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Biomedical subjects

M K Brenner

Publications and source records attributed to M K Brenner.

At least 199 records · Page 11Linked to original sources
PubMed1986

Production of anti-cytomegalovirus antibody following T-cell depleted bone marrow transplant.

The serological status to cytomegalovirus (CMV) was examined in 24 patients with no detectable CMV excretion, following T-lymphocyte depleted bone marrow transplantation. The results show that seropositive recipients continue to produce CMV antibody regardless of the serological status of the donor but that seronegative recipients fail to produce CMV antibody even when the donor is seropositive. These findings suggest that when an effective CMV vaccine becomes available vaccination of the donor would be unlikely to confer protection on the recipient but that vaccination of the recipient may achieve this.

Antibodies, Viral↗
PubMed1986

Standardization of T-cell depletion in HLA matched bone marrow transplantation.

The IBM 2991 Blood Cell Processor has been used to isolate a mononuclear cell (MNC) fraction from the marrow of 31 allogeneic donors. The MNC fraction was then incubated with a combination of two murine monoclonal antibodies MBG6 (CD6) and RFT8 (CD8) followed by two rounds of treatment with rabbit complement resulting in a marrow inoculum significantly reduced in the number of T-lymphocytes. We report here new specifications for the use of Ficoll-Metrizoate, the method used to calculate T-lymphocyte depletion and the details of our attempts to improve T-depletion. Following marrow transplantation with this T-depleted fraction, 29 patients are evaluable for engraftment, one patient failed to engraft and one died too early for evaluation. Twenty-two had no acute graft-versus-host disease (aGvHD), at a minimum of 60 d, six had grade I acute GvHD and one grade III. No correlation was found between the absolute number of MNC infused and time to engraftment, nor any relationship between the number of residual viable T-lymphocytes in the infused marrow and the incidence of GvHD, but the patient with the most severe aGvHD also had the highest number of T-lymphocytes infused.

Antibodies, Monoclonal↗
PubMed1986

Recovery of immunoglobulin isotypes following T-cell depleted allogeneic bone marrow transplantation.

After conventional bone marrow transplantation serum IgG, IgM and IgA levels fall from pre-transplant levels and may not return to normal for 3-12 months. In contrast IgE may rise to supranormal levels, an event that may be associated with graft-versus-host disease. We have investigated the recovery of immunoglobulin isotypes in the recipients of allogeneic marrows depleted of T-cells to prevent graft-versus-host disease. We find that pre-transplant IgG, IgM and IgA levels are maintained throughout the post-transplant period but that there is a short-lived rise in IgE about 3 weeks after transplantation: this rise occurs in the absence of clinically detectable graft-versus-host disease. We conclude that specific T-cell depletion does not impair and may actually enhance the functional recovery of B cells after allogeneic BMT.

Adolescent↗
PubMed1986

Haemolysis after T-cell depleted bone marrow transplantation involving minor AB0 incompatibility.

9 recipients of T-cell depleted allogeneic bone marrows (8 group A, 1 group AB) from group 0 donors were monitored after transplantation. Free anti-A/B was demonstrable in 8 of the 9 recipients 10-19 d post-transplant, 5 patients developed a positive direct anti-globulin test and 7 showed a rise in bilirubin. The presence of antibody was generally unrelated to the infusion of incompatible plasma, although 2 patients who also received anti-CMV immunoglobulin subsequently shown to contain high titre IgG anti-A/B were more severely affected, sustaining a fall in Hb of up to 2 g/d. These observations suggest that, after T-cell depleted bone marrow transplantation, immunocompetent B lymphocytes of donor origin are transferred, secrete antibody in the recipient, and may be responsible for self-limiting haemolytic episodes.

ABO Blood-Group System↗
PubMed1986

The effect of breast-feeding on proliferation by infant lymphocytes in vitro.

The effect of breast-feeding on the development of lymphocyte responsiveness in infants has been studied. Peripheral blood mononuclear cells from 15 breast- and 15 bottle-fed infants were obtained sequentially between 6 days and 9 months of age. A number of agents were used to stimulate the cells in vitro and the resulting proliferative responses were compared between the two feeding groups. A hanging drop microculture system using serum-free medium, enabled spontaneous proliferation and proliferative responses to several stimuli (T and B cell mitogens, allogeneic lymphocytes, and antigen) to be studied at a range of cell concentrations and days of culture. Significant age-related differences were found between the responses of cells from the two feeding groups. Spontaneous proliferation and proliferative responses to the T cell mitogen phytohaemagglutinin and the antigen tetanus toxoid were significantly greater in the breast-fed group at the two earliest ages studied (6 days and 6 wk). Responses to mitogens which predominantly affect B cells, such as pokeweed mitogen and Staphylococcus aureus (Cowan), were similar in both feeding groups at this age. In contrast, from 3 to 9 months of age, responses of cells from bottle-fed infants were significantly greater to all stimuli than responses from breast-fed infants. One possible explanation for the higher level of proliferation by cells from newborn breast-fed infants, is that these infants may absorb the cell-growth factors and lymphokines known to be present in human colostrum and milk. These factors may stimulate T cells and/or their precursors in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Feeding↗
PubMed1986

T lymphocyte regeneration after transplantation of T cell depleted allogeneic bone marrow.

The regeneration of T cell subsets was studied with double immunofluorescence marker methods in 37 patients who received HLA matched T lymphocyte depleted bone marrow transplants (BMT) as part of the treatment for their haematological disease. A cocktail of anti-pan-T (CD6: MBG6) and anti-suppressor/cytotoxic-T cell (CD8: RFT8) monoclonal antibodies was used with rabbit serum as a source of cytolytic complement to achieve selective T cell lysis. The T8+ cells reached low normal values around 60 days post-transplant and remained within the normal range throughout the study (greater than 150 days). This observation is in contrast to our previously published results in patients who, after receiving BMT without efficient T cell depletion, had increased numbers of circulation T8+ cells from 60 days post-transplant. In the present study Leu-7+, RFT8- cells reached normal values rapidly but the reconstitution of T4+ lymphocytes was slow: low normal levels were reached only around day 150 following BMT. The degree of graft-versus-host disease (GVHD) seemed to be related to the number of residual T cells infused: two of the three patients who received the highest numbers of T cells developed Grade II III; otherwise GVHD was minimal. Among the clinical parameters studied cytomegalovirus (CMV) immune status moderately influenced reconstitution: at 55-90 days post-transplant T8+ cells were present at the upper normal levels in seven out of 15 patients receiving BMT from CMV seronegative donors, but in none of the 16 individuals receiving BMT from seropositive donors. CMV related complications were relatively uncommon. Thus the most significant factor in preventing 'T8+ cell overshoot' and T cell imbalance during regeneration appears to be the depletion of T (including T8+) lymphocytes from marrow. The differences of T8+ cell reconstitution in this and previous studies may reflect a different regeneration pattern from T cell precursors as opposed to inoculated mature T cells.

Adolescent↗
PubMed1986

The use of monoclonal antibodies in graft versus host disease prevention.

One of the most important causes of procedure related death after bone marrow transplantation (BMT) is graft versus host disease (GvHD) in which donor T-lymphocytes recognise alloantigens in the recipient and attack and damage the cells bearing them. Even when donor and recipient are matched at all loci of the major histocompatibility complex (MHC) 40%-70% of recipients develop severe graft versus host disease after conventional BMT: in a third of those affected the outcome is fatal. When donor and recipient are less than identical at the MHC the incidence and severity of acute graft versus host disease are correspondingly higher. The morbidity and mortality associated with acute GvHD has limited the application of bone marrow transplantation in two ways: first by restricting the procedure to patients with serious haematological disease and second by excluding individuals who might benefit from BMT but who lack an MHC identical sibling. In this review we discuss briefly the theoretical work that led us to our protocol for T-cell depletion for GvHD prevention and then describe the results of our own and other groups undertaking T-cell depleted bone marrow transplants. Finally, we discuss some of the new problems--and benefits--associated with T-cell depletion and outline the improvements in techniques now taking place.

Antibodies, Monoclonal↗
PubMed1985

Human clones with natural killer function can activate B cells and secrete B cell differentiation factors.

Large granular lymphocyte clones were prepared from normal human mononuclear cells. Seven clones were studied in detail. All had high cytotoxic activity against the natural killer (NK) cell target K562 and all were T11- and DR-positive but T4- and T8-negative: none released migration inhibitory factor, a characteristic of helper T cell clones. When these NK cell clones were co-cultured with autologous B cells in a 1:1 ratio, 4 of the 7 induced both IgM and IgG synthesis. Ig production could not be further enhanced by the addition of B cell differentiation factors. The cells stimulated included antigen-specific memory B cells, as the Ig induced contained specific antibody to an antigen, tetanus toxoid, to which the B cell donors had recently been immunized. Supernatants from the helper/NK clones contained B cell differentiation factors, and were able to induce IgG synthesis from the lymphoblastoid cell line CESS and from co-cultured T and B cells. However, NK clone supernatants, unlike the clones themselves, were not effective at inducing Ig synthesis from purified B cells. Instead it appears that NK clones first activate B cells and thus render them responsive to the factors that the clones secrete.

Antibody Formation↗
PubMed1984

Intravenous gammaglobulin treatment in patients with hypogammaglobulinaemia.

Intravenous gammaglobulin was compared with the standard British intramuscular preparation in patients with hypogammaglobulinaemia and chronic bronchitis. Five patients were given six months' treatment with the weekly intramuscular preparation and six months' treatment with intravenous gammaglobulin given once every 18 days. During the trial they recorded symptoms of infection, absence from work, and sputum volume; lung function tests were performed during the intravenous treatment. The half life of the intravenous IgG and changes in serum IgG and C1q concentrations were also measured in seven other patients who received intravenous gammaglobulin every two weeks for 12 weeks. IgG concentrations, sputum volume, and infection scores were significantly better during intravenous treatment and there were no adverse effects from the intravenous gammaglobulin. These five patients were significantly more healthy when they received an intravenous gammaglobulin preparation, probably because the intravenous preparation increased serum IgG concentrations. Although longer studies are needed, intravenous gammaglobulin should be considered for patients with severe chest disease and those who cannot tolerate intramuscular injections.

Agammaglobulinemia↗
PubMed1984

Evaluation of test immunisation in the assessment of antibody deficiency syndromes.

Antibody responses after immunisation with pneumococcal polysaccharide did not correlate with the severity and frequency of infections in 22 patients with severe hypogammaglobulinaemia, when these were measured by a Farr radioimmunoassay. Five "healthy" patients with severe hypogammaglobulinaemia not only failed to make antipneumococcal polysaccharide antibody, when measured by radioimmunoassay, but also had very low or unrecordable antibody responses to Escherichia coli and failed to produce antibody when immunised with tetanus toxoid. Some of these subjects, however, did make small amounts of IgM antipneumococcal polysaccharide antibody when this was measured by an enzyme linked immunosorbent assay, while others retained some ability to produce IgM or IgA or both in their saliva. These findings show that the measurement of serum antibody responses after immunisation, with the possible exception of IgM antibodies to polysaccharides, is unlikely to be helpful in assessing the requirement for gammaglobulin replacement therapy in patients with hypogammaglobulinaemia.

Adult↗
PubMed1984

Production of antibody by human B cells under serum-free conditions.

A method is described for growing human B cells in 20 microliter hanging drops in Terasaki plates under serum-free conditions. B cell proliferation and differentiation has a critical dependence for added soybean lipid, while T cell proliferation does not. In this medium, pokeweed mitogen stimulation of separated human B cells induces high levels of immunoglobulin in a T dependent manner. Cells from donors vaccinated with tetanus toxoid and shown to be responders by a conventional culture system, produce high levels of IgG anti-tetanus antibody after antigen stimulation in these serum-free microcultures. The serum free culture system has the novel features of high sensitivity to dose of mitogen or antigen, low background responses and high antibody production with low cell numbers.

Antibodies, Bacterial↗
PubMed1984

The role of B cell differentiation factors and specific T cell help in the pathogenesis of primary hypogammaglobulinemia.

We have examined the function of T and B cells from patients with late onset primary acquired hypogammaglobulinemia (PHG). T cells from these patients give effective help to normal B cells for antigen-dependent antibody synthesis. PHG mononuclear cells also synthesize normal quantities of B cell differentiation factors, which enhance IgG, IgM and antigen-dependent antibody synthesis by normal lymphocytes. While patient T cells appear to behave appropriately, the responsiveness of patient B cells is abnormal. Although they respond to differentiation factors with increased synthesis of IgM, overall levels are 10-50-fold lower than normal B cells, and they produce little or no IgG. This pattern of response is not altered if normal T cells are the source of help. The poor response of the B cell appears to represent immaturity rather than an inherent defect, as IgG-secreting clones can be obtained after Epstein-Barr virus transformation of lymphocytes from certain patients, and some of these clones respond to differentiation factors with increased IgG production. The lack of any functional defect in the T population, and the apparent immaturity rather than abnormality of the B cells, may implicate accessory cells in the pathogenesis of the disease.

Agammaglobulinemia↗
PubMed1984

In-vivo immune responses of breast- and bottle-fed infants to tetanus toxoid antigen and to normal gut flora.

The effects of breast- and bottle-feeding on serum immunoglobulin levels and specific antibody responses have been examined in 30 infants on five occasions from 6 days until 9 months of age. No significant differences were found on any sample occasion between the two feeding groups in total immunoglobulin levels of G, M and A classes or in class-specific antibody responses to tetanus toxoid vaccine. This suggests that the capacity of the two groups to make serum antibodies develops similarly. Concentrations of antibodies to commensal Escherichia coli 'O' lipopolysaccharide antigens, however, were significantly greater in the bottle-fed group, and it is suggested that this difference is due to an increase in the exposure of the systemic immune system to these gut antigens in the bottle-fed infants. There are several possible explanations for this increased exposure and the resulting effects on the infants' immune system. These experiments also illustrate a possible role of breast milk in stimulating the immune system.

Antibodies, Bacterial↗
PubMed1984

Thymoma and hypogammaglobulinaemia with and without T suppressor cells.

Patients with acquired hypogammaglobulinaemia usually have near normal numbers of B cells and normal T cell function. When hypogammaglobulinaemia occurs in association with thymoma, then B cell numbers have been reported as low, and distinctive T cells are present which inhibit immunoglobulin production by normal cells. It has been suggested that these T cells are responsible for the observed hypogammaglobulinaemia. We report a patient with thymoma and hypogammaglobulinaemia who lacks these distinctive suppressor cells and has normal B cell numbers. It is therefore incorrect to propose a single pathogenic mechanism for hypogammaglobulinaemia in association with thymoma.

Agammaglobulinemia↗
PubMed1984

Non-specific factor enhancement of human in vitro antigen-dependent antibody synthesis: role of B cell activation and T cell help.

Lectin-free supernatants obtained from PWM-stimulated lymphocytes, enable B cells to proliferate and secrete immunoglobulin. Both functions are augmented by the addition of irradiated T cells. In the presence of antigen, these supernatants also enhance specific anti-tetanus toxoid antibody production. The components of the supernatant responsible for these activities have a molecular weight between 30,000 and 60,000, and have the characteristics of non-specific factors: they are genetically unrestricted, and do not bind to either antigen or anti-DR affinity columns. There is no evidence that the partial T dependency of these factors is an indication that their target is a T cell. Instead, T cells appear necessary to move the B cell into a state of activation in which it becomes responsive to the factor. Alternative activation signals such as Staph. A. Cowan can substitute for T cell help in the proliferative response, but not for immunoglobulin or antibody synthesis. The implications of these results for the approaches used to detect and classify B cell growth factors are discussed.

Antibody Formation↗
PubMed1983

Human B cell growth factors overcome T cell-mediated inhibition of specific antibody production: a possible mechanism for the exacerbation of autoimmune disease.

Under normal circumstances, antigen-dependent antibody production in man requires autologous T cells, B cells and macrophages. If allogeneic T cells are substituted, then antibodies are not synthesized, due to the development of inhibitory interactions. Addition of B cell growth and differentiation factors changes this pattern of response, and allows antibodies to be produced even when allogeneic T cells are the source of help. There is evidence that such B cell growth factors are released during most normal immune responses: we suggest that their ability to allow B cells to escape from inhibitory interactions and secrete antibodies, may underlie the observed exacerbation of certain autoimmune diseases by intercurrent infection.

Antibody Formation↗