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PubMed1989

Thymosin enhances the production of IL-1 alpha by human peripheral blood monocytes.

Incubation of human peripheral blood monocytes (PBM) with a partially purified thymic preparation, thymosin fraction (TF5), results in a dose dependent production of an interleukin-1 (IL-1)-like factor. The biological activity of this factor can be blocked by anti-IL-1 alpha, but not by anti-IL-1 beta which neutralizes bacterial induced IL-1 activity. Studies with further purified TF5 fractions show that this activity is not due to the well-characterized peptide, thymosin alpha 1 (T alpha 1), but rather a new thymosin peptide(s) isolated from a more basic fraction. Intraperitoneal injection of TF5 also induces the expression of a membrane-bound IL-1 (mIL-1) on mouse peritoneal cells. This study provides the first evidence that TF5 can influence macrophage activity directly by enhancing IL-1 production. This observation may help explain the mechanism by which TF5 modulates immune responses. These results also point to a more selective role for thymic hormones, growth factors and cytokines which may trigger macrophages to secrete different forms of IL-1, which can then regulate either immune and/or inflammatory processes.

Antibodies↗
PubMed1990

Potentiation of autoimmune response in rats infected with Toxoplasma gondii. Inhibition of suppressor system and impairment of thymic cellular populations.

In the present work we studied the influence that an infection with Toxoplasma gondii in thymus proximity produces on the suppression of autoimmune response to autoantigen of rat male accessory glands (RAG). The suppression was achieved injecting syngeneic animals with low doses of autoantigen of RAG previous to the immunization with chemically modified rat male accessory glands (MRAG). Rats were infected in thymus proximity with 3 x 10(3) trophozoites of T. gondii before or after to be suppressed. Controls were rats only infected or only suppressed. The delayed hypersensitivity response against MRAG, (DTH test), was significantly potentiated in rats only infected and in the animals suppressed before the infection (p less than 0.001). The suppression was not inhibited in the animals suppressed after infection. The suppression of humoral response against MRAG studied by ELISA and passive hemagglutination test was prevented in rats infected before as well as in rats infected after the induction of suppression (p less than 0.001). Decrease of CD4+ CD8+ and Ox18+ (class I MHC antigen) and increase of CD4+ CD8- and CD4- CD8- thymocytes was observed in the rats where the DTH response was potentiated. These results indicate that the infection with T. gondii in thymus proximity was able to inhibit the suppression of response to autoantigen of RAG producing selective impairment in thymic suppressor influence.

Animals↗
PubMed1993

Surface antigens of human thymocyte populations defined by CD3, CD4 and CD8 expression: CD1a is expressed by mature thymocytes but not peripheral T cells.

Three colour flow cytometric analysis has been used to analyze the expression of a series of surface antigens on human thymic and peripheral T-cell populations. CD4, CD8 and CD3 were used to divide the populations into the conventional major categories, and the distribution of CD1a, CD2, CD7, CD34, CD44, class I MHC and class II MHC was then determined. Some characteristics of 'single positive' (CD4+8- and CD4-8+) T-lineage cells were unexpected. Amongst thymocytes, some 'immature single positives' were delineated as larger sized cells lacking cell surface CD3 and expressing low levels of class I MHC; however, in contrast with murine thymocytes, these were all CD4+8-, rather than being predominantly CD4-8+. Amongst peripheral T cells, a small proportion of CD7- cells were detected, within both the CD4+8-3+ and the CD4-8+3+ categories. Finally, in contrast to previous conclusions, CD1a was expressed at high levels on mature (CD4+8-3+ and CD4-8+3+) human thymocytes, although in agreement with previous reports it was absent from peripheral T cells. CD1a is therefore a useful marker of post-selection, post-thymic T-cell maturation.

Adolescent↗
PubMed1997

Thymosin alpha 1 antagonizes dexamethasone and CD3-induced apoptosis of CD4+ CD8+ thymocytes through the activation of cAMP and protein kinase C dependent second messenger pathways.

It is well established that glucocorticoid hormones and anti-CD3 monoclonal antibodies induce apoptosis in immature developing thymocytes. This process can be modulated by soluble factors, anti-oxidants and adhesion receptors. Previously we have demonstrated that thymosin alpha 1 (T alpha 1), a 28-amino acid thymic peptide hormone, is a dose and time dependent antagonist of dexamethasone (DEX) and CD# induced DNA fragmentation of murine thymocytes in vitro. To further investigate the mechanism of T alpha 1 action we determined a T alpha 1 sensitive thymocyte population and examined some of the molecular events associated with T alpha 1 anti-apoptotic activity. Phenotypic analysis of the sub-populations of thymocytes, based on CD4 and CD8 expression, revealed that T alpha 1 exerts its effect on CD4+ CD8+ immature thymocytes. T alpha 1 treatment of thymocytes delays the production of free radicals and the subsequent consumption of glutathione, that is observed during both DEX and CD3 induced apoptosis. We further demonstrate that T alpha 1 stimulates the production of cAMP and activates PKC in thymocytes. These data suggest that T alpha 1 exerts an influence on the development of a population of immature T-cells in the thymus by effecting the sensitivity of thymocytes to apoptosis during the pre-selection stages of thymic development. Our studies also suggest that the mechanism of T alpha 1 action involves the induction of both cAMP and PKC dependent second messenger pathways.

Animals↗
PubMed1999

Abnormal thymic expression of epithelial cell adhesion molecule (EP-CAM) in New Zealand Black (NZB) mice.

New Zealand Black (NZB) mice have been well documented to have a variety of thymic epithelial cell microenvironmental abnormalities, including disruption of corticoepithelial cell networks and medullary cell clusters. These abnormalities of the thymic stromal network are particularly important because similar observations have been noted in other models of murine lupus. Thymic epithelial cells, a key component of the microenvironment, play an important role in selection of the mature T cell receptor repertoire. Recently, a homotypic calcium-independent human and murine epithelial cell adhesion molecule, Ep-CAM, has been described which is located at the thymocyto-cortical cell junction. The function of Ep-CAM is still unclear but its unique location within the thymus suggests that it is critical in the process of providing maturation signals. Consequently, we examined the thymic expression of Ep-CAM in a series of autoimmune prone mice by thymic distribution of Ep-CAM in NZB, NZW, NZB/W, BXSB-Yaa, MRL- lpr/lpr, C3H- gld/gld and the control strains BALB/c, C57BL6, C3H and MRL(+/+), by immunohistology and flow cytometry. Interestingly, NZB mice are similar to control mice from day 4 to 2 weeks of age, having a very low expression of Ep-CAM at the thymocyto-cortical junction. In control strains, there is a marked increased in expression of Ep-CAM beginning at 5 weeks of age. In contrast, NZB mice fail to show significant expression of Ep-CAM even well into adulthood. This abnormality of NZB mice was also noted in NZB/W F1 and BXSB mice, but not MRL- lpr/lpr or C3H- gld/gld mice. Given the potential importance of Ep-CAM in thymic selection, this study provides important evidence that a defective stromal microenvironment is likely to be of etiological significance in the susceptibility of NZB to autoimmune disease.

Animals↗
PubMed1994

Influence of human leukocyte antigen genes on TCR V gene segment frequencies.

Human leukocyte antigen (HLA)-dependent selection mechanisms exerted during thymic maturation are supposed to be main contributing factors to the genetic predetermination of the TCR repertoire and may have a detectable effect on adult peripheral blood lymphocyte V segment frequencies. Here, we analyzed whether polymorphic or non-polymorphic HLA determinants are associated with selected expression of some V gene segment specificities. We first examined the reactivity of 17 V segment specific mAb on purified CD4+ and CD8+ cell fractions in 10 unrelated people. We found a significant overexpression of only three V segment products (V beta 2, V beta 5.1 and V beta 6.7) in CD4+ and none in CD8+ cell fractions in most individuals. Skewing of certain V beta segments by non-polymorphic HLA determinants (i.e. class II for CD4+ and class I for CD8+ cells) is therefore more limited (3/17) than previously thought. Considering the effects of polymorphic HLA determinants, we compared TCR V segment frequencies in HLA-identical siblings to sibling pairs who differ at one or both HLA haplotypes, using 13 V beta specific mAb. In pairwise comparisons, we found that the HLA complex had no detectable effect on TCR repertoire in five large families with multiple siblings. Together, these observations suggest that HLA-predicted selection mechanisms exerted during thymic maturation might not have a predominant influence shaping the TCR repertoire of normal adults.

Antibodies, Monoclonal↗
PubMed1989

Persistent immunogenicity of rat thymic epithelium.

Culture of thymus tissue in 2-deoxyguanosine (2dGua) is thought to reduce tissue immunogenicity by selectively depleting highly immunogenic, thymic migrants of bone marrow origin. In the mouse 2dGua-treated thymus tissue survival is markedly enhanced compared with untreated tissue when transplanted under the kidney capsule of allogeneic recipients. These experiments were repeated in a rat model. As expected, DA strain neonatal thymus tissue was rejected when transplanted under the kidney capsule of normal allogeneic strain PVG rats. Surprisingly, acute rejection occurred when the tissue was cultured in 4 mM 2dGua, a dose capable of destroying rat thymocytes in vitro and 3 times the effective dose in mice. To test whether residual marrow-derived cells that escaped 2dGua treatment were responsible for inducing rejection, the treated DA tissue was "parked" in T cell-depleted PVG rats. Our working hypothesis was that the few remaining donor-derived cells of marrow origin would be overgrown by host-type cells. When 2dGua-treated DA thymus tissue was transplanted into T cell-depleted PVG recipients rejection did not occur. However this DA tissue, parked for as long as 200 days in T cell-depleted rats, was acutely rejected when retransplanted into normal PVG recipients. These results suggest that rat thymic epithelium devoid of marrow-derived cells in innately immunogenic.

Animals↗
PubMed2003

A central role for peripheral dendritic cells in the induction of acquired thymic tolerance.

Despite extensive negative selection in the thymus, numerous clones of self-reactive T cells are normally exported to the periphery. In most instances, autoimmunity is prevented by regulatory T (Tr) cells, many of which are also of recent thymic origin. We have demonstrated recently that natural killer (NK) Tr thymocytes (THYr) can be induced by the injection of antigen into the eye, an immunologically privileged site; and that the intravenous infusion of antigen-presenting cells (APCs) from such animals also induces NKT THYr. Furthermore, we have also observed that some of these APCs migrate to the thymus as CD11c(+) dendritic cells (DCs). Other authors have correlated the migration of DCs to the thymus with the generation of CD4(+)CD25(+) THYr. We therefore propose a novel tolerance induction pathway by which tolerogenic DCs routinely transport antigen (both self and nonself) from the periphery to the thymus, where they positively select THYr. We also propose that the ability of tolerogenic DCs to induce acquired thymic tolerance on demand might have important implications for the immunotherapy of autoimmunity and allotransplantation.

Animals↗
PubMed1992

A viral peptide can mimic an endogenous peptide for allorecognition of a major histocompatibility complex class I product.

Alloreactive class I-restricted T cells may recognize the class I structure alone, in association with a specific peptide, or with any stabilizing peptide. We have tested the role of endogenous peptides in the recognition of H-2Kb molecules by two alloreactive cytolytic T lymphocyte (CTL) clones using the mutant tumor line RMA-S, which expresses its surface H-2b molecules devoid of peptides and is not lysed by these two CTL clones. Empty H-2b molecules on RMA-S cells can be stabilized by binding exogenously added peptides. H-2Kb-specific recognition of the RMA-S cells by one of the CTL clones was restored by endogenous peptide extracts which only minimally stabilized H-2Kb on the surface of RMA-S cells, indicating the requirement for a specific peptide on a limited number of H-2Kb molecules. In addition, one out of three peptides which greatly enhance the expression of H-2Kb, the nucleoprotein peptide 52-59 from vesicular stomatitis virus (VSV), was also able to restore the lysis of RMA-S cells by the clone. The recognition of a common motif by an alloreactive clone (H-2k anti-H-2Kb) and virus-specific Kb-restricted clones suggests that both H-2k and H-2b thymic environments allow selection of T cells capable of recognizing H-2Kb+VSV and that tolerance to self, as would be the case in the (H-2k x H-2b)F1 mice, would partially delete the repertoire of antiviral T cells.

Amino Acid Sequence↗
PubMed1993

Development of gamma delta T cells in the adult murine thymus.

The development of T cells belonging to the gamma delta lineage is not well understood. We have analyzed the cells in the adult murine thymus which express the gamma delta TcR on the surface in order to learn more about this process. Our data demonstrate a number of clear subpopulations of gamma delta expressing cells in the thymus based on the expression of Thy-1 and HSA (heat-stable antigen). Only one of these subpopulations, the one expressing both Thy-1 and HSA, contains dividing cells or has a significant rate of turnover. Together with the fact that emigrant gamma delta cells are HSA+Thy-1+, this suggests that this thymic subpopulation is the sole, or major, source of exported cells. However, the turnover of cells from this population is 5 x 10(4) - 10 x 10(4) cells per day, while previous estimates of the rate of export of gamma delta cells are in the order of 10(4) cells per day. Furthermore the V gamma profile of recent gamma delta+ emigrants differs from that of the thymic HSA+Thy-1+ cells. This raises the possibility that only a selected subpopulation of the thymic gamma delta+HSA+Thy-1+ population is exported, and that some gamma delta cells may die in situ in the thymus. The function of the other gamma delta thymic subpopulations, which are turning over very slowly or not at all, (i.e. the HSA-Thy-1- and HSA-Thy-1+ subpopulations) remains unclear.

Animals↗
PubMed1994

Cholinergic stimulation modulates apoptosis and differentiation of murine thymocytes via a nicotinic effect on thymic epithelium.

Effects of cholinergic agonists/antagonists on apoptosis and differentiation of murine thymus cells were investigated in two in vitro models. Treatment with 10(-7) M carbachol was found to counteract the effects of a cortical thymus epithelial cell line (TEC 1.4), on apoptosis and the ratio of CD4 CD8 DP/DN cells in cocultured fetal thymus lobes. A medullary line (TEC 2.3) did not influence apoptosis in fetal thymus lobes. Both TEC lines had the same strong apoptotic effect on thymus cells in suspension, but only the effect of TEC 1.4 was counteracted by carbachol. This cholinergic influence on TEC 1.4 cells is mediated via nicotinic cholinergic receptors, since d-tubocurarine, but not atropine, effectively blocked the effect of carbachol. The results suggest that cholinergic signals to thymic epithelial cells may have regulatory influence on thymic differentiation and selection processes.

Animals↗
PubMed1997

Interleukin-2-activated killer cell activity in colorectal tumor patients: evaluation of in vitro effects by prothymosin alpha1.

The effects of prothymosin alpha1 (Pro alpha1) in combination with interleukin-2 (IL-2) on peripheral blood lymphocytes from 50 colorectal tumor patients at different stages were studied with respect to immunocytotoxicity, adhesion to cultured SW620 colon carcinoma cells, secretion of cytokines and expression of adhesion and surface marker molecules. On average, the patients showed lower natural killer (NK) cell activity than healthy donors, which was associated with a lower adhesion capacity to the tumor target cells. The NK cell activity of the patients was inversely related to the tumor stage. The generation of lymphokine(IL-2)-activated killer (LAK) cell activity was found to be comparable on lymphocytes from healthy individuals and patients and was not correlated to tumor stage. Pro alpha1 stimulated patients' LAK cell activity only, primarily at the early stage (Dukes A/B). The Pro alpha1 effect was associated with an increased adhesion of lymphocytes to tumor target cells and an increased secretion of the deficient IL-2-induced IFN gamma secretion. No significant effects on the low level of TNF alpha secretion was noted. By flow cytometry, Pro alpha1 in combination with IL-2 augmented the expression of the NK cell markers CD56, CD16/56, the subset CD3/16/56 and CD25 on lymphocytes of the patients. In contrast, Pro alpha1 was equally effective by increasing the expression of CD18 and CD11a on lymphocytes from the patients and from normal controls. In conclusion, Pro alpha1, in combination with IL-2, can partially normalize lymphocyte deficiencies of colon cancer patients in vitro. This potential might provide an experimental basis for applying Pro alpha1 or related thymic peptides in selected immunotherapies against colorectal tumors.

Adult↗
PubMed2005

Shaping the T cell repertoire to a bona fide autoantigen: lessons from autoimmune gastritis.

Murine autoimmune gastritis is one of the most well-defined organ-specific autoimmune diseases. CD4(+) T cells, which mediate the disease, recognize the highly abundant gastric H(+)/K(+) ATPase heterodimer. The H(+)/K(+) ATPase alpha subunit is also expressed in the thymus, in an aire-independent manner, whereas the H(+)/K(+) ATPase beta subunit is absent from the thymus. Analysis of both H(+)/K(+) ATPase-specific T cell receptor transgenic mice with different affinities for the gastric antigen and mice deficient in the H(+)/K(+) ATPase subunits has provided information on thymic and peripheral selection events. The H(+)/K(+) ATPase antigens play an important role in purging the repertoire of gastritogenic T cells, and recent data have suggested that this tolerance induction occurs primarily in the periphery. The gastritis system provides a powerful approach to determine the impact of peripheral antigen presentation in the target organ draining lymph node on tolerance and autoimmune disease.

Animals↗
PubMed2004

Ancestral founder mutation of the nude (FOXN1) gene in congenital severe combined immunodeficiency associated with alopecia in southern Italy population.

Genetic alterations of the FOXN1 transcription factor, selectively expressed in thymic epithelia and skin, are responsible in both mice and humans for the Nude/SCID phenotype. The first described human FOXN1 mutation was a C792T transition in exon 5 resulting in the nonsense mutation R255X, and was detected in two probands originated from a small community in southern Italy. In this community, four additional children affected with congenital alopecia died in early childhood because of severe infections. In this study, we report on the screening for this mutation in 30% of the village population. This analysis led us to identify 55 heterozygous carriers (6.52%) of the R255X mutation out of 843 inhabitants screened. A genealogical study revealed that these subjects, belonging to 39 families, were linked in an extended 7-generational pedigree comprising 483 individuals. Through the archival database a single ancestral couple, born at the beginning of the 19th century, was identified. To confirm the ancestral origin of the mutation we genotyped two microsatellite markers, D17S2187 and D17S1880, flanking the FOXN1 gene on chromosome 17. The three haplotypes identified, 3/R255X/3, 3/R255X/2 and 3/R255X/1, are consistent with a single ancestral origin for the mutation R255X.

Alopecia↗
PubMed1992

Genetic analysis of susceptibility to radiation-induced apoptosis of thymocytes in mice.

Genetic control of thymocyte susceptibility to radiation-induced apoptosis was investigated in BALB/cHeA, STS/A and five other strains of mice by counting pyknotic cells in a selected area of thymic cortex on histological specimens after whole-body X-irradiation. Number of dead cells increased almost linearly with doses (range 0.25-0.75 Gy) in BALB/cHeA and STS/A mice. However, dead cell counts in BALB/cHeA mice were more than twice those in STS/A mice at each dose. Of five other strains of mice, C57BL/6N and B10.BR mice exhibited a sensitive phenotype similar to BALB/cHeA mice, while C3H/HeAMsNrs and NFS/N mice showed a resistant phenotype similar to STS/A mice. A/J mice seemed to be rather resistant. A sex difference was not recognized in BALB/cHeA and STS/A mice. Resistance was dominant over susceptibility in the progenies of reciprocal crosses between the two strains, indicating an autosomal inheritance and no maternal effect. Segregation ratio of susceptible phenotype to resistant one in the backcrosses of female (BALB/cHeA x STS/A)F1 mice with male BALB/cHeA mice was not significantly different from 1:1 and all backcrosses of female (BALB/cHeA x STS/A)F1 mice with male STS/A mice exhibited a resistant phenotype. Results suggested that thymocyte susceptibility to radiation-induced apotosis is controlled by one major autosomal allele.

Animals↗
PubMed1988

Thymus and autoimmunity. Transplantation of the thymus from cyclosporin A-treated mice causes organ-specific autoimmune disease in athymic nude mice.

Organ-specific autoimmune diseases such as gastritis, oophoritis, thyroiditis, or insulitis developed in athymic nu/nu mice after engraftment of the thymus from euthymic nu/+ mice treated with cyclosporin A (CsA), a potent immuno-suppressant. The development of autoimmune disease in the nu/nu mice was prevented by inoculation of thymocyte suspensions prepared from normal nu/+ mice, but not by thymocyte suspensions from CsA-treated nu/+ mice. Cotransplantation of normal nu/+ mouse thymus with CsA-treated thymus also suppressed the development of autoimmune disease. Inoculation of spleen cell suspensions prepared from normal adult nu/+ mice prevented autoimmune disease, but inoculation of those from newborn nu/+ mice did not. Thus, CsA appears to interfere selectively with the thymic production of certain suppressor T cells controlling self-reactive (autoimmune) T cells, allowing the latter to expand and cause autoimmune disease.

Animals↗
PubMed1992

Induction of tolerance to autoimmune diabetes with islet antigens.

The development of T cell tolerance to self-antigens is imparted principally through negative selection events during thymic ontogeny. However, this tolerance may be limited to antigens that are expressed in the thymus, and additional mechanisms are probably required to regulate autoimmune responses to tissue-specific antigens. Autoimmune diabetes can be induced experimentally by treating susceptible stains of mice with multiple low doses of streptozotocin (STZ). In this report we show that transplantation of isolated islets of Langerhans into the thymuses of adult C57BL/KsJ mice will induce tolerance to the subsequent induction of autoimmune diabetes. This tolerance is tissue specific and thymus dependent. It was not induced by thymic transfer of adrenal tissue or by kidney transfer of islets. Furthermore, depletion of mature T cells was required and the tolerant state was abrogated by the adoptive transfer of normal splenocytes. It is interesting that pretreatment of the islets with STZ enhanced their ability to induce tolerance, and suggests that antigen shedding induced by tissue damage may facilitate transfer of islet antigens to tolerizing cells in the thymus. These findings indicate that thymic tolerance specific for tissue can be stimulated to occur in the presence of atopic tissue-specific intrathymic antigens. Elimination of disease-related T cells in the absence of global immunosuppression represents a novel approach for the prevention of autoimmune disease.

Animals↗
PubMed2006

Spontaneous autoimmunity prevented by thymic expression of a single self-antigen.

The expression of self-antigen in the thymus is believed to be responsible for the deletion of autoreactive T lymphocytes, a critical process in the maintenance of unresponsiveness to self. The Autoimmune regulator (Aire) gene, which is defective in the disorder autoimmune polyglandular syndrome type 1, has been shown to promote the thymic expression of self-antigens. A clear link, however, between specific thymic self-antigens and a single autoimmune phenotype in this model has been lacking. We show that autoimmune eye disease in aire-deficient mice develops as a result of loss of thymic expression of a single eye antigen, interphotoreceptor retinoid-binding protein (IRBP). In addition, lack of IRBP expression solely in the thymus, even in the presence of aire expression, is sufficient to trigger spontaneous eye-specific autoimmunity. These results suggest that failure of thymic expression of selective single self-antigens can be sufficient to cause organ-specific autoimmune disease, even in otherwise self-tolerant individuals.

Animals↗