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PubMed1994

Appearance of extrathymic early differentiated CD4-CD8- T cells with T cell receptor gamma/delta or alpha/beta after thymus grafting to nude mice: influence of thymus on extrathymic T cell differentiation.

Fetal thymus grafting into athymic nude mice has been used as an experimental model of T cell development. To understand the early events of T cell development, we have examined the sequence of appearance of T cell subsets in lymph nodes (LN) of BALB/c nu/nu mice after grafting with syngeneic fetal thymus. T cells expressing T cell receptor (TCR) alpha/beta or gamma/delta increased in LN from 1 week after grafting, although no host-derived CD3+ T cells were detected in the grafted thymus and no donor thymus-derived T cells were detected in the LN. The early appearing T cells of both TCR alpha/beta and TCR gamma/delta showed a CD4-CD8- phenotype. V region usage analysis of the early appearing TCR alpha/beta T cells revealed that they contained cells bearing V beta 3 or V beta 11, which are potentially reactive to self-superantigen Mls-2a or Dvb11, respectively, and are deleted in the course of T cell development in the thymus of euthymic BALB/c mice. The early appearing T cells showed neither mixed lymphocyte reaction nor cytotoxic T cell activity against allogeneic cells. In contrast, lymphokine-activated killer cells from early appearing T cells, which contained high percentages of TCR gamma/delta T cells, exhibited higher cytotoxic activity against P815 mastocytoma than those from euthymic mice or untreated nude mice. All these results suggest that the early appearing T cells are developed extrathymically. We propose that the thymus may induce extrathymic T cell development without direct cell-to-cell interaction. It seems likely that the extrathymically developed T cells, especially TCR gamma/delta T cells, induced by the thymus have some role in the defense mechanism in the absence of conventional thymus-derived T cells.

Animals↗
PubMed1978

Independent precursors for thymus dependent and thymus independent IgG memory B cells.

Spleen cells from mice primed with the thymus dependent antigen trinitrophenyl keyhole limpet hemocyanin several months earlier can be cultured in vitro to give vigorous IgG antihapten PFC responses to thymus dependent and thymus independent forms of the hapten. The IgG memory precursors responding to these two forms of the hapten constitute functionally distinct subpopulations which we have designated as B1gamma and B2gamma to represent the precursor cells responding to the thymus independent and thymus dependent antigens respectively. Four types of evidence for these subpopulations are presented 1) the responses to the two types of antigen are additive when both forms are added to the same culture; 2) the precursor frequency for the thymus dependent and thymus independent populations is different although expansion over primary IgM precursor frequencies was not detectable; 3) the avidities of the PFC elicited by each antigen are distinct; the thymus independnet antigens elicit lower avidity PFC; 4) selective killing of one population can be accomplished by BUdR and light treatment without affecting the other population.

Animals↗
PubMed1992

The effects of thymus supernatant on the thymus homing ability of aged murine bone marrow cells.

This study examined the effect of thymus supernatant on the ability of bone marrow cells from senescent mice to home to the thymus. An in vitro and an in vivo assay were employed. The in vitro assay used a blind well migration of aged bone marrow cells to thymus supernatant across a membrane with 5-microns pores. The in vitro assay measured the ability of aged bone marrow to repopulate the thymus of an irradiated host. Our results support previous reports that the bone marrow from old mice has a greatly reduced ability to migrate to thymus supernatant and to repopulate the thymus of an irradiated host. Further, we found that a brief treatment of the old bone marrow with thymus supernatant significantly improved its thymus homing ability both in vitro and in vivo.

Aging↗
PubMedDate not supplied

The thymic epithelial reticulum and interdigitating cells in SIV-induced thymus atrophy and its comparison with other forms of thymus involution.

Alterations in the thymus were investigated in the early course of SIV infection of rhesus monkeys and compared with age-related and acute accidental thymus atrophy. The SIV-induced pathology was characterized by shrinkage of the thymic parenchyma and capsule, whereas in age-related thymus atrophy, the size of the capsule remained unaltered and the emerging space was filled by fatty tissue. Acute accidental thymus involution is characterized by massive cell death of the thymocytes, but there was no increase in pycnotic thymocytes either in SIV-induced or in age-related thymus atrophy. Ultrastructural analysis revealed no major differences between the juvenile control and the aged thymus. In contrast, SIV-induced thymus atrophy exhibited severe alterations of the epithelial cells of the cortex and the interdigitating dendritic cells, which were not found in the aged thymus nor in the juvenile control cortex.

Aging↗
PubMed1977

The influence of dietary protein insufficiency on the murine thymus. Evidence for an intrathymic pool of progenitor cells capable of thymus regeneration after severe atrophy.

Low protein diets initiated at wearning in Balb/c mice cause a rapid and profound reduction in thymus weight and cellularity. Thymus weight falls to less than that of involuted thymus of adult mice and remains depressed for as long as diets are fed. Although most peripheral T cell functions do not appear to be depressed, suppressor cell activity was not as vigorous in deprived animals despite the presence of functional suppressor populations. Thymus growth was reinitiated promptly when high protein diets were fed to deprived animals. Thymus regeneration appeared to be due to both a resident population of stem cells which persisted in the thymus through the period of deprivation and a second, probably bone-marrow derived, population of stem cells. It is suggested that in normal mice the synchronized growth of the first population produces the characteristic innate growth pattern of the thymus. This is superimposed on the growth of the second population which continuously seeds the thymus and is constantly replaced. Protein deprivation severely restricts the growth of the first and second population, but both maintain their capacity for growth during long periods of protein restriction.

Animals↗
PubMed1990

Thymus and autoimmunity: capacity of the normal thymus to produce pathogenic self-reactive T cells and conditions required for their induction of autoimmune disease.

BALB/c athymic nu/nu mice spontaneously developed organ-specific (gastritis, thyroiditis, oophoritis, or orchitis) and systemic (arteritis, glomerulonephritis, and polyarthritis) autoimmune diseases when transplanted with neonatal BALB/c thymuses. Transplantation of thymuses from adult BALB/c mice was far less effective in inducing histologically evident organ-specific autoimmune disease in nu/nu mice. Autoimmune disease developed, however, when adult thymuses were irradiated at a T cell-depleting dose before transplantation. Engrafting newborn thymuses into BALB/c mice T cell depleted by thymectomy, irradiation, and bone marrow transplantation produced similar organ-specific autoimmune disease as well, but thymus engrafting into T cell-nondepleted BALB/c mice (i.e., mice thymectomized as adults, but not irradiated) did not, despite the fact that transplanted thymuses grew well in both groups of mice. The mice with organ-specific autoimmune disease produced autoantibodies specific for the respective organ components, such as gastric parietal cells, thyroglobulins, oocytes, or sperm. The thymus-transplanted nu/nu mice also had hypergammaglobulinemia and developed anti-DNA autoantibodies, rheumatoid factors, and immune complexes in the circulation. These results indicate that: (a) the thymus of a murine strain that does not develop spontaneous autoimmune disease can produce pathogenic self-reactive T cells that mediate organ-specific and/or systemic autoimmune diseases; and (b) such self-reactive T cells, especially those mediating organ-specific autoimmune disease, spontaneously expand and cause autoimmune disease when released to the T cell-deficient or -eliminated periphery.

Animals↗
PubMed2005

Up-regulation of IL-7, stromal-derived factor-1 alpha, thymus-expressed chemokine, and secondary lymphoid tissue chemokine gene expression in the stromal cells in response to thymocyte depletion: implication for thymus reconstitution.

Three in vivo adult mouse models were established to study which signals are required to restore the postnatal thymus. Single administration of dexamethasone, estradiol, or exposure to sublethal dose of gamma irradiation served as prototype thymus-ablating therapies. In all models, transient thymic atrophy was manifested due to the loss of the predominant portion of CD4- CD8- double negative and CD4+ CD8+ double positive thymocytes and was followed by a complete regeneration of the thymuses. Acute atrophy/regeneration was observed in the dexamethasone and irradiation models; in the estradiol-treated animals, slow kinetics of atrophy and regeneration was observed. Importantly, in both acute and chronic models, high levels of IL-7 mRNA were detected in the thymuses isolated from mice during maximum atrophy. In addition, chemokine gene array analysis of involuted thymuses revealed high levels of mRNA expression of stromal-derived factor-1alpha (SDF-1alpha), thymus-expressed chemokine (TECK), and secondary lymphoid tissue chemokine (SLC) but not of other chemokines. The levels of IL-7, SDF-1alpha, TECK, and SLC mRNA inversely correlated with the kinetics of regeneration. RT-PCR analysis of stromal cells purified from involuted thymuses confirmed increased IL-7, SDF-1alpha, and SLC gene expression in MHC class II+ CD45- epithelial cells and increased IL-7 and TECK gene expression in class II+ CD45+ CD11c+ dendritic cells. Thus, our data showed for the first time that expression of IL-7, SDF-1alpha, TECK, and SLC mRNA is induced in the thymic stroma during T cell depletion and may play an important role in the reconstitution of the adult thymus.

Animals↗
PubMed1980

Acetylcholine receptor in rabbit thymus: antigenic similarity between acetylcholine receptors of muscle and thymus.

This study was performed to examine the presence and immunological properties of acetylcholine receptor (AChR) in rabbit thymus. Binding of 125I-alpha Bungarotoxin (alpha BGT) to Triton extract from rabbit thymus was saturable (half saturation value: 10 X 10(-9) M) and occurred with at least two affinities, a high one with a dissociation constant of 1.1 X 10(-10)M and a low affinity one with a dissociation constant of 2 X 10(-9)M. The complex formation of 125I-alpha BGT-thymus extract was inhibited by both carbamylcholine and D-tubocurarine. These results indicate the existence of AChR in rabbit thymus. Antibody to AChR which was purified from experimental myasthenic rabbits with Narke AChR-affinity gel and labelled with 125I was used to identify the receptor antigenicity in rabbit thymus. Specific binding of 125I-antibody to thymic extract was demonstrated by the DEAE-paper disc assay. It is concluded from these results that AChRs with a similar antigenicity to that of skeletal muscle AChR exist in rabbit thymus. Our findings obtained in this study will support a hypothesis that the primary immunogen in myasthenia gravis may be AChR in thymus and an autoimmune reaction against AChR might be initiated within the thymus gland itself.

Acetylcholine↗
PubMed1981

Thymus in mice bearing the Steel mutation. Morphologic studies on fetal, neonatal, organ-cultured, and grafted fetal thymus.

Mice with the Steel mutation were studied to determine whether they showed a morphologic difference in the epithelial-reticular microenvironment of the thymus when compared with their normal and heterozygous littermate controls. Thymuses taken directly from fetal and newborn homozygous SlWehi/SlWehi mice, after culture, and after subcapsular renal grafting were compared by light and electron microscopy with similarly treated thymuses from heterozygous SlWehi/+ and normal homozygous (+/+) littermates. At all developmental stages studied, the homozygous mutants had smaller thymuses with fewer lymphoid cells than their homozygous normal and heterozygous littermates. The homozygous mutants also showed ultrastructural abnormalities in the thymic epithelial cells. After organ culture, homozygous fetal mutant thymuses produced fewer lymphocytes and showed abnormalities of epithelial cell ultrastructure when compared with littermate controls. When mutant and control fetal thymuses were grafted under opposite kidney capsules of normal syngenic recipients, the mutant thymuses developed poorly and showed decreased lymphopoiesis and abnormalities of epithelial cell structure. The data suggest that there is a primary epithelial microenvironmental defect in the thymus of mice with the Steel mutation.

Aging↗
PubMed1969

Carcinogen-induced tumors of the thymus. IV. Humoral influences of normal thymus and functional thymomas and influence of posthymectomy period on restoration.

A progressive decrease of the restoring effectivity of syngeneic or allogeneic thymus and functional thymoma grafts was observed when the treatment of neonatally thymectomized mice was delayed. Early treatment (5-20 days postthymectomy) was effective, while the number of restored animals was markedly decreased after late treatment (30-50 days postthymectomy). Similar results were obtained with subcutaneous or intraperitoneal thymus grafts and with thymus grafts within cell-impenetrable diffusion chambers. After the onset of the postthymectomy-wasting syndrome the only successful treatment was the implantation of multiple thymus grafts. On the other hand, single thymus grafts, thymoma grafts, or thymus or thymoma within diffusion chambers were ineffective. When spleen cells from 5-day old or 45-day old neonatally thymectomized animals were given in association with thymoma grafts, only the cells derived from the 5-day old thymectomized mice proved effective in restoring wasted thymectomized hosts. These results suggest that a population of cells sensitive to the action of the thymus decreases progressively with time in the absence of thymic function.

Age Factors↗
PubMed1975

Studies on the regulation of lymphocyte production in the murine thymus and some effects of a crude thymus extract.

Cell proliferation in the murine thymus was studied in vivo under normal conditions and from 0 to 24 hr after a single injection of a water-soluble extract from mouse thymus, mouse spleen, and mouse skin. The thymus extract reduced during the first 24 hr the mitiotic activity 40%; the spleen extract had a weaker inhibitory effect. The skin extract had no such effect. The thymus extract and spleen extract inhibited the flux of cells into the S phase 0-8 hr after the injection of the extract. Initial labelling index was also reduced in this period. Eight hours after injection of the thymus or spleen extracts the inhibited cells initiated DNA synthesis. The rate of progression of blast cells through the cell cycle was normal 24 hr after the injection of the extracts. It was deduced from the analysis that the thymus extract inhibits processes triggering G0/G1 cells into DNA synthesis, the inhibition of G2 efflux being of minor importance. Finally a model for the regulation of proliferating thymic blast cells and the emigration of small lymphocytes from the thymus is proposed.

Animals↗
PubMed1979

Detection of thymosin 5 in calf and mouse thymus and in nude mouse dysgenetic thymus.

Thymosin 5 was traced in calf and mouse thymuses by fluorochrome-labelled rabbit anti-calf thymosin. The presence of thymosin 5 or its individual components was found 1. in groups of cortical epithelial cells in calf thymuses and in single cortical epithelial cells in mouse thymuses. 2. In some marginal (blastema) cells of the thymus cortex of calves and 14-day-old mice. 3. In perivascular epithelial cells of the calf thymus. 4. In occasional medullary epithelial cells of the calf and mouse thymus. In all cases there was a marked alternation of entirely negative and positive cell-containing thymic lobuli. In 4 of 13 cases comparatively strong positivity was found in tightyly arranged epithelial cells in an individual acinus in the dysgenetic thymus of nude mice, the positive cases being concentrated among the youngest mice studied.

Animals↗