand, the ratio between the stimulation indices and spontaneous thymidine incorporation values of aged subjects of impaired T lymphocyte reactivity deviated from that of the control group. This group had an increased frequency of subjects giving maximal transformation values at relatively high PHA doses (hyposensitives) at the expense of normosensitives and showed reduced numbers of resting T cells, but normal B cell compartment. These results suggest that immunodeficiencies developing with age can possibly be of individually different types.

HLA and T-lymphocyte function in old age.

The role of the major histocompatibility complex in the genetic control of reactivity of peripheral blood mononuclear cells (T lymphocytes) to lectins and allogeneic cells as a function of age was investigated. In randomly selected aged subjects the frequencies of HLA-A, B, and some C locus alleles did not differ significantly from those in the control group. However, some tendencies of haplotype frequency differences between young and aged subjects were found. Significant associations of impaired or preserved T-lymphocyte function could be detected in connection with some HLA-A (A3, A11) antigens only. The tendency of some phenotypic HLA-A and B or C and B antigen associations to be in correlation with impaired or preserved T-lymphocyte reactivity in old age seemed to be independent of their age-related frequency differences. In family studies of a partially inbred Hungarian population, differences were found in the rate of diminution of allogeneic reactivity in groups sharing different HLA haplotypes. Based on statistical analysis of these data, a genetic factor segregating with the MHC and taking part in the regulation of the age-dependent decline of T-lymphocyte reactivity can be postulated.

Increased killer cell activity in aged humans.

Natural cell-mediated cytotoxicity (NCMC) against a cell line (K-562) and antibody-dependent cellular cytotoxicity (ADCC) against the same target and against chicken red blood cells were investigated in two age groups (20--45 and 70--98 years old). Proliferative response to PHA and to allogenic cells as well as some subpopulation determinations were also carried out only lymphocytes of the same subjects. In contrast to the significantly decreased proliferative responses, NCMC showed a moderate, and the two ADCC values a highly significant increase in the group of aged subjects. These increased values showed some similarities with the quantitative changes within the T-lymphocyte subpopulations. The incidence of serum samples of NCMC inhibitory activity was only moderately increased in the group of aged subjects as compared to that of the young individuals. On the basis of these results, we concluded that the immune system of healthy aged subjects seems altered or inbalanced rather than depressed to that of the young individuals.

Human immunodeficiency virus (HIV) protease inhibitors have no effect on hepatitis C virus (HCV) serum levels of HIV-HCV co-infected patients.

Ten severely immunocompromised HIV-HCV co-infected patients were enrolled in a quantifiable HCV-RNA assay. Serum alanine aminotransferase, HCV-RNA levels and HIV viral loads were determined at baseline, at month three and at month six after initiation of a highly active antiretroviral therapy including an HIV protease inhibitor. HCV genotypes were determined using a line probe assay kit. Our results suggested that this therapy did not result in lower HCV viraemia, whatever the HCV genotypes, and probably had no effect on the outcome of chronic viral hepatitis C. As our patients were severely immunocompromised and their mean increase of CD4 cell counts was less than 50/mm(3), we cannot reach any conclusions about the impact of the improvement of immune status on the HCV-RNA load.

Comparison of clarithromycin-sensitive and clarithromycin-resistant Mycobacterium avium strains isolated from AIDS patients during therapy regimens including clarithromycin.

OBJECTIVES: Sixteen Mycobacterium avium strains were isolated from the blood of eight AIDS patients over a period of months. All the patients were on combination therapies including clarithromycin, and all had treatment failure and relapses of M.avium bacteremia. Paired clarithromycin-sensitive and resistant M.avium strains isolated at the beginning of treatment and at the first relapse of bacteremia were compared. METHODS: The M.avium isolates were identified after hybridization with DNA probes specific for M.avium rRNA and typed epidemiologically with random amplified polymorphic DNA analyses using three arbitrary primers. The rate of intracellular cell entry or the tumour necrosis factor alpha induction by the M.avium isolates were studied in human monocytes and J774 cells. RESULTS: When the M.avium isolates were hybridized with the rRNA probes, we obtained lower hybridization values with clarithromycin-resistant isolates than with clarithromycin-sensitive isolates. This appeared to be due to smaller amounts of rRNA available for hybridization than to mutation of the 23S rRNA sequences in clarithromycin-resistant strains. The RAPD analyses showed that the clarithromycin-resistant isolates were clonally related to the clarithromycin-sensitive strains in six of the eight patients. The other two patients had a RAPD profile, suggesting a re-infection and/or polyclonal infection. The M.avium isolates obtained on day 0 and after the emergence of resistance to clarithromycin did not differ in terms of their intracellular entry rate, or in terms of tumour necrosis factor alpha induction. CONCLUSIONS: We infer that M.avium strains isolated during bacteraemic relapses on combination therapies including clarithromycin are epidemiologically related to the initial strain and do not show changes in the rate of intracellular cell entry and in terms of tumour necrosis factor alpha induction. Re-infections and/or polyclonal infections however, although less frequent, can also occur.

Autoimmunity and normal immune functions in aged humans.

The high frequency of ANA, A-LDL and RF in advanced age suggests that AABs are present in the majority of aged subjects. CIC incidence determined by three methods is far below AAB incidence; only the Clq solubility test suggests an increased CIC incidence in aged as compared to young subjects. Simultaneous occurrence of AABs of different specificities or CIC determined by two or three methods is rare and both AAB and CIC levels are usually low. AAB prevalence in CIC-positive individuals seems to depend on the specificity of the AAB. CIC positivity is associated with relatively low Clq concentrations; however, usually not with Clq concentrations below the normal range. Neither ANA nor CIC positivity seems to correlate with DNA synthetic response to PHA, but ANA positivity may be associated with low responses to allogeneic cells. ANA positivity and, to a lesser extent, CIC positivity seems to be connected with enhanced killer cell activity. The concept of some AABs and CIC as autoregulatory factors of the humoral immune system compensating for the thymus-dependent regulation in old age is stressed.

Cell-mediated and humoral immune response in various vascular diseases.

Cellular and humoral immune reactions were studied in patients with myocardial infarction, arteriosclerosis obliterans and superficial thrombophlebitis. Antigens were prepared from human aortic wall with lipid plaques and from vena cava tissue. Migration of leukocytes was inhibited and both DNA-synthesis and antibody production were increased in all groups of patients. No immune reaction could be observed in the controls. A cross-reactivity between aortic and vascular extracts was detected by the leukocyte migration test and by the passive hemagglutination technique, while the induction of DNA-synthesis proved to be specific. Investigating the time-kinetics of cellular and humoral immune response, cellular immune reactions were found to be still present long after the appearance of humoral antibodies.

Lack of resistance to erythromycin, rifampicin and ciprofloxacin in 98 clinical isolates of Legionella pneumophila.

Ninety-eight consecutive clinical isolates of Legionella pneumophila were tested for erythromycin, rifampicin and ciprofloxacin susceptibility. MICs, determined by agar dilution testing, were in the range 0.06-1 mg/L of erythromycin, 0.007-0.015 mg/L of rifampicin and 0.015-0.03 mg/L of ciprofloxacin. No resistance against the antibiotics tested was detected. It is thus likely that therapeutic failures in legionnaires' disease are not related to the emergence of resistance against commonly used antimicrobial agents.

Evaluation of the Etest for rapid susceptibility testing of Mycobacterium avium to clarithromycin.

MICs of clarithromycin were determined by the Etest method for thirty clinical strains of Mycobacterium avium complex (MAC) and compared with MICs results as determined by the reference agar dilution method. Agreement (within +/- 1 log2 dilution) between the Etest and the reference method was 70% for susceptible strains and 100% for resistant strains. No major errors resulting in misclassification in susceptibility or resistance categories were detected for the Etest MIC method. It is suggested that the Etest is easy to perform and is an accurate method for determining susceptibility of MAC strains to clarithromycin.

Age-dependent responsiveness of T lymphocytes to allogeneic and PHA stimulation.

In the course of family investigations a linear age-dependent decrease of reactivity against pooled allogeneic lymphocytes was found between 20 and 70 yr of age. This decreasing tendency was ascertained also by the investigation of unrelated people of a more advanced age. In the elderly, maximal transformation values in PHA stimulation investigated at different PHA doses showed a similar degree of reduction as allogeneic reactivity, and a good correlation between the two parameters of T-lymphocyte function has been found.

Mixed lymphocyte culture search for HLA-D homozygous typing cells in the Hungarian inbred population of Ivád.

Six functionally HLA-D homozygous typing cells were identified by a restricted investigation into the Hungarian inbred population of Ivád. These putative HLA-D homozygous typing cells were then tested against a highly selected Scandinavian population sample of 60 individuals previously typed by histocompatibility reference reagents. The different HLA-D specificities could thus be identified: one closely matching HLA-Dw5, another resembling the Oslo LDoH specificity, while the last seems to be unique. Only one of the typing cells thus ascertained were HLA-B homozygous and were selected on the basis of the Ivád family structure and not on the basis of serological HLA typing.

Studies of the HLA--D determinants in the Hungarian population.

A Hungarian random population sample was tested for six well-known and two new HLA--D specificities. HLA--D antigen and gene frequencies in the studied population agree with the frequencies observed in pooled random Caucasians, only HLA--Dw3 being significantly elevated. The incidences of Dw1 and Dw4 are, however, lower while the incidences of the Dw5 and Dw6 alleles seem to be higher in our population sample without reaching statistical significance. As for the two new specificities, the IVAD-1 specificity has a low frequency, while IVAD-3 occurs quite frequently. HLA--B and HLA--D associations seem to be different in our population sample as compared to others. In spite of the high incidence of the HLA--Bw35 antigen, no HLA--D association was found. The two new HLA--D specificities did not show association with any of the established HLA--B antigens.