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Biomedical subjects

L Brent

Publications and source records attributed to L Brent.

At least 73 records · Page 4Linked to original sources

Supposed lamarckian inheritance of immunological tolerance.

The notion that an adaptation acquired during an organism's lifetime can somehow be imprinted on the genome and so become heritable has been faulted by every critical test to which it has hitherto been exposed, but many naturalists have lost their faith in what seems to them to be the all-encompassing explanatory glibness of neo-darwinism. Although this criticism is unfair it is entirely proper that neo-darwinism should be under constant critical scrutiny. Interest was therefore aroused by the claim of Gorczynski and Steele that tolerance of A strain antigens induced in CBA mice by injecting into them (CBA x A/J)F1 spleen and bone marrow cells could be transmitted down the male line. Such a claim is of particular interest because spermatozoa, unlike oocytes, are produced throughout life and might thus conceivably have participated in the mechanism envisaged by Steele as that responsible for the supposed transfer of genetic information from soma to germ plasm. It was claimed that as many as 60% of the progeny of tolerant fathers mated with normal CBA females were unresponsive or hyporesponsive in an in vitro assay in which their spleen cells were tested for reactivity against A/J strain histocompatibility antigens in the cell-mediated lympholysis assay (CML). We describe here our failure to confirm these findings and our inability to extend them by testing the progeny for their reactivity against skin allografts from the tolerance-conferring strain.

Adaptation, Physiological↗

Specific unresponsiveness to skin allografts in mice. VI. Graft survival in mice pretreated with blood.

Very small amounts (0.5 to 2 microliters) of H-2-incompatible blood given 16 days before skin grafting led to the induction of a long-lived unresponsiveness when the mice were given a short postoperative course of alternating doses of procarbazine hydrochloride and antilymphocyte serum. This unresponsiveness, which was specific for the blood donor strain, was wholly attributable to the white cell moiety, plasma and red blood cells having proved to be ineffective. The optimal dose range of white blood cells was fairly narrow (7 x 10(3) to 1.4 x 10(4)). Of the various attempts made to demonstrate that the blood inoculum modified the response of normal mice, only direct skin grafting gave a positive result in that the survival of allogeneic skin grafts was curtailed. Mixtures of blood from several mouse strains injected into CBA recipients induced long-term unresponsiveness to skin grafts of the blood donor strains. However, although it was possible to create unresponsiveness to DBA/2, C57Bl, or strain A skin grafts in CBA mice pretreated with blood from a closed colony outbred strain (TO), this pretreatment had no beneficial effect to induce unresponsiveness to TO skin grafts in TO recipients. It is argued that these findings are no necessarily inconsistent with the observation that, in inbred animals, the induction of unresponsiveness was strain specific.

Animals↗

Suppression of in vitro lymphocyte reactivity by cyclosporin A: existence of a population of drug-resistant cytotoxic lymphocytes.

Cyclosporin A (CS-A) is an unusual endecapeptide isolated from the fungi Cylindrocarpon lucidum Booth and Trichoderma polysporum. It is a potent immunosuppressive drug that prevents rejection of kidney and heart allografts whilst having a low myelotoxicity. Its mode of action is still unclear but its main target appears to be the T lymphocyte. The mixed lymphocyte reaction (MLR) and cell-mediated lymphocytoxicity (CML) used here are generally regarded as in vitro correlates of allograft rejection. Our data show that CS-A is a powerful inhibitor of MLR reactivity, regardless of whether the cells were obtained from normal or presensitized donors; that the CML of lymph node cells is likewise totally inhibited if the drug is added early during cell culture; and that, by contrast, the cytotoxic response of spleen cells from presensitized but not from normal mice is only partially inhibited, even with a tenfold increase in dose. It is therefore suggested that there exists a population of cytotoxic spleen cells that is relatively resistant to the action of this drug.

Animals↗

Failure to increase the in vivo immunosuppressive activity of antilymphocyte globulin by conjugation with melphalan.

An attempt was made to increase the in vivo immunosuppressive powers of antilymphocyte globulin (ALG) by conjugating it with malphalan (MEL), an alkylating agent, via an inert intermediate carrier (polyglutamic acid). Careful controls to distinguish between increased activity attributable to the conjugate per se, as opposed to synergy between the components of the complex, were included. Conjugation did not destroy the alkylating properties of the drug nor the cytotoxic activity of the antibody. The effect of MEL-ALG complexes on skin allograft survival in both inbred and outbred strains were appraised. In neither system did the immunosuppressive powers of the conjugate exceed those of ALG alone, regardless of the dose used. We conclude that alkylating drugs are not suitable for this particular purpose.

Animals↗

Development of cell-mediated lympholysis in human foetal blood lymphocytes.

White cells from pure foetal blood obtained by fetoscopy, or from the cord at birth, were sensitized in mixed lymphocyte culture with irradiated adult peripheral blood lymphocytes. After 6-8 days of culture they were assayed in a standard 4-hr 51Cr-release cytotoxicity assay (CML) using lymphoblastoid cell targets from the stimulator cell donor. The age of the foetuses ranged from 15-22 weeks of gestation. Third-party target cells and adult blood served as controls. The mean cytotoxic responses of cord (11 donors) and adult (10 donors) blood lymphocytes were not significantly different and had similar kinetics. Foetal lymphocytes (25 donors) displayed a wide range of reactivity with half, scattered throughout the age range, totally negative and a further 23% with marginal responses. Definite cytotoxicity was found in the remainder, but not before the 18th week; these responses were evenly distributed in the range 18-22 weeks. Third-party responses were never more than one-quarter of the specific cytotoxicity. It was shown that the negative and very weak responses were almost certainly not due to technical factors. It is concluded that the majority of human foetuses in the range 15-22 weeks, though capable of giving clear mixed lymphocyte reactions, cannot develop full effector function as measured by the CML assay.

Adult↗