Alkaline phosphatase in the thymus.

(1) Fetal thymuses, organs from patients who died from diseases that are not clinically known to be associated with concomitant lymphoid tissue involvement, as well as thymuses from patients dying from diseases which effect the lymphatic complex of the body, one way or another, have been investigated for their alkaline phosphatase activity, using Gomori technique and applying four different phosphate esters as substrates. (2) Three substrates (beta-glycerophophate, riboflavin 5-phosphate and adenosine triphosphate) showed essentially the same pattern of activity in which the cortex and Hassall's corpuscles were reactive, while the medulla was negative. A reversal of this pattern was demonstrated with 5-monophosphoric acid. (3) Before the age of 32-36 weeks of intra-uterine life there is no alkaline phosphatase activity in the thymus; therafter, the enzyme begins to make its first appearance. (4) There is a definite increase in the intensity of the reaction with advance of intra-uterine life. This increase in phosphatase content is continued postnatally, to reach its maximum at about the age of 10 years: after that, the enzyme activity gradually subsides. (5) There is a tremendous augmentation of phosphatase activity in the case of disease which are known to affect the lymphoid complex. (6) The phosphatase activity of the thymus has been discussed in relation to the prevailing concepts about the function of the thymus, with special emphasis on a possible association with 'lymphocyte-stimulating factor' production and/or secretion.     

Localization of thymostimulin in mouse and rat thymuses

Anti-bovine thymostimulin serum reacts with reticulo-epithelial cells in the cortex and in the medulla of rat and mouse thymuses. The immuno-reaction is present in a smaller number of cells which have more pallid color than those found in calf thymus. Comparative examination as to the distribution of other thymic factors and as to species-specificity was conducted.     

The restoration of the T-lymphoid system of nude mice: lower efficiency of nonlymphoid, epithelial thymus grafts.

The T-cell deficiency of nude mice is due to an abnormal differentiation of the thymus epithelium; it can be persistently corrected by grafting a neonatal thymus. However, grafted adult thymuses or epithelial thymuses are not repopulated by large numbers of host-derived lymphocytes, as is the case when a whole neonatal thymus is grafted. Furthermore, the repopulation of the spleen and lymph nodes by T cells is less pronounced than after whole neonatal thymus transplantation, and the restoration of the reactivity to T-cell mitogens is irregular. Therefore, the integrity and the age of the thymus graft are important for a good restoration of the T-lymphoid system of congenitally athymic animals.     

Repopulation of the mouse thymus after sublethal fission neutron irradiation. II. Sequential changes in the thymic microenvironment

The stromal cells of the thymus of sham-irradiated and sublethal fission neutron-irradiated CBA/H mice were analyzed with immunohistology, using monoclonal antibodies directed to I-A and H-2K antigens as well as specific determinants for cortical and medullary stromal elements. In the control thymuses, I-A expression in the thymus shows a reticular staining pattern in the cortex and a confluent staining pattern in the medulla. In contrast, H-2K expression is mainly confluently located in the medulla. Whole body irradiation with 2.5 Gy fission neutrons reduces within 24 hr the cortex to a rim of vacuolized "nurse cell-like" epithelial cells, largely depleted of lymphoid cells. The localization of I-A antigens changes in the cortex and I-A determinants are no longer associated with or localized on epithelial reticular cells. Medullary stromal cells, however, are more or less unaffected. A high rate of phagocytosis is observed during the first 3 days after irradiation. About 5 days after irradiation, the thymus becomes highly vascularized and lymphoid cells repopulate the cortex. The repopulation of the thymic cortex coincides with the appearance of a bright H-2K expression in the cortex which is associated with both stromal cells as well as lymphoid blasts. During the regeneration of the thymus, the thymic stromal architecture is restored before the expression of cell surface-associated reticular MHC staining patterns. The observed sequential changes in the thymic microenvironment are related to the lymphoid repopulation of the thymus.     

Influence of surgical and chemical orchidectomy on weight and distribution of AChE-nerve fibres in thymuses of adult rats

The thymus is a crossroad between the immune and neuroendocrine systems. As such, it is innervated by acetylcholinesterase (AChE)-positive fibres of the vagus, the recurrent laryngeal and the phrenic nerves. It is well know, that the innervations density of the thymus increases with age. In our study, adult rats were orchidectomized (surgically and chemically by the application of a luteinizing hormone-releasing hormone). The density of AChE-positive nerve fibres in thymuses, as well as the weight of thymuses was examined. The authors found that both surgical and chemical orchidectomy result in macroscopic and microscopic regeneration of the atrophied thymuses. In regenerated rat's thymuses after orchidectomy the density of AChE-positive nerve fibres was markedly higher in comparison with the control animals. The distribution, as well as the density of AChE-positive nerve fibres in regenerated thymuses after orchidectomy evokes the images of its innervations like in young animals before age-related involution. The authors also found a markedly higher weight of thymuses of orchidectomized rats in comparison with the control groups. In recent study the authors proved that after 8 weeks surgical orchidectomy leads to the regeneration of thymic AChE-positive innervation and chemical orchidectomy by administration of luteinizing hormone-releasing hormone after 4 weeks of adult rats.     

Localization of thymostimulin in mammalian thymuses: comparative evaluation

An anti-thymostimulin (TS) serum was tested on rabbit, guinea-pig, lamb and pig thymuses to study the localization of the hormonal factor. The immuno-peroxidase method, with some modifications, was applied to tissue fixed in Bouin's or in Bouin-PAF liquids and embedded in paraffin wax. Immuno-reactivity was shown in reticulo-epithelial cells in the cortex, in the medulla and in the external cells of the Hassall's corpuscles. The intensity of the immuno-reaction is stronger in pig thymus, whereas in lamb, rabbit and guinea-pig thymuses it is more uniform and pale, but to varying degrees. Comparison with the localization of TS in thymuses of other mammals and man and the problem of species-specificity were discussed.     

Quantification of acetylcholinesterase-positive structures in human thymus during development and aging

Acetylcholinesterase (AChE) localization in the human thymus has been studied by biochemical and morphological methods during development and aging. The occurrence, the amount and the distribution of acetylcholinesterase and the changes with age were examined in 24 human thymuses. The whole human thymus was removed during autopsies in males of the following age-groups: prenatal of six months, new-born, infant, young, adult and elderly. The thymuses were weighed, measured and dissected: the microanatomical details were stained with Eosin-orange, nervous structures were identified by means of Bodian's method. Protein content was determined with biochemical methods. Histoenzymatical and biochemical demonstration of acetylcholinesterase was performed. The morphological results obtained were submitted to quantitative image analysis. Our results show that the thymic microenvironment changes with age; moreover, an increase of acetylcholinesterase-positive structures can be observed with age. Biochemical results are in agreement with morphological results and both are confirmed by the outcome of quantitative analysis of images. Acetylcholinesterase activity in human thymus may play a key role in thymic functions.     

Proliferation, apoptosis and thymic involution.

The thymus reaches its maximal size at the age of 1 month in ICR mice and thereafter, the thymic cortex undergoes an exponential decline. This study was designed to compare the proliferation and apoptosis of thymocytes in different parts of the thymus of ICR female mice at the beginning and after the rapid phase of decline of the thymic cortical cellularity. The pattern of proliferation and apoptosis of the thymus was studied in situ in 1-month-old ICR female mice (10 mice) compared to mice at 7 months of age (10 mice). Staining for argyrophylic nucleolar organizer region by histochemistry was used to determine the proportion of type 2 thymocytes, which are considered as cells at S phase of the cell cycle. The mean number of type 2 cells in four random samples of 50 cells in each part of the thymus was defined as the proliferation index of this part of the thymus. In situ detection of apoptosis of thymocytes was carried out using the Apoptag kit, which can detect a single cell apoptosis. The mean number of apoptotic cells in five randomly selected fields of each part of the thymus was defined as the apoptotic index of this part of the thymus. The proliferation index of the peripheral cortex of the 1-month-old mice was 3.6 times higher than the proliferation index of the deep cortex and 5.8 times higher than the proliferation index of the medulla (P < 0.0001). The proliferation index of the peripheral cortex of the 7-month-old mice was reduced by 45% compared to the 1-month-old mice (P < 0.005). The apoptotic index of the corticomedullary junction of the 1-month-old mice was six times higher than the apoptotic index of the cortex and 18 times higher than the apoptotic index of the medulla. The apoptotic index of the thymic cortex was elevated by 66% in the 7-month-old mice compared to the 1-month-old mice (P < 0.0001). We conclude that there is a reduction of the proliferation index and an elevation of the apoptotic index of the thymic cortex in adult mice compared to young mice. These changes might account for the reduction of thymic cortical cellularity during thymic involution.     

Development of lymphoid tissue in a marsupial, Setonix brachyurus (quokka).

The development of the lymphoid tissues in a macropod marsupial is described. The liver is the only functional haemopoietic tissue at birth. Large lymphocytes first appear in the cervical thymus at 2 days, and in the thoracic thymus at 4 days after birth. Small lymphocytes appear 1-2 days later. The histological development of the two glands is similar, but the thoracic thymus develops much more slowly than the cervical. The appearance of Hassall's corpuscles in both thymus glands correlates with the onset of humoral immune responses in this animal. Lymph nodes first appear as aggregates of lymphocytes around the lymphatic vessels at 5 days, differentiate into cortex and medulla at about 14 days, but do not develop germinal centres until about 90 days. Small lymphocytes are not observed in the spleen until the 2nd week, and reactive centres do not appear until after 90 days of pouch life. Peyer's patches are not found until 60 days of age. Large lymphocytes are seen in the bone marrow at 14 days, but small lymphocytes are not found until the 1st month. Although the sequence of lymphoid development is similar to that seen in other animals, the rapidly with which it becomes functional suggests that it is an adaptive response to early contact with environment pathogens.     

Localization of eosinophils in the thymus by the peroxidase reaction

Summary Thymuses of human fetuses and infants and of young mice were investigated histochemically for peroxidase. Eosinophils were shown to be the only peroxidase-positive cells in the thymus.In human thymuses the eosinophilic cells were predominantly localized in medullar areas, with concentration of cell clusters at the cortico-medullar junction, around or inside Hassall's bodies and occasionally in high numbers in the intraseptal vessels of the cortex.In the normal mouse the eosinophils were evenly distributed throughout the medulla.Treatment with corticosteroids or X-rays produced a severe involution of the thymus with concommitant change in cellular pattern. The central areas of the thymus residue contained lymphocytes while the peripheral regions consisted of reticuloepithelia, macrophages and numerous eosinophils.Azathioprine did not change the morphology of the thymus. The numbers of eosinophils were slightly reduced, the distribution pattern remaining unchanged.     

Neuroendocrinology of the thymus

The neuropeptides oxytocin (OT) and vasopressin (VP) are synthesized in the human thymus in a similar way as in the hypothalamo-neurophypophyseal system. Immunocytochemistry with polyclonal and monoclonal antibodies revealed that immunoreactive OT- and VP-producing cells are localized in the subcapsular cortex and medulla of human and murine thymuses. The epithelial nature of the neuroendocrine thymic cells is demonstrated by their immunostaining with a monoclonal antibody against cytokeratin. An original example of a neuroendocrine-immune microenvironment is given by the thymic nurse cells which are composed of a large neuroendocrine epithelial cell enclosing numerous mitotic immature thymocytes. These observations and the previously reported mitogenic and immunomodulatory properties of VP and OT upon mature T cells and thymocytes strongly support the existence of a neuroendocrine thymo-lymphoid axis and an active role of thymic VP and OT in T cell differentiation and activation.     

Development and ontogeny of hamster T cell subpopulations

The Syrian hamster is unique among laboratory animals because products of class I MHC genes are monomorphic. Thus, this species may be a model in which to test the relationship between MHC polymorphism and the T cell antigen receptor repertoire. Recently, cytotoxic and helper T cell subpopulations have been distinguished on the basis of cell surface phenotype detected with monoclonal antibodies (mAb). We used these reagents (mAb 110 detects all peripheral T cells and mAb 38 detects cytotoxic T cells) to dissect and categorize thymic populations according to relative maturational status. The two mAb divide thymocytes into four subpopulations in the young adult. Two (110+ 38+, 110+ 38-) were peripheral-like and were housed in the medulla, exclusively; another subset (110- 38+) consisted almost entirely of TdT+ cortical thymocytes. The fourth subset (110- 38-), bearing neither marker, was heterogeneous and consisted mostly of medium-large-size thymocytes, including cells with an early phenotype (nuclear TdT+). Cells with the cortical phenotype proved to be the most sensitive to cortisone treatment, whereas those which expressed the medullary marker, 110, were most resistant. To ascertain the relationship between 110- and 110+ T lineage cells, we followed the appearance of the four thymic subpopulations during ontogeny of the hamster thymus. Adult-like thymic architecture (delineation of cortex and medulla) as well as the two 110- subsets were established before expression of 110 antigen was apparent in the thymus. However, lymphocytes bearing the 110 antigen were found in lymph nodes prior to thymus during ontogeny, concomitant with developing T cell function in peripheral tissue. This finding implies that cells lacking 110 antigen were exported from the thymus and subsequently acquired expression of the molecule in the periphery, and we suggest that acquisition of 110 antigen may be a stage of postthymic maturation. Although 110+ cells appeared to be the most mature subset by several criteria, all functional thymocytes of adults or neonates were not 110+. Thus, we conclude that the 110 marker is acquired after T cells reach functional maturity. Moreover, the response profile of isolated 38+ thymocytes was analogous to peripheral 38+ T cells, suggesting that the dichotomy of function detected with our mAb also occurs before acquisition of 110 antigen. We have modeled what is known about hamster T cell development into a hypothetical scheme.     

Effect of Chemical Thymectomy on Skin Homografts: A Preliminary Report

In an attempt to combine the results obtained by Miller (mice thymectomized at birth accepted homograft at six weeks of age) and those obtained by Selye (selective calcification of the cortex of the thymus with calciphylaxis), calcification of the thymus was produced by the combined injection of dihydrotachysterol and triamcinolone, in non-inbred Sprague-Dawley and hooded, eight-week-old rats. Six days after the beginning of treatment, full-thickness skin homografts were performed on the rats.Homografts exchanged between two rats with complete calcification of the thymus cortex were accepted for an extended period of time, which in the oldest rats at the time of writing was seven months. Homografts exchanged between rats with incomplete calcification of the thymus resulted in a prolonged homograft survival with final rejection within a period of three weeks. Homografts exchanged between rats that were not treated, surgically thymectomized at the same age as the treated animals, or treated with only one of the two substances used for thymus calcification, resulted in rejection in the average time of eight days.     

The role of the thymus medulla of newborn rats in lymphocytopoiesis

By means of 3H-thymidine, radioautographic investigation of lymphocytopoiesis has been performed in the cortex and medulla of the rat thymus for 2 weeks after birth. In the newborn animals the index of labelled nuclei (ILN) in the medulla is higher than in the cortex. By the 14th day after birth a progressive drop of lymphocytes including the isotope takes place in the medulla. The decrease of ILN in the medulla occurs against the background of increasing amount of epithelioreticulocytes with vacuoles and dystrophic changes in the nucleus and cytoplasm, that make groups of Hassal's bodies.     

The stroma of the thymus of the rat: morphology and antigen diffusion, a reconsideration

This work reconsiders aspects of the morphology of the capsule, of the blood vasculature, of the distribution of reticular fibers, and of the diffusion of intramediastinally injected antigens in the stroma of the thymus of the rat. This was done by an analysis of standard sections of normal thymuses, of sections of thymuses perfused with colloidal carbon, of silver-impregnated sections, and of sections of thymuses of rats injected intramediastinally with a fluorescent antigen or intravenously with Trypan blue, and by electron microscopy of the thymic capsule. The capsule consisted of two layers: an outer layer covering the entire periphery of a thymic lobe, and an inner layer which outlined the entire convoluted peripheral cortex of a lobe. Cortical vessels entered the capsule and septa in which they formed a capillary network. These capsular capillaries were fenestrated and leukocytes were often present near them. Adipocytes were also seen near these vessels in some areas of the capsule, and often at the bases of septa and trabeculae. Furthermore, much of the medulla had a dense network of coarse reticular fibers, whereas the remainder of the medulla and the cortex contained a loose network of fine fibers stretching out from the capsule, septa, and trabeculae. Intramediastinally injected fluorescent antigens were observed to spread in the capsule and septa and to diffuse in the fiber networks stretched across the cortex and the medulla. Fluorescence also highlighted cortical reticular cells but not the thymocytes. Intravenously injected Trypan blue stained the capsule, the septa, the cortical reticular cells, and the autofluorescent cells outlining the corticomedullary junction of each lobule. The unusual penetration of capillaries from the thymic parenchyma into the thymic capsule suggested that the capsular capillaries participate in peculiar thymic events, such as the recruitment of blood stem-cells. It is concluded that small amounts of blood antigens normally exude from capsular capillaries and diffuse into the fibers extending from the capsule across the cortex. The phenomenon would be increased under conditions causing thymic involution. An explanation is proposed to account for the development of involution which involves the exudation of antigens from the capsular capillaries. A comparable mechanism could also account for the development of a particular experimental immune tolerance.     

斜带石斑鱼胸腺的显微和超微结构

本文通过解剖及组织切片技术、光学显微镜、透射和扫描电子显微镜技术,对斜带石斑鱼(Epinephelus coioides)胸腺器官组织进行了观察研究。结果表明:斜带石斑鱼胸腺实质主要由胸腺细胞(淋巴细胞)和网状上皮细胞构成。鱼体从Ⅰ龄之后,其胸腺发生明显的变化,与幼鱼有所不同,主要是胸腺可明显区分为三个区域:胸腺外皮质区、内皮质区和髓质区。外皮质区主要由网状上皮细胞、黏液细胞、成纤维细胞和少量淋巴细胞构成,细胞排列疏松;内皮质区主要由密集的淋巴细胞和网状上皮细胞组成,以含有大量的淋巴细胞为特征;髓质区主要由淋巴细胞和较多的网状上皮细胞构成,总体特征是淋巴细胞数量比内皮质区的少,且细胞排列较疏松。外皮质区、内皮质区相当于高等脊椎动物的皮质;髓质区相当于高等脊椎动物的髓质。髓质区之下有结缔组织,在Ⅱ龄以上的成体出现胸腺小体(Hassall's corpuscles)或类似胸腺小体的结构,而且随着年龄的增加,胸腺外皮质区增厚,结缔组织增加,还表现在内皮质区和髓质区组织逐渐萎缩变薄,胸腺的细胞组成类型和淋巴细胞数量上有所变化等等。这些现象在Ⅱ龄鱼开始出现,即胸腺呈现退化迹象,在Ⅲ龄以上鱼体呈现明显的退化和萎缩。胸腺表面扫描电镜结果表明:其上皮细胞表面具有微嵴以及由微嵴组成的指纹状结构,有一些微孔分布。透射和断面扫描电镜的结果进一步表明:胸腺组织内的细胞成分复杂,除了淋巴细胞和网状上皮细胞外,还具有巨噬细胞、肥大细胞、肌样细胞、浆细胞、指状镶嵌细胞和纤维细胞等。     

Cholinesterase activity in quail primary lymphoid organs

The present histochemical study was carried out to analyze the distribution and topography of acetylcholinepositive nerve fibers in the thymus and bursa of Fabricius of quails. The AChE-positive nerve fibers were demonstrated by direct thiocholine histochemical method. Nerve fibers present in the thymuses form periarterial nerve plexuses located mostly in the interlobular septa and on the cortico-medullary junction. Vessels-independent nerve fibers occur also in the parenchyma of thymic medulla, but rarely in parenchyma of the cortex. Within the connective tissue between the bursa of Fabricius and the wall of proctodeum we observed conspicuous AChE-positive ganglia, often in close relationship to greater arteries. Within the wall of bursa of Fabricius, AChE-positive nerve fibers create nerve plexuses around arteries. We observed a close relationship between lymphoid follicules in bursal submucosa and mucosa and AChE-positive nerve fibers. Nerve fibers create a ring around lymphoid follicles, but do not penetrate into the germinal center of the follicle. Arteries inside quail thymuses and bursae of Fabricius contain rich AChE-positive nerve plexuses, when compared to the veins, which have a very poor presence of AChE-positive nerves. According to lesser presence and decreased density of AChE-positive nerve fibers in older animals, we described age-dependent changes in both quail primary lymphoid organs.     

Changes in the thymus of peripubertal rats induced by centrally applied somatostatin-28

The aim of this study was to investigate the effects of centrally applied somatostatin-28 on morphometric characteristics of the thymus, the thymocyte subpopulations, as well as, on apoptosis and phases of cell cycle in thymocytes. For this purpose, peripubertal male rats were cannulated intracerebroventriculary and treated with repeated, nanomolar concentrations of somatostatin-28 (experimental group) or saline (control group). Animals were sacrificed and their thymuses were used for the analysis of thymocyte subpopulations, cell cycle and apoptosis by flow cytometry and for the evaluation of morphometric parameters by stereological analysis. Our results showed that somatostatin-28 caused decrease of the thymic mass and volume, as well as total thymocytes number. Stereological analysis revealed volume decrease of thymic cortex and medulla accompanied with cellularity decrease. Somatostatin in the deeper cortex decreased the number of thymocytes, per volume unit, while in outer cortex raised their number. A significant increase in the percentage of double-negative and both single-positive thymocyte subpopulations, in parallel with a diminished percentage of double-positive cells was found. The cellularity of double-positive and single-positive thymocyte subpopulations was decreased. Somatostatin-28 treatment augmented the percentage of apoptotic cells, while the percentage of the cells represented in phases of cell cycle was reduced. These results suggest that somatostatin-28 induce thymus hypotrophy as result of decreasing cortex and medulla volume and cellularity. Changes in the percentage and cellularity of thymocyte subpopulations and numerical density of thymocytes in outer and deeper cortex, indicate that somatostatin-28 evoked disturbance in transition of double-negative to double-positive thymocytes.     

Thymic epithelial cells of severely undernourished mice: accumulation of cholesteryl esters and absence of cytoplasmic vacuoles

The thymic epithelium was compared in weanling male and female CBA/J mice when fed ad libitum and when subjected to severe food intake restriction for 14 days. The restriction protocol elicited predominantly a metabolic response to caloric deficit rather than to protein deficiency. Electron microscopy revealed intracytoplasmic accumulations of large, circular, homogeneously electron-dense profiles (with no limiting membrane) in a high proportion of cortical and medullary epithelial cells of thymuses from restricted mice, but not from controls. The electron-dense material was not preserved in the absence of osmium. Thin-layer chromatography (TLC) indicated elevated levels of free and esterified cholesterol, particularly the latter, in whole thymus extracts of restricted mice. Measurements of total cholesterol levels in the thymic extracts were consistent with the results obtained by TLC. In addition, cryostat sections of thymuses from restricted mice, but not from controls, exhibited numerous stained foci throughout the cortex and medulla when treated with oil red O (a general neutral lipid stain) or by the Schultz procedure which is specific for cholesterol. Collectively the results suggest accumulations of cholesteryl esters, together with some free cholesterol, as non-membrane-bound droplets in the cytoplasm of thymic epithelial cells of undernourished mice. It is also of interest that the lipid-laden epithelial cells exhibited none of the cytoplasmic vacuoles observed in controls and believed to be important in thymic hormone secretion. This work provides the first direct evidence of thymus epithelial abnormalities in severe protein-energy malnutrition.     

Tumor necrosis factor-alpha and IFN-gamma expression in human thymus. Localization and overexpression in Down syndrome (trisomy 21).

In vitro studies suggest that TNF-alpha and IFN-gamma regulate thymocyte proliferation, but little evidence exists for the constitutive production of these cytokines in normal human thymus. In paired experiments, we examined frozen sections of postnatal human thymus from four control children and four age-matched children with Down syndrome (DS) (trisomy 21) for TNF-alpha and IFN-gamma mRNA expression using in situ hybridization. We studied thymuses from children with DS because this aneuploid condition is associated with a greatly increased incidence of infection and has abnormal thymic anatomy and patterns of thymocyte maturation. We found cells expressing constitutive levels of TNF-alpha mRNA in the trabeculae, corticomedullary junctions, and medulla of both control and DS thymuses and the number of these cells was an average of 3.9-fold higher in DS thymuses than in age-matched control thymuses. DS thymuses also contained an average of 3 fold higher numbers of cells with mast cell morphology, identified by toluidine blue histologic staining and electron microscopy. In both DS and control thymuses the mast cells colocalized with TNF-alpha mRNA-expressing cells. In addition, TNF-alpha protein- expressing cells, identified by immunohistochemistry, displayed a granular pattern of staining that is characteristic of mast cells. These results suggest that mast cells may be one source of TNF-alpha in human postnatal thymus. Discrete cells expressing IFN-gamma mRNA were distinctly localized to the cortical region of both DS and control thymuses and were 2.4-fold more abundant in DS thymuses than in the controls. Our results demonstrate, for the first time, the constitutive production and location of TNF-alpha and IFN-gamma in postnatal human thymus. The overexpression of both of these cytokines in DS thymuses suggests a dysregulation in cytokine production in DS and may provide an explanation for the abnormal thymic anatomy and thymocyte maturation associated with this syndrome.