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Biomedical subjects

R J Levinsky

Publications and source records attributed to R J Levinsky.

At least 109 records · Page 6Linked to original sources
PubMed1987

Heterogeneity of biochemical, clinical and immunological parameters in severe combined immunodeficiency due to adenosine deaminase deficiency.

There was considerable heterogeneity of the biochemical, clinical and immunological findings in 12 patients and two fetuses from 16 kindreds affected by severe combined immunodeficiency (SCID) due to a complete deficiency of the enzyme adenosine deaminase (ADA). Despite this heterogeneity a consistent pattern was observed, in which levels of abnormal purine metabolites paralleled the severity of the immunodeficiency. A high level of urinary deoxyadenosine was a universal finding for homozygous ADA deficiency. ATP depletion, in association with raised deoxy-ATP (dATP) levels, was found in the erythrocytes of nine infants with profound cellular and humoral immunodeficiency. There was no erythrocyte ATP depletion in two patients with some residual immunity, who presented later, but adenosine accumulated in their plasma and urine. This finding, together with the presence of some T and normal B-lymphocytes in less severely affected patients, suggests that adenosine is relatively non-toxic. The other results are consistent with the hypothesis that the sequence of deoxyadenosine accumulation, dATP formation and ATP depletion represents the major mechanism of toxicity to the immune system. Low numbers of T lymphocytes and dATP accumulation were also found in the blood of affected fetuses at 18 weeks gestation. Since extreme instability of erythrocyte ADA was demonstrated in some heterozygotes, and heterozygote ADA levels were detected in one infant with SCID, simultaneous immunological and biochemical analysis of fetal blood are important for precise antenatal diagnosis.

Adenosine Deaminase↗
PubMed1986

T cell help in human antigen-specific antibody responses can be replaced by interleukin 2.

Recombinant IL 2, and immunosorbent/high performance liquid chromatography-purified interleukin 2 (IL 2) obtained from the human T cell leukemic line Jurkat, but not interferon-alpha or -gamma, were able to substitute for T cells in specific antibody responses to influenza virus by T cell-depleted (E-) human peripheral blood mononuclear cells, and resulted in antibody formation equivalent to that obtained in the presence of T cells. The antibody response was shown to be antigen specific by using two non-cross-reacting strains of influenza virus (A/X31 and B/HK). IL 2 in this assay therefore functions as a T cell-replacing factor. Less than 1% of T (UCHT1+) cells were present in the E- preparations, and this number did not increase during the 7-day culture with antigen and IL 2. Because the frequency of T helper cells for X31 is known to be less than 5 X 10(-5), this low number of contaminating cells excluded indirect action of IL 2 through antigen-specific T helper cells. Three to four times less IL 2 was required for antibody production by E- cells than was needed for optimal proliferation by an IL 2-dependent T cell line. Moreover, the concentration of anti-Tac required for 50% inhibition of the IL 2-induced antibody response was 50 times less than required for 50% inhibition of IL 2-dependent proliferation by the T cell line. But when T cells were added back to the E- cells, the anti-Tac inhibition curve shifted back to that obtained with the T cell line. In cell labeling experiments, Leu 11+ cells but not HNK1+ cells were increased in E- cells cultured with antigen and IL 2. This increase in Leu 11+ cells was abolished by prior passage of the E- cells through Sephadex G-10 columns without affecting the IL 2-induced antibody response. From these experiments we conclude that IL 2 can replace T cells in specific antibody responses, and that the IL 2 effect is not mediated indirectly through T cells or large granular lymphocytes.

Antibody Formation↗
PubMed1986

Generation of phenotypically different T cell populations by cell-free or cell-bound preparations of varicella zoster virus.

We used three different preparations of varicella zoster virus (VZV) to sensitise mononuclear cells obtained from VZV immune donors. These were autologous infected fibroblasts, live cell free virus and heat inactivated cell free virus. After 14 days of in vitro sensitisation and expansion with interleukin-2, the mononuclear cells which had been exposed to autologous infected fibroblasts had generated mainly cells of the cytotoxic/suppressor phenotype (CD8) while those stimulated with cell free virus (live or heat inactivated) had generated cells of the helper/inducer phenotype (CD4). Functional assays showed that the effector cells generated after exposure to autologous infected fibroblasts lysed autologous virus infected target cells but not uninfected cells. Effector cells generated in the same way but lacking HLA identity with the virus infected target cells failed to demonstrate cytotoxicity. None of these effector cells showed any significant natural killer cell activity. No specific cytotoxicity was obtained by effector cells generated after exposure to cell-free virus. We conclude that the way in which VZV antigen is presented to the mononuclear cells influences the cell type responding in tissue culture. These findings would be useful in the generation of T cell clones of different cell surface phenotype and function.

Bone Marrow↗
PubMed1986

Successful haploidentical mismatched bone marrow transplantation in severe combined immunodeficiency: T cell removal using CAMPATH-I monoclonal antibody and E-rosetting.

Six patients with severe combined immunodeficiency were transplanted with bone marrow from their HLA haploidentical parents. T-lymphocytes were removed by complement mediated lysis with a monoclonal antibody (CAMPATH-I) followed by rosetting with sheep erythrocytes. The patients were pre-conditioned with marrow ablative chemotherapy, using busulphan and cyclophosphamide. There was graft take in five patients, with evidence of transient acute graft-versus-host disease only. Three patients are alive and well greater than 5 months after transplant, and one who is 12 months post graft has full reconstitution of cell mediated and humoral immunity, including specific antibody response to immunization. Transplantation across major histocompatibility barriers can be successfully achieved using this method of treatment of donor marrow.

Antibodies, Monoclonal↗
PubMed1986

A family study of the X-linked lymphoproliferative syndrome: evidence for a B cell defect contributing to the immunodeficiency.

The X-linked lymphoproliferative syndrome (XLPS) is an immunodeficiency characterized by severe primary infection with the Epstein Barr (EB) virus, which is often fatal. This has been attributed to failure to generate T lymphocytes which are specifically cytotoxic for EB virus-infected B lymphocytes, and which develop in all normal individuals following primary infection. We have studied a kindred which carried the defective gene for XLPS and have confirmed that the pattern of serum antibody responses to EB viral antigens can be used to detect affected males and female carriers. Furthermore, an EB virus genome-carrying B cell line which grew spontaneously from a culture of bone marrow cells from a male child with XLPS at the time of primary infection showed a decreased sensitivity to MHC-restricted, EB virus-specific killing by a T cell clone when compared to its in vitro EB virus-transformed counterpart. From these results we suggest that a subset of EB virus-infected B lymphocytes which were resistant to EB virus-specific killing existed in this child, and may have contributed to the overwhelming EB virus infection and its fatal outcome.

Antibodies, Viral↗
PubMed1986

Evaluation of C3b/C3bi opsonization and chemiluminescence with selected yeasts and bacteria using sera of different opsonic potential.

C3 fragment opsonization and chemiluminescence were assessed using two yeasts (Saccharomyces cerevisiae and Candida albicans) and two strains of bacteria (Staphylococcus aureus and Escherichia coli) following incubation with sera previously shown to be either efficient or poor in the opsonization of baker's yeast. Sera with poor function consistently fixed lower levels of C3 fragments and generated less chemiluminescence with all four organisms than sera with normal function. The differences were most marked with the two yeasts. We conclude that sera with normal complement function but manifesting a relatively common defect in the opsonization of baker's yeast have a general opsonic defect.

Adult↗
PubMed1985

Immunological cross-reactivities among three herpesviruses.

Sixty adults were tested for humoral and cell-mediated immunity to varicella zoster virus (VZV), type 1 herpes simplex virus (HSV-1) and the human cytomegalovirus (CMV). Since herpesviruses share common antigens, we compared results in these individuals to assess whether our tests gave false positives due to cross-reactions. Of the 60, IgG antibody to VZV, HSV-1, CMV tested by ELISA was detected in 51 (85%), 34 (57%) and 20 (33%) respectively. All possible permutations of results were obtained and there was no evidence of cross-reactivity among the viruses. Lymphocyte transformation performed in 20 was found to be positive in 16 (80%), 13 (65%) and 8 (40%) for VZV, HSV-1 and CMV respectively. Similarly, all possible permutations of results were obtained. In addition, 8 subjects were found to have positive lymphocyte transformation responses for one or other of the viral antigens but no specific antibody was found in their sera. Thus, the antibody and lymphocyte transformation test were not influenced by possible cross-reacting antigens among the 3 herpesviruses we studied. Both tests are necessary to firmly establish whether a subject has had a prior infection.

Adolescent↗
PubMed1985

Immunisation of nurses with a live varicella vaccine.

34 nurses who had no previous history of chickenpox and were seronegative to varicella zoster virus (VZV) were immunised with a live attenuated varicella vaccine (OKA-RIT strain) and followed up for up to 36 months. No major vaccine reactions were observed. At 5 months and at 1 year, 94% of the nurses had seroconverted but at 3 years only 64% had detectable antibody. Lymphocyte transformation to VZV antigen tested in seven nurses in whom antibody was no longer detectable gave positive stimulation indices. 2 of 13 vaccinated nurses who looked after children with chickenpox became infected but 1 of them had not seroconverted after vaccination. Chickenpox developed in 6 out of 7 unvaccinated seronegative nurses who looked after children with chickenpox. This study shows that the OKA-RIT strain VZV vaccine is safe and immunogenic in adults and may therefore be considered for use in susceptible health care workers. The investigations also show that both cell-mediated and antibody tests are needed for long-term assessment of immunity to chickenpox after vaccination.

Adolescent↗
PubMed1985

Platelet immune complex interaction in pathogenesis of Kawasaki disease and childhood polyarteritis.

The role of platelets in the pathogenesis of vasculitis and the formation of coronary artery aneurysms was studied in 19 children with Kawasaki disease and five with polyarteritis. All patients with Kawasaki disease developed thrombocytosis in the third week of illness. The peak platelet count was significantly correlated (p less than 0.005) with the subsequent development of coronary artery aneurysms. The rise in platelet count was associated with the appearance in the circulation of a factor that induced aggregation and serotonin release in normal platelets. This factor was shown to be of high molecular weight, and its activity was lost at low pH--features suggestive of an immune complex. Immune complexes, detected by precipitation with polyethylene glycol, also appeared in the circulation as the platelet count increased. These complexes induced platelet aggregation, and there was a significant correlation (p less than 0.001) between the concentrations of IgG and IgA in the polyethylene glycol precipitated material and the platelet aggregating activity. Similar platelet aggregating activity was also detected in patients with polyarteritis but followed a different time course, persisting in the circulation for several months in association with continued disease activity. These findings imply that different mechanisms have a role in distinct phases of Kawasaki disease. The initial feverish phase (probably infective) is probably followed by an immune complex vasculitis that occurs when antibodies to the initiating agent appear in the circulation. The immune complexes aggregate platelets and induce release of serotonin. Platelet derived vasoactive mediators may increase vascular permeability and facilitate further deposition of complexes in the tissues.

Aneurysm↗
PubMed1985

Immunity to varicella-zoster virus in a normal adult population.

Sera from 489 trainee nurses were examined, by the ELISA technique, for the presence of varicella-zoster virus specific antibody; antibody was found in 446 (91.2%). In more detailed investigations of specific immunity in 33 healthy adults with a past history of chickenpox, 32 (97%) showed a positive lymphocyte transformation test, but only 11 out of 23 examined (48%) demonstrated mononuclear cell production of specific antibody in vitro; serum antibody was found in 30 (91%) by the ELISA and in 25 out of 26 examined (96%) by the FAMA technique. A high degree of correlation was found between both a positive lymphocyte transformation and the presence of serum antibody and a past history of chickenpox.

Adult↗
PubMed1985

Treatment of respiratory papillomatosis with adenine arabinoside.

Nine children with respiratory papillomatosis have been treated with adenine arabinoside with limited success. No long term benefit was obtained in six, and although resolution was achieved in one and probably two others, this could not be attributed confidently to treatment.

Adolescent↗
PubMed1985

Live varicella immunization in healthy non-immune nurses.

Thirty-four varicella-zoster virus (VZV) seronegative nurses were vaccinated with the live varicella vaccine (Varilrix) and followed for periods of up to 36 months. No major vaccine reactions were observed. At 5 and 12 months, 94% of the nurses had seroconverted but at 3 years, only 64% retained antibody activity. However, lymphocyte transformation to VZV antigen was positive in 7 seronegative nurses, all of whom had previously seroconverted. The one nurse who developed chickenpox had not seroconverted after vaccination. Two out of 11 seroconverted nurses had a subclinical reinfection, as shown by a rise in antibody, upon exposure to varicella. In contrast, 4 out of 5 seronegative nurses who had refused vaccination developed chickenpox. Varilrix is therefore safe, immunogenic, and protective in adults and can be considered for routine use in susceptible health workers. However, it is still uncertain whether lifelong immunity is obtained with this vaccine. Both cell-mediated and antibody tests are needed for long-term assessment of immunity to chickenpox.

Adult↗
PubMed1985

Bone marrow T cell colony-forming cells: studies of their origin and use in monitoring T cell-depleted bone marrow grafts.

Peripheral blood T cell colony forming cells (T-CFC) are mature T cells. When blood was fractionated into sheep red blood cell receptor positive (E+) and negative (E-) fractions, T cell colony growth was largely restricted to the E+ population. When bone marrow was similarly fractionated, many colonies grew from the E- cells but myeloid colonies also grew making interpretation of colony numbers difficult. We have, therefore, also assessed T cell proliferation during culture as an expansion index (EI) by determining the absolute number of T cells pre and post culture. This data shows that T cell expansion is on average nine times greater in the E- marrow fraction than in the E+ fraction. Studies are presented suggesting that this is because marrow E- cells contain appropriate accessory cells and that high numbers of T cells inhibit T cell growth. The cells giving rise to bone marrow T cell colonies thus appear to be contaminating mature T cells rather than pre-thymic progenitor cells. We have measured T cell expansion in culture as a sensitive assay of T cell contamination following procedures to remove T cells from bone marrow grafts for the prevention of graft versus host disease (GVHD).

Bone Marrow↗