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Biomedical subjects

P McCullagh

Publications and source records attributed to P McCullagh.

At least 55 records · Page 3Linked to original sources
PubMed1989

Resistance of fetal PVG rats to induction of allograft tolerance.

Artificially induced immunological tolerance is often envisaged as experimental mimicry of events which occur naturally during the acquisition of self tolerance. Thus, it has been inferred that similar circumstances will facilitate the induction of both types of unresponsiveness. Since tolerance to most self determinants appears to have been established by the time of birth and allograft tolerance can be experimentally induced more readily, if not exclusively, in very young animals, it is commonly assumed that susceptibility to induction of tolerance to foreign antigens will continue to increase as progressively younger animals are tested. The experiments reported in this study extend the range of circumstances under which younger animals may be found to be less susceptible, or even completely resistant, to tolerance induction. While neonatal PVG rats were highly susceptible to the induction of tolerance to (PVG x DA)F1 hybrid determinants, fetal PVG rats were only partially susceptible at 19 days and were completely resistant at 17 and 18 days of gestation. Furthermore, only 39% of neonatal PVG rats that had been inoculated with F1 hybrid bone marrow cells at 18 days of gestation could be rendered tolerant by procedures which were effective in 100% of previously untreated neonates. These observations were interpreted to indicate that a certain stage of maturity must be attained before fetal rats become susceptible to tolerance induction. Asymmetry in susceptibility to tolerance induction in response to the inoculation of F1 hybrid bone marrow cells was observed when PVG and DA fetuses, but not neonates, were compared. This difference in the response of the two strains recalls the divergence in immune reactivity of offspring, previously reported when PVG and DA embryos were transferred to surrogate mothers of the other strain. It is also in agreement with earlier reports of substantial differences in the ease of tolerance induction between different strain combinations. The asymmetry between PVG and DA rats in the present experiments is speculatively attributed to differences in rates of immunological maturation of the two strains.

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PubMed1989

Interception of the development of self tolerance in fetal lambs.

Investigation of the nature of immunological self tolerance has usually relied upon experimental protocols in which the tolerant state is interrupted in mature animals with the production of autoimmune disease. While such research has improved the understanding of those processes operative in overt autoimmunity, it has not been informative in relation to events associated with the establishment of self tolerance. Any description of this state which is to be based on observation will necessitate the use of experimental systems that permit observation of animals during the development of self tolerance. The present experiment entailed intervention approximately one third of the way through the gestation period of fetal lambs. An earlier experiment had established that 54-day fetal lambs would accept allografts of adult skin. This indicated that the capacity to discriminate between self and non-self had not been acquired at that age. Fetuses at this stage of gestation were submitted to either partial or total removal of the thyroid gland. The excised tissue was then implanted in nude mice for periods of 5 to 9 weeks. It was subsequently replaced subcutaneously, either in the original donor or in another fetus at a comparable stage of gestation. At postmortem examination, several weeks later, self implants in lambs from which the thyroid gland had been completely removed displayed autoimmune thyroiditis of varying degrees of severity. However, self implants in partially thyroidectomized animals were uniformly free from autoimmune manifestations. This implied that these reactions had not been directed against contaminating murine tissues in the implants replaced in completely thyroidectomized lambs. All allogeneic implants were subject to vey heavy lymphocytic infiltration, usually with accompanying necrosis consistent with allograft rejection. This was taken as an indication that hypothyroid fetal lambs had become immunocompetent by the time of thyroid reimplantation. Spontaneous immunological reactivity against reimplanted self thyroid tissue by thyroidectomized lambs was interpreted as a failure to acquire the capacity for self recognition as a result of antigen deprivation.

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PubMed1989

Inability of fetal skin to induce allograft tolerance in fetal lambs.

Fetal lambs of 53-55 days gestation invariably failed to accept skin allografts from fetal donors of similar age but retained allografts from adult donors. Autografts of skin were accepted by 53-55-day fetuses. When the survival of allografts transplanted from fetal donors of a range of gestational ages was examined, skin from fetuses of up to 85 days was rejected but that from a 95-day donor was retained. Histological examination of fetal skin allografts revealed that these were subject to lymphocytic invasion, evident as the entry of lymphatic vessels and extravasation of lymphocytes within the first week after placement. These manifestations of an allograft reaction became more prominent during the following 2 weeks, with graft rejection being evident by the end of a month. Allografts of adult skin were subject to occasional focal lymphocytic infiltration but otherwise healed in uneventfully.

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PubMed1988

The relative contributions of immune system and target organ to variation in susceptibility of rats to experimental allergic thyroiditis.

Previous investigations of the cellular basis of genetic susceptibility to experimental allergic thyroiditis (EAT) in semi-allogeneic mice bearing thyroid grafts from resistant, parental strain donors have indicated that these grafts remain relatively resistant to EAT when this is induced in the susceptible bearer. It was concluded that genetic control of susceptibility to EAT is expressed in both the immune system and the thyroid gland. Our experiments in which thyroid grafts were transferred to fully allogeneic, but immunologically tolerant, recipient rats indicate that thyroid tissue from an EAT-resistant strain of rat becomes entirely susceptible when transplanted into a susceptible host. The differing susceptibility of thyroid grafts in semi-allogeneic and tolerant allogeneic hosts may result from restrictions on interaction between host lymphocytes and the graft in the former situation. The present findings call into serious doubt the proposition that genetically determined resistance to EAT is mediated, to any extent, at the level of the target organ.

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PubMed1988

Maturation of immunological reactivity in the fetal lamb infected with Akabane virus.

The development of cell-mediated immunological reactivity was studied in fetal lambs infected with Akabane virus. Examination of hepatic cells from fetuses between 40 and 75 days' gestation that had been infected via the transplacental route revealed inconsistent responses to Akabane, together with a uniform failure to respond to non-specific mitogens which contrasted with the behaviour of control, uninfected lambs. Following direct inoculation of fetal lambs with virus between 50 and 120 days' gestation, specific proliferative responses were observed on the part of the spleen cells from some. Direct challenge of fetal lambs of 4 months' gestation evoked cellular responses in lymph draining from the site of virus inoculation similar to those produced by challenge of adult sheep. The proliferative response of lymph-borne cells was substantially better if live, rather than inactivated, virus had been used.

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PubMed1988

Transmission of Akabane virus from the ewe to the early fetus (32 to 53 days).

The role of the placental junction in AKA virus infection in the ewe was examined during the time when the chorionic villi were first becoming firmly attached to the maternal caruncles. The studies were made over 21 days covering the period between 32 and 53 days of pregnancy. Viral tropism in the fetal membranes and tissues of the fetuses was identified by virus isolation and immuno-fluorescence studies. Areas of virus replication were noted from 24 h post-inoculation in the fetal membranes and persisted in these tissues throughout the experiment. Viral antigen was first detected in the fetus from day 5 post-inoculation by virus isolation and immuno-fluorescence. From this time on, viral activity increased in specific areas of the fetus, notably in the brain and, to a lesser extent, the skeletal muscles. Gross pathological changes occurred in the fetuses between day 14 and day 21 post-inoculation (46 to 53 days gestation). Despite the relatively high titres of AKA virus present in the placental tissues and the developmental changes occurring in the fetus due to the virus, the placental junction continued to carry out its physiological function of maintaining pregnancy.

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PubMed1988

PVG rats, resistant to experimental allergic thyroiditis, develop high serum levels of thyroglobulin after sensitization.

Following challenge with rat thyroglobulin and adjuvants, DA rats invariably develop the histological features of severe experimental allergic thyroiditis while the thyroid glands of PVG rats remain histologically normal. It has been reported previously that some PVG rats develop high titers of anti-thyroglobulin antibody when challenged despite apparent resistance to thyroiditis. In the present experiment, PVG rats consistently developed high serum levels of both antibody and thyroglobulin. Although release of thyroglobulin from the thyroid is usually considered an indication of damage to the gland, the thyroid remained completely normal in all challenged PVG rats.

Animals↗
PubMed1988

Immunological tolerance of sheep to skin allografts.

A majority of grafts of adult sheep skin placed on fetal lambs at 55 days gestation were retained and increased 50-100-fold in area by the time of birth. Although the original grafts placed in utero survived, second and third grafts from the same donors were rejected. Lambs bearing skin grafts attained full mixed leukocyte reactivity against cells from the skin donors.

Animals↗
PubMed1988

Regulation of experimental allergic thyroiditis.

The susceptibility to experimental allergic thyroiditis (EAT) of rats that had previously been immunized against thyroglobulin was examined. Challenge with thyroglobulin 5 weeks previously conferred strong resistance to the induction of EAT after exposure to a sensitization protocol that was otherwise highly effective. Resistance to induction of EAT could also be conferred by the inoculation of spleen cells from thyroglobulin-sensitized donors on the day of birth. Heavily irradiated spleen cells from sensitized donors were able to confer resistance on neonatal recipients, indicating that prolonged survival of the transferred cells was not required.

Animals↗
PubMed1988

Acquisition of immunological self-recognition by the fetal rat.

Rats in which normal development of the thyroid gland had been interrupted by the injection of 131I during fetal life are liable to mount autoimmune responses against grafts of syngeneic thyroid tissue transplanted in adult life. Although autoimmune thyroiditis developed spontaneously in grafted tissue, the recipients' own thyroid glands remained free from autoimmune changes, showing only irradiation damage. Other syngeneic endocrine grafts transplanted to these rats were not susceptible to autoimmune attack. This experiment demonstrates that contact of self-determinants with the developing mammalian immune system is required if autoimmunity is to be prevented.

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PubMed1987

Lymphocyte migration between mutually tolerant parabiotic rats.

Lymphocytes exchanged rapidly and extensively between mutually tolerant, allogeneic rats following surgical parabiosis. Tolerated allogeneic cells persisted for an extended period in parabiotic partners after separation. A rapid exchange of cells was also observed between parabiosed syngeneic pairs of normal and allograft tolerant rats. This was accompanied by early termination of the tolerant state manifested by skin graft rejection and return of specific lymphocyte alloreactivity.

Animals↗
PubMed1986

The significance of the variety of mechanisms of allograft tolerance.

The influence of variations in protocol on the induction and early stages of maintenance of allograft tolerance in neonatal rats was studied. Allogeneic bone marrow cells, the anti-recipient activity of which was specifically reduced because of their origin from immunologically tolerant donors, possessed diminished tolerogenic capacity. This was commonly manifested by development of an unreactive state in only one of the two parameters of reactivity--allograft rejection and graft-versus-host reactivity--that were monitored. A similar deviation from the occurrence of unreactivity in both forms that characterizes tolerant rats was observed in animals which had been inoculated with syngeneic thymus cells at the time of induction of tolerance. Attempts to demonstrate a requirement for an extended period of exposure of young rats to semi-allogeneic bone marrow cells before specific unreactivity on the part of host cells became irreversible were unsuccessful.

Animals↗
PubMed1985

Rejection of syngeneic skin grafts following retransplantation from histo-incompatible rats.

Normal syngeneic recipients rejected a substantial proportion of skin grafts following their retransplantation after a period of residence on tolerant allogeneic or normal semi-allogeneic hosts. Rejection was often atypical in its delayed onset and protracted course. Examination of the effect of a variety of manipulations of graft donors and of intermediate hosts revealed that active involvement of cells derived from both categories was required for the initiation of an allograft reaction after transfer to the ultimate, syngeneic recipient. Liability of retransplanted syngeneic skin grafts to rejection could be almost entirely abolished by their exposure to 300 rads irradiation before placement on the intermediate host. Skin from neonatally thymectomized donors or from rats specifically tolerant of the intermediate F1 hybrid host was much less liable to ultimate rejection than was skin from normal hosts. These experiments suggest that rejection of re-transplanted, syngeneic grafts may result from some form of activation of cells of the graft during its period on the intermediate host.

Animals↗
PubMed1985

Heterogeneous expression of antigenic determinants by rat lymphocytes.

Exposure of lymphocytes from F2 hybrid and backcross rats of the PVG and DA strains to inter-parental strain alloantisera and complement frequently and unexpectedly revealed incomplete susceptibility within a population of cells. This heterogeneity did not appear to result from variable susceptibility to cytotoxic mechanisms. A more likely explanation was that variation occurred in the expression of the target determinants within the lymphocyte population. A similar heterogeneity was also demonstrable in populations of lymphocytes from rats of the inbred DA strain, provided appropriate alloantisera were used. Antisera raised in PVG rats against individual (PVG X F1) backcross rats frequently effected intermediate levels of DA cell destruction in the presence of complement, although exposure of DA lymphocytes to PVG anti-DA serum plus complement resulted in their uniform destruction. The nature of the target antigens that were subject to variable expression was not established, but it seemed likely that they were related to histocompatibility determinants.

Animals↗
PubMed1985

The relationship of the antigenic determinants expressed by rat lymphoid cells to their participation in graft-versus-host reactions.

The relationship between the graft-versus-host reactivity of lymphocytes from F2 hybrid and backcross rats and their susceptibility to inter-parental strain alloantisera has been investigated. Apart from associations between the immunological responsiveness of individual rats and the extent of alloantiserum susceptibility of their lymphocytes, selective reactivity of groups of lymphocytes that were separable from the general population by means of their alloantiserum susceptibility was observed. Those host lymphocytes which expressed a preponderance of DA-derived determinants were preferentially implicated in graft-versus-host reactions elicited by PVG lymphocytes in (PVG X DA)F2 hybrid rats. The anti-(PVG X DA)F1 hybrid reactivity of some (PVG X F1) backcross rats was selectively concentrated in that fraction of the lymphocyte population which expressed the highest levels of PVG-derived determinants. It is proposed that heterogeneously expressed MHS determinants may have a role in regulating selective participation by subpopulations of lymphocytes in allogeneic reactions.

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PubMed1985

The immunological consequences of allogeneic rat embryo transfer.

Blastocysts of the PVG and DA rat strains were transferred to pseudopregnant females of the opposite strain. Those embryos of which the biological and surrogate mothers were allogeneic with respect to each other exhibited a significantly impaired rate of survival. Lymphocytes from PVG rats born following the transfer of blastocysts to DA surrogates invariably possessed anti-(PVG X DA)F1 hybrid graft-versus-host reactivity substantially in excess of that of cells from normal PVG rats.

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