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Biomedical subjects

L Brent

Publications and source records attributed to L Brent.

At least 55 records · Page 3Linked to original sources
PubMed1987

Activation of lymphocytes isolated from the gastric mucosa of the mouse.

A method for the isolation of lymphocytes and epithelial cells from the murine gastric mucosa has been developed. Gastric lymphocytes were stimulated by T-cell mitogens in vitro. When mice were sensitized systemically with human gammaglobulin (HGG) and given the antigen orally 4 days before cell isolation, both the number of mucosal lymphocytes and their capacity to incorporate [3H]thymidine ([3H]TdR) was enhanced. Gastric epithelial cells added to cultures of syngeneic spleen cells enhanced both phytohaemagglutinin (PHA) responsiveness and mixed lymphocyte reactions (MLR) in low numbers, but significantly suppressed these responses at high concentrations. These findings suggest that gastric lymphocytes, like those of the gut, are involved in the immune response against antigens taken in by mouth, and that there may be in vivo interactions between gastric mucosa lymphocytes and epithelial cells.

Animals↗
PubMed1987

Human fetal lymphocytes require T cell growth factors for cytotoxic responses.

Lymphocytes isolated from the blood of 17 human fetuses, varying in gestational age between 16 and 26 weeks, were tested for their capacity to generate specific cytotoxic cells after mixed lymphocyte culture (MLC) with allogeneic cells in the presence or absence of exogenous T cell growth factor (TCGF). Blood cells from seven fetuses, distributed throughout the age range, failed to generate cytotoxic cells even when TCGF was added in MLC, whereas six others gave positive responses but only when exogenous TCGF was present during the sensitisation phase. The maturation induced in the latter was not caused solely by a direct, non-specific effect of the TCGF, for control responder cells incubated with TCGF in the absence of allogeneic stimulator cells always responded less strongly or not at all. Fetal blood lymphocytes from the remaining four fetuses gave significant cytotoxic responses that were not augmented by TCGF. It is concluded that there can be a clear dichotomy between proliferative and cytotoxic responses to alloantigens and that the inability of human fetal blood lymphocytes to mount cytotoxic responses at this stage of development might be due to deficiencies in helper cells, cytotoxic precursors or both. For three fetuses it was possible to study, additionally, cytotoxic responses of spleen, liver and thymus with and without TCGF. None of them made specific responses even when TCGF was added, though cells from two spleens and one thymus responded directly to TCGF. To ascertain whether the absence of cytotoxic responses might have been caused by a failure of blood, spleen, thymus or liver cells to proliferate, their mixed lymphocyte reactivity, as detected by the uptake of 3H-thymidine, was studied without exogenous TCGF. Whereas thymus cells from only one of five fetuses responded, cells from all other tissues (including blood) responded consistently.

Adult↗
PubMed1986

Presentation of alloantigens by host cells.

Presentation of alloantigens by host cells has been examined in vivo by means of a murine cell transfer system. Primary (1 degree) hosts were activated by the i.p. administration of allogeneic spleen cells and their spleen or peritoneal cells were transferred into syngeneic secondary (2 degrees) hosts 3 days later. Sensitization of 2 degrees hosts was assessed by their ability to reject donor strain skin grafts prematurely. The transferred cells were routinely depleted of T lymphocytes. We show that (a) 5 X 10(7) spleen and 3 X 10(6) peritoneal cells consistently caused marked accelerated graft rejection; (b) this effect was antigen specific and observable in all strain combinations studied; (c) it was caused by the active sensitization of 2 degrees hosts, but not by contaminating donor strain cells; (d) the cells involved were plastic adherent and viability was not a requirement; and (e) both class I and II, but not minor, histocompatibility antigens played a role in this model. We conclude that presentation of alloantigens by host antigen-presenting cells can be a potent route of allosensitization.

Animals↗
PubMed1986

Red cell volume distribution curves and intracellular globin chain precipitation in the alpha-thalassaemic mouse, Hbath-J.

Red cell volume distribution curves were studied in alpha-thalassaemic mice (Hbath-J/+ mice) and normal mice (+/+ mice) of various ages. Individual Hbath-J/+ mice could not be reliably distinguished from their +/+ littermates on the basis of modal cell volume either at birth or during the first 3 weeks of life. However, between the ages of 4 and 30 weeks Hbath-J/+ mice displayed a degree of microcytosis that enabled them to be readily distinguished from their normal littermates using the criterion of modal red cell volume. Preliminary studies of alpha:beta globin chain synthesis ratios given by blood reticulocytes of Hbath-J/+ and +/+ mice after incubation with 3H-leucine for 5 min and 2 h suggest that there is little or no proteolysis of excess beta-chains in the alpha-thalassaemic mouse. Electron microscope studies revealed that the erythroblasts, marrow reticulocytes and circulating red cells of Hbath-J/+ but not +/+ mice contain stellate and branching intracytoplasmic inclusions, presumed to consist of precipitated beta-chains. These inclusions were ultrastructurally similar to the inclusions which have been previously reported in the erythroblasts and marrow reticulocytes of people with various alpha-thalassaemia syndromes. The proportion of erythropoietic cell profiles with inclusions was higher in Hbath-J/+ mice (in which two of the four alpha-globin genes are deleted) than in Thai patients with HbH disease (in whom there is usually a deletion of three of the four alpha-globin genes); this finding is probably related to a relatively low proteolytic capacity in the more mature mouse erythroid cells when compared with human cells. The presence of inclusion-containing red cells (mainly reticulocytes) in the peripheral blood of unsplenectomized Hbath-J/+ animals contrasts with the absence of such cells in unsplenectomized patients with alpha-thalassaemia I trait and HbH disease; this difference seems to be at least partly due to a poorly-developed pitting function in the mouse spleen.

Age Factors↗
PubMed1984

The effect of T lymphocyte depletion on neonatal tolerance induction, graft-vs.-host disease and cellular chimerism.

Treatment with a monoclonal anti-Thy-1 antibody and complement completely prevented C57BL spleen cells from causing graft-vs.-host disease following their inoculation into newborn CBA mice. The proportion of mice that became tolerant to C57BL antigens, as measured by skin grafting, was significantly less compared with mice given (CBA X C57BL)F1 hybrid cells. This was not due to the elimination of T cells, for antibody-treated F1 cells induced tolerance as readily as complement-treated control F1 cells. To investigate whether the apparent superiority of F1 cells over C57BL cells is attributable to differences in the mechanism inducing and maintaining unresponsiveness, two approaches were followed. First, the level of donor cell chimerism in the spleens of tolerant animals was studied. Though no difference between F1 and C57BL cells was uncovered, the presence of T cells in the donor inocula favored the establishment of chimerism. Second, the involvement of suppressor T cells was examined in adoptive transfer experiments. Splenic suppressor T cells were associated with tolerance regardless of how it was elicited. Preliminary results with F1 cells show that the tolerogenic property is not confined to any one cell type. It is proposed that the greater tolerogenicity of F1 cells is brought about by the presence of host-type (self) antigens, which enable the tolerogenic signals to operate without recourse to antigen processing by host cells.

Animals↗
PubMed1983

Host recognition of fetal antigens: do they induce specific antibodies?

The purpose of this study was to ascertain whether the protection afforded to adult mice against the induction and growth of 3-methylcholanthrene-induced tumours by prior exposure to syngeneic fetal cells has an immunological basis. Adult CBA mice were inoculated with fetal cells according to a variety of protocols and the sera were tested for their ability to bind to fetal and adult tissue cells, using a staphylococcal protein A binding assay. All 10 sera tested showed some degree of binding though this varied from strong to weak, and there was some cross-reactivity with adult thymic cells but relatively little with adult spleen cells. Absorption studies were carried out with one of these sera and with two others raised against testicular and thymic cells, respectively. The absorption patterns obtained so far suggest that fetal cells possess at least three, and possibly up to five, distinct antigens. Although none of the anti-fetal sera were produced with a sensitizing protocol identical with that used in in vivo protection, some of them were so close as to suggest that protection is associated with, and perhaps causally related to, these IgG antibodies. The in vitro evidence presented here, together with the in vivo data of P. B. Medawar & R. Hunt, shows that antigens are shared between fetal cells and adult thymic and testicular cells. It therefore lends support to the notion that the production of a vaccine against anaplastic neoplasms, using immunogens derived from adult tissues, is within the realms of possibility.

Animals↗
PubMed1983

Tolerance, immunocompetence, and secondary disease in fully allogeneic radiation chimeras.

The aim of this study was to ascertain the extent to which secondary disease and mortality in fully allogeneic chimeras (C57BL leads to CBA) is caused (if at all) by a delayed graft-versus-host reaction. Adult CBA males were thymectomized, irradiated, and reconstituted with T-lymphocyte-depleted C57BL or CBA bone marrow cells (BMC), followed three weeks after irradiation by implantation under the kidney capsule of thymic lobes from C57BL or CBA fetal or adult donors. These mice were observed for the development of secondary disease for periods in excess of 250 days, and they were examined at 5 weeks or 4 months for T lymphocyte reactivity and tolerance to alloantigens, using the cell-mediated lympholysis assay (CML). The following results were obtained. First, removal of T lymphocytes with anti-Thy 1 antibody and complement from allogeneic bone marrow did not prevent wasting and eventual death, although it prolonged the lifespan of mice substantially. Second, T lymphocytes generated from bone marrow-derived precursor cells became tolerant of the histocompatibility antigens of the thymus donor strain but remained normally reactive to third-party antigens. Third, allogeneic radiation chimeras did not survive as well as animals reconstituted with syngeneic cells, even when they were demonstrably tolerant in CML. Fourth, C57BL BMC maturing in a CBA host equipped with a C57BL thymus graft did not become tolerant of host antigens, indicating that extra-thymic tolerance does not occur in fully allogeneic--as opposed to semiallogeneic--chimeras. It is argued that the function of B lymphocytes and/or accessory cells is impaired in fully allogeneic radiation chimeras, and that the mortality observed was directly related to the resulting immunodeficiency. The relevance of the results described in this paper to clinical bone marrow transplantation is discussed.

Animals↗
PubMed1983

Specific unresponsiveness to fully allogeneic kidney allografts in rats induced by procarbazine hydrochloride and antilymphocyte serum.

A short course of procarbazine hydrochloride (PCH; 50 mg/kg) and antilymphocyte serum (ALS; 5 ml/kg), administered to Lewis (LEW;RT1(1] rats in the first week following transplantation of Brown Norway (BN;RT1n) kidneys, substantially prolonged allograft survival and induced long-term survival in 62% of the grafts. The two agents acted synergistically, in that neither of them administered alone had much effect. Graft recipients did not produce detectable cytotoxic antibodies and antigen-reactive cells injected i.v. were not diverted to the liver, thus showing that neither antibodies nor immune complexes are likely to mediate the unresponsiveness. Spleen cells from graft-bearing recipients failed to cause graft-versus-host responses (GVHR) in both (LEW X BN)F1 and (LEW X DA)F1 hybrids, but they specifically suppressed the GVHR given by normal syngeneic cells to donor strain (BN) antigens. This suppression was specific because the response against third-party antigens (DA; RT1a) was unaffected. Adoptive transfer of spleen and thymus cells from PCH-ALS-treated LEW rats bearing healthy BN kidneys caused a profound prolongation of BN graft survival in sublethally irradiated LEW recipients. This transfer was specific and mediated by W3/13+ (T) lymphocytes. It is concluded that a limited regimen of PCH and ALS given in the first postoperative week incites the generation of specific suppressor T lymphocytes and that this form of immunosuppression, even without preoperative donor antigen, is an effective way of prolonging kidney allograft survival.

Animals↗
PubMed1982

Suppression of natural cell-mediated cytotoxicity in man by maternal and neonatal serum.

the natural cytotoxicity of cells prepared from the blood of human neonates and women at the time of parturition was investigated, using a 4 hr 51Cr release assay and two established cell lines as targets. Although cord cells proved to be cytotoxic, the overall level was distinctly lower than that of normal adult cells. Whereas adult cells from males gave higher levels of cytotoxicity compared with cells from females, this was not the case for cord cells. Cells from women in labour showed even lower cytotoxic values. Neonatal and maternal serum or plasma caused a profound inhibition of the cytotoxicity shown by adult cells when present during the assay or following preincubation of effector cells with serum. Cord cells were not suppressed by either autologous or allogeneic cord sera. The nature of these suppressive factors and their origin and ontogeny remain to be elucidated. It would appear that in the neonate, and possibly also in the fetus, natural cytotoxicity is largely suppressed by serum factors, both in mother and offspring. This could represent yet another example of immunological modulation in pregnancy.

Adult↗