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Biomedical subjects

J D Horton

Publications and source records attributed to J D Horton.

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

Attempts to break perimetamorphically induced skin graft tolerance by treatment of Xenopus with cyclophosphamide and interleukin-2.

The maintenance of skin allotolerance induced by perimetamorphic application of MHC-disparate skin to isogeneic Xenopus is investigated. Removal of the perimetamorphically applied first-set graft after 4 weeks did not, in general, completely break allotolerance; however, many second-set semi-allogeneic grafts, applied up to 14 weeks after first-set removal, were no longer maintained in perfect condition. Skin allografts tolerated for up to 42 weeks continued to express donor histocompatibility antigens, as indicated by their survival times when transplanted back to the original donor or recipient strain. Treatment with human recombinant IL-2 (rIL-2), shown elsewhere to be an effective immunoregulatory lymphokine for Xenopus in vivo, failed to cause long-term-tolerated 1st-set allografts, or newly-applied 2nd-set grafts, to be rejected. In contrast, cyclophosphamide (CyP) treatment led to acute (less than 4 weeks) destruction of both 1st- and 2nd-set allografts; breaking of tolerance was regularly seen when donor and host differed by two MHC haplotypes, but occurred infrequently in semiallogeneic combinations. The experiments suggest that skin-induced allotolerance is maintained by an immunosuppressive mechanism, that is CyP-sensitive but resistant to rIL-2 treatment.

Animals↗
PubMed1987

Thymocyte/stromal cell chimaerism in allothymus-grafted Xenopus: developmental studies using the X. borealis fluorescence marker.

These experiments employ the X. borealis (quinacrine-fluorescence) cell marker to illustrate that froglet (normal or in vivo-irradiated) thymuses, alloimplanted to 4- to 6-week-old, 7-day-thymectomized hosts, become filled with host lymphoid cells, while a range of thymic stromal cell types (e.g. epithelial derivatives and reticuloendothelial cells) remain donor derived. A time-course study of 4 micron historesin-embedded sections reveals that for normal thymus implants, host cells begin to immigrate in good number only after metamorphosis. In contrast, 3000 rad-irradiated thymus implants begin to be repopulated with host lymphocytes within 2 weeks postimplantation, when hosts are still at a late larval stage of development. Despite rapid colonization by host lymphoid cells, irradiated thymuses remain small and often disappear in early adult life. Donor-derived lymphocytes frequent the blood and both the red pulp and perifollicular regions of the spleen following normal thymus implantation, whereas such thymic emigrants were not seen in the periphery of thymectomized hosts grafted with irradiated thymus glands.

Animals↗
PubMed1987

Cytoarchitecture of the Xenopus thymus following gamma-irradiation.

This paper describes in vitro and in vivo attempts to deplete the 4- to 8-month-old Xenopus laevis (J strain) thymus of its lymphocyte compartment. Gamma irradiation (2-3000 rad) of the excised thymus, followed by two weeks in organ culture, is effective in removing lymphocytes, but causes drastic reduction in size and loss of normal architecture. In contrast, in vivo whole-body irradiation (3000 rad) and subsequent in situ residence for 8-14 days proves successful in providing a lymphocyte-depleted froglet thymus without loss of cortical and medullary zones. In vivo-irradiated thymuses are about half normal size, lack cortical lymphocytes, but still retain some medullary thymocytes; they show no signs of lymphocyte regeneration when subsequently organ cultured for 2 weeks. Light microscopy of 1 micron, plastic-embedded sections and electron microscopy reveal that a range of thymic stromal cell types are retained and that increased numbers of cysts, mucous and myoid cells are found in the thymus following whole-body irradiation. In vivo-irradiated thymuses are therefore suitable for implantation studies exploring the role of thymic stromal cells in tolerance induction of differentiating T lymphocytes.

Animals↗
PubMed1987

In vivo studies on allotolerance perimetamorphically induced in control and thymectomized Xenopus.

Implantation of either major histocompatibility complex (MHC)-disparate thymus to 7-day thymectomized (Tx) Xenopus in late larval life, or allogeneic skin to perimetamorphic controls, routinely induces tolerance towards implant-strain skin grafts applied in adult life. To characterize this allotolerance further, additional in vivo approaches were attempted. Injection of gamma-irradiated (5000 rads) implant-strain splenocytes into frogs bearing tolerant skin grafts revealed (within 3 days) significantly elevated tritiated thymidine uptake by host spleen cells, compared to siblings injected with isogeneic cells. Although this in vivo 'mixed leucocyte reaction' proved to be thymus dependent, the identity of the cells involved awaits clarification. When non-restored Tx Xenopus are injected with live MHC-disparate splenocytes, graft-versus-host (GVH)-induced mortality ensued within 2 weeks. Such GVH disease also occurred (albeit more chronically) when Tx allothymus-implanted animals were given MHC-incompatible splenocytes, but only when these came from the thymus donor strain. Splenocytes from thymus-implanted animals failed to achieve GVH-induced splenomegaly when transferred to appropriate hosts (bearing MHC antigens of the thymus donor strain). Overall, the experiments indicate that alloreactivity against donor cells is impaired but not completely inhibited in Xenopus following perimetamorphic implantation.

Animals↗
PubMed1986

Impaired rejection of minor-histocompatibility-antigen-disparate skin grafts and acquisition of tolerance to thymus donor antigens in allothymus-implanted, thymectomized Xenopus.

We examine whether J strain Xenopus laevis and X laevis/gilli (LG) isogeneic hybrids, thymectomized (Tx) at 7 days and implanted with larval or postmetamorphic thymus (either normal or irradiated) in late larval life, can be used to explore the role of the developing thymus in the education of minor histocompatibility (H) antigen-reactive T cells and in the acquisition of tolerance to MHC (major histocompatibility complex) antigens. Tx LG Xenopus implanted with isogeneic thymus display fully restored ability to reject both MHC-incompatible and minor H-disparate grafts. Allothymuses (both MHC- and minor-H-disparate) restore normal rejection of skin grafts with MHC incompatibility to thymus donor and Tx (J or LG) host, but reactivity to grafts with putative minor H disparity is impaired. Defective minor-H-disparate skin graft rejection occurs even when the Tx host has received a thymus of the "correct" MHC haplotype (i.e., the same MHC as the assay skin graft). This defect may be attributable to inadequate establishment of minor-H-reactive T lymphocytes, to sharing of minor antigens, or to "nonspecificity" of tolerance induction to minor antigens, since such tolerance is demonstrated here following perimetamorphic grafting of skin to control LG clones. Skin grafts from Xenopus isogeneic to the donors of the MHC-incompatible larval and adult thymus implants are always tolerated by Tx hosts. In contrast, in vitro one-way MLC (mixed leukocyte culture) reactivity of splenocytes to thymus donor MHC antigens occurs when certain donor/host combinations are used but not when others are tested. Postmetamorphic thymus implants appear to promote in vitro MLC tolerance more effectively than larval thymus implants.

Animals↗
PubMed1985

Elevated CK-MB and CK-BB in serum and tumor homogenate of a patient with lung cancer.

Elevated serum levels of creatine kinase (CK) were found in a patient with small-(oat) cell carcinoma of the lung. Fractionation of the enzyme showed markedly elevated CK-MB and CK-BB isoenzymes. Clinical and subsequent pathological examination showed no evidence of infarction, inflammation, or tumor involvement of the heart; however, analysis of tumor tissue for CK showed predominance of CK-MB and CK-BB isoenzymes, thus implicating tumor as the source of the circulating levels of CK-MB and CK-BB. Our case is the first to document CK-MB from neoplastic tissue homogenates, and illustrates that markedly elevated circulating levels of CK-MB, or increased levels of CK-MB in combination with CK-BB may point away from a myocardial source, and toward the existence of a malignancy.

Aged↗
PubMed1984

Changes in antibody and complement production in Xenopus laevis during postmetamorphic development revealed in a primary in vivo or in vitro antibody response.

Xenopus laevis (G-line) mounts a primary plaque forming cell (PFC) response either in vivo or in vitro following challenge with foreign erythrocytes. Methods are described for generating and assaying the response, which specify criteria such as antigen dose, antigen choice, response kinetics, and complement source. The results suggest that at the peak of the primary response (approximately day 6), animals of different ages produce predominantly different 'classes' of antibody which display markedly different complement-fixing characteristics. Antibodies produced by larvae and 4-month-old postmetamorphic animals appear here to be unable to fix either guinea pig complement (GPC') or adult Xenopus complement, but can readily fix complement from 6-month-old Xenopus. The proportion of spleen PFC's producing antibody capable of fixing GPC' progressively increases from about six months to 18 months of age. Possible explanations for such ontogenetic changes are discussed.

Animals↗
PubMed1984

Restoration of the antibody response to sheep erythrocytes in thymectomized Xenopus implanted with MHC-compatible or MHC-incompatible thymus.

These experiments make use of an amphibian model system for investigating the role of the thymus in T helper cell education. Clawed toads (Xenopus laevis), thymectomized at 7 days, are unable to mount an antibody response to thymus-dependent antigens, such as sheep red blood cells (SRBC). When thymectomized larvae are implanted with larval thymuses (either irradiated or non-irradiated), incompatible at the major histocompatibility complex (MHC) or with MHC-compatible or -incompatible 'adult' thymuses, their splenic plaque-forming cell response and serum haemolytic antibody production to SRBC are both restored, to some extent. However, levels of mercaptoethanol-resistant antibody were extremely poor in those animals implanted with MHC-incompatible 'adult' thymus. Larval thymus implants were shown, by ploidy-labelling studies, to become repopulated with host-derived lymphocytes. Whether or not these lymphocytes acquire their MHC restriction specificities in the thymus awaits clarification.

Animals↗
PubMed1983

Ontogeny and characterization of mitogen-reactive lymphocytes in the thymus and spleen of the amphibian, Xenopus laevis.

The ontogeny of the proliferative response of Xenopus thymocytes to the T-cell mitogens concanavalin A (Con A) and phytohaemagglutinin and to the B-cell mitogen E. coli lipopolysaccharide (LPS) is examined during the first 2 years of life. Responses after metamorphosis are compared with those occurring in the spleen. During much of larval life, mitogen-treated thymocytes display no sign of elevated [3H]TdR uptake. A low level in vitro response to Con A and LPS emerges transiently just prior to metamorphosis, the latter period being associated with a temporary disruption of thymocyte mitogen reactivity. Appreciable stimulation of both thymocytes and splenocytes with all three mitogens emerges within the first few months post-metamorphosis, and, with the exception of the thymocyte response to LPS, these induced proliferative levels are maintained or increased in toadlets aged 7-24 months. Maximal levels of LPS responsiveness in thymocyte cultures are found at 6 months of age. LPS-induced thymocyte proliferation at this time is confirmed morphologically by autoradiography; furthermore, immunofluorescence experiments, using an anti-Xenopus-mu chain antiserum, reveal that LPS induces the differentiation of cytoplasmic IgM cells in both spleen and thymus. The results indicate the presence of substantial populations of mitogen-sensitive cells in B lineage in the anuran thymus.

Aging↗
PubMed1982

Restoration of antibody responsiveness in early thymectomized Xenopus by implantation of major histocompatibility complex-mismatched larval thymus.

The restorative potential of isogeneic and fully allogeneic thymic implants to restore in vivo antibody responsiveness to a thymus-dependent antigen has been examined in thymectomized clawed toads. Isogeneic clones (Xenopus laevis/gilli and X. laevis/muelleri hybrids) of known major histocompatability complex (MHC) haplotypes were thymectomized at 5-7 days, implanted with MHC-identical or -mismatched (normal or irradiated ) thymuses from 5-week-old larvae and 4 months later injected with dinitrophenylated keyhole limpet hemocyanin. IgM antibody responsiveness (measured by phage inactivation) was restored in terms of its quantity, affinity and specificity in those thymectomized animals given two haplotype-different thymuses. Isoelectric focusing data revealed that low molecular weight antibody production was also restored with isogeneic and allogeneic thymus and that the antibody spectrotypes were of the host type. The finding that in vivo T-B collaboration in thymectomized animals develops normally following thymus implantation, even when the thymus genotype is disparate from the host, is discussed both in the light of previous experiments revealing MHC restriction of Xenopus T helper cells in vitro and in terms of the role of the thymus in promoting adaptive differentiation of this lymphocyte subset.

Animals↗
PubMed1980

Pericardial effusion associated with minoxidil therapy in dialyzed patients.

Pericardial effusion, diagnosed clinically or by echocardiography, was found in 13 of 16 regularly dialyzed patients (81%) receiving minoxidil for refractory hypertension. In a comparable group of 125 patients not receiving minoxidil, 28 patients (23%) had evidence of pericardial effusion, the difference between the groups being highly significant (p less than 0.0005). In minoxidil treated patients, the effusions resolved spontaneously in 4 (3 remaining on treatment), required pericardiocentesis (3), or pericardiectomy (1), and persisted in 4 (3 remaining on treatment). It is suggested that minoxidil treated dialysis patients be regulary examined for the development of potentially threatening pericardial effusions.

Adult↗
PubMed1977

Critical role of the thymus in establishing humoral immunity in amphibians: studies on Xenopus thymectomized in larval and adult life.

Proliferative studies on spleen lymphocytes suggest the absnece of induced cellular activity to sheep erythrocytes in Xenopus thymectomized at 7 days of age. Immunological studies (measurement of splenic rosette-forming and plaque-forming cells and serum haemolysins) show that throughout larval life the thymus plays a critical role in establishing reactivity to red cells, since thymectomy as late as 40 days (stage 57) impairs the antibody response. In contrast, thymectomy during metamorphosis or in early adult life has no apparent debilitating effect.

Aging↗
PubMed1977

Allograft rejection in larval and adult Xenopus following early thymectomy.

The effect of thymectomy (performed on 7- to 8-day old larvae) on the development of alloimmunity in the clawed toad is examined. Rejection of first-set skin grafts applied in larval life (30 days of age) and at intervals following metamorphosis (70 to 370 days of age) was always impaired following thymectomy. However, most of the thymectomized animals, even those grafted as larvae and blocked in the larval state by thiourea treatment, were able to destroy the transplants, albeit with prolonged rejection times. The pattern of graft rejection in thymectomized larvae was similar to that seen in adults. After thymectomy, these seemed to be no improvement or impairment of the alloimmune response with the passage of time. Experiments with second-set grafts applied subsequent to first-set destruction demonstrated the existence of an alloimmune memory component throughout ontogeny in both control and thymectomized animals. The results indicate that a population of cells involved in graft rejection develops early in ontogeny, independent of the thymus and the emergency of bone marrow at metamorphosis.

Aging↗