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PubMed1990

Radiostrontium-induced oncogenesis and the role of immunosuppression. II. Influence of 90Sr dose, adult thymectomy and antilymphocyteglobulin treatment on the development of lympho-reticular and extraskeletal, neoplastic lesions in CBA mice.

The significance of depressed immune function for the development and progression of tumours induced by 90Sr (mainly osteosarcomas and malignant lymphomas) was investigated in a series of experiments by comparing the tumour responses in normal mice with those in immunocompromised mice. The present paper (part II) reports on lympho-reticular (LR) and extraskeletal neoplastic lesions in male CBA/SU mice after exposure to different single doses of 90Sr with or without additional immunosuppression by adult thymectomy (ATx) and/or prolonged antilymphocyteglobulin (ALG) treatment. Neoplastic lesions in bone were reported in part I. The status of the animal's immune system and responsive ability were examined in parallel experiments. The tumour yields were analysed in relation to the dosage of 90Sr and the immunosuppressive treatments employed. Although the incidences and latency times of induced tumours were clearly dose-dependent, they were never significantly influenced by ATx/ALG treatments. Thus, no substantial support was gained for the theory that the immune system plays a controlling or modifying role in 90Sr carcinogenesis. The results, which are in agreement with the bone tumour responses, suggest that 90Sr induced tumours either do not express the antigens necessary for immune rejection or that the decline in immune responsiveness induced by ATx/ALG was of little consequence for tumour development and spread. The pathogenesis of 90Sr induced malignant lymphomas (MLs) and their immunophenotypes are discussed.

Animals↗
PubMed1976

Thymic diseases as revealed by a series of consecutive thymectomies and biopsies from the thymus.

A series of 85 thymis biopsies and specimens from thymectomies were re-examined. Forty-five of these were taken from patients with myasthenia gravis. A relatively low frequency of thymitis (57%) was found in these patients, while the frequency of thymoma (9%) was as expected. Two cases of thymitis in thyrotoxicosis were included in the material. In all, 22 thymomas of various kinds (18% of the total material) were diagnosed. A fairly low proportion of these thymomas (18%) were from patients with myasthenia gravis.

Adolescent↗
PubMed1988

Antithyroid drugs ameliorate thymectomy-induced experimental autoimmune thyroiditis.

The possible immunosuppressive action of antithyroid drugs in vivo has been assessed using Buffalo (Buf) strain rats with thyroiditis produced by neonatal thymectomy; this model shares many features with spontaneous thyroiditis in man. Both propylthiouracil and methimazole significantly reduced the severity of thyroiditis (P less than 0.01 compared to controls), irrespective of effects on thyroid status. Thyroidal Ox 8 (suppressor/cytotoxic) and W3/25 (helper) T-cells were reduced in number equally in treated animals, and thyroid follicular cell Ia expression was absent in a high proportion of these glands. Neither agent alone altered circulating antithyroglobulin antibody levels but there was a significant fall in antibody levels in animals treated with propylthiouracil and thyroxine. Antithyroid drugs had no effect on circulating T-cell subsets, and there was no direct suppressive action in vitro on Ia expression by the FRTL5 thyroid cell line. These results provide further support for a direct action of antithyroid drugs on autoimmune process in thyroid disease exerted in particular on the thyroid lymphocytic infiltrate.

Animals↗
PubMed1993

Post-thymectomy organ-specific autoimmunity: enhancement by cyclosporine A and inhibition by IL-2.

It has previously been shown that the administration of cyclosporine A to newborn mice results in the development of autoimmunity later in life. It has been proposed that the neonatal administration of cyclosporine A results in altered thymic selection or inhibition of the development of suppressor cells. In the present study, treatment of day 3 thymectomized C3H/HeN mice with cyclosporine A (20 mg/kg/day) for 9 d post surgery increased the prevalence of antigastric autoantibodies. In contrast, the administration of IL-2 (300-600 Units/g/day) for 7 days after thymectomy inhibited the development of antigastric antibodies. We hypothesize that CsA may act by causing transient lymphokine abnormalities in the extrathymic environment during the first few weeks of life which lead to the development of antigastric antibodies. In contrast to the inhibition of development of antigastric antibodies, the administration of a similar course of IL-2 produced only a transient suppression of diabetes in NOD mice. These results and other data suggest that diabetes in NOD mice is probably due to a different immunologic defect.

Animals↗
PubMed1985

Effect of antilymphocyte serum and neonatal thymectomy upon onset of diabetes in the Chinese hamster.

Prediabetic Chinese hamsters were treated with antilymphocyte serum (ALS), or thymectomized in order to test the hypothesis that beta-cell loss leading to diabetes in this animal model was related to cell-mediated autoimmunity. In addition, passive transfer of diabetes from the Chinese hamster to the nude mouse was attempted by transplantation of lymphocytes. Treatment of prediabetic Chinese hamsters with ALS or thymectomy did not alter development or severity of diabetes in this animal model. Lymphocytes from newly diagnosed diabetic Chinese hamsters did not cause hyperglycemia in nude mice. These three lines of evidence suggest that cell-mediated autoimmunity does not contribute to the etiology of diabetes in the Chinese hamster. The Chinese hamster remains a good model for the study of those forms of diabetes not related to cell-mediated autoimmune phenomena.

Animals↗
PubMed2001

Endogenous oocyte antigens are required for rapid induction and progression of autoimmune ovarian disease following day-3 thymectomy.

Female (C57BL/6xA/J)F(1) mice undergoing thymectomy on day 3 after birth (d3tx) developed autoimmune ovarian disease (AOD) and autoimmune disease of the lacrimal gland. As both were prevented by normal adult CD25(+) T cells, regulatory T cell depletion is responsible for d3tx diseases. AOD began as oophoritis at 3 wk. By 4 wk, AOD progressed to ovarian atrophy with autoantibody response against multiple oocyte Ag of early ontogeny. The requirement for immunogenic endogenous ovarian Ag was investigated in d3tx female mice, d3tx male mice, and d3tx neonatally ovariectomized (OX) females. At 8 wk, all mice had comparable lacrimalitis but only those with endogenous ovaries developed AOD in ovarian grafts. The duration of Ag exposure required to initiate AOD was evaluated in d3tx mice OX at 2, 3, or 4 wk and engrafted with an ovary at 4, 5, or 6 wk, respectively. The mice OX at 2 wk did not have oophoritis whereas approximately 80% of mice OX at 3 or 4 wk had maximal AOD, thus Ag stimulus for 2.5 wk following d3tx is sufficient. AOD progression requires additional endogenous Ag stimulation from the ovarian graft. In mice OX at 3 wk, ovaries engrafted at 5 wk had more severe oophoritis than ovaries engrafted at 6 or 12 wk; moreover, only mice engrafted at 5 wk developed ovarian atrophy and oocyte autoantibodies. Similar results were obtained in mice OX at 4 wk. Thus endogenous tissue Ag are critical in autoimmune disease induction and progression that occur spontaneously upon regulatory T cell depletion.

Animals↗
PubMed2002

Interacting quantitative trait loci control loss of peripheral tolerance and susceptibility to autoimmune ovarian dysgenesis after day 3 thymectomy in mice.

Day 3 thymectomy (D3Tx) results in a loss of peripheral tolerance mediated by CD4(+)CD25(+) T cells and the development of autoimmune ovarian dysgenesis (AOD) in A/J and (C57BL/6J x A/J)F(1) (B6AF(1)) hybrids but not in C57BL/6J mice. Quantitative trait loci (QTL) linkage analysis using a B6AF(1) x C57BL/6J backcross population verified Aod1 and Aod2 that were previously mapped as qualitative traits. Additionally, three new QTL intervals, Aod3, Aod4, and Aod5, on chromosomes 1, 2, and 7, respectively, influencing specific subphenotypes of AOD were identified. QTL linkage analysis using the A x B and B x A recombinant inbred lines verified Aod3 and confirmed linkage to H2. Aod5 colocalized with Mater, an ovarian-specific autoantigen recognized by anti-ovarian autoantibodies in the sera of D3Tx mice. Sequence analysis of Mater identified allelic, strain-specific splice variants between A/J and C57BL/6J mice making it an attractive candidate gene for Aod5. Interaction analysis revealed significant epistatic effects between Aod1-5 and Gasa2, a locus associated with susceptibility to D3Tx-induced autoimmune gastritis, as well as with H2. These results indicate that the QTL controlling D3Tx-induced autoimmune phenomenon are both organ specific and more generalized in their effects with respect to the genesis and activity of the immunoregulatory mechanisms maintaining peripheral tolerance.

Amino Acid Sequence↗
PubMed2003

Aod1 controlling day 3 thymectomy-induced autoimmune ovarian dysgenesis in mice encompasses two linked quantitative trait loci with opposing allelic effects on disease susceptibility.

Day 3 thymectomy (D3Tx) leads to a paucity of CD4(+)CD25(+) suppressor T cells, a loss of peripheral tolerance, and the development of organ-specific autoimmune disease in adult mice. Importantly, D3Tx does not lead to autoimmune disease in all mouse strains, indicating that this process is genetically controlled. Previously, we reported linkage of D3Tx-induced autoimmune ovarian dysgenesis (AOD) and its intermediate phenotypes, antiovarian autoantibody responsiveness, oophoritis, and atrophy, to five quantitative trait loci (QTL), designated Aod1 through Aod5. We also showed interaction between these QTL and H2 as well as Gasa2, a QTL controlling susceptibility to D3Tx-induced autoimmune gastritis. To physically map Aod1, interval-specific bidirectional recombinant congenic strains of mice were generated and studied for susceptibility to D3Tx-induced AOD. Congenic mapping studies revealed that Aod1 controls susceptibility to oophoritis and comprises two linked QTL with opposing allelic effects. Aod1a resides between D16Mit211 (23.3 cM) and D16Mit51 (66.75 cM) on chromosome 16. Aod1b maps proximal of Aod1a between D16Mit89 (20.9 cM) and D16Mit211 (23.3 cM) and includes the candidate genes stefin A1, A2, and A3 (Stfa1-Stfa3), inhibitors of cathepsin S, a cysteine protease required for autoantigen presentation, and the development of autoimmune disease of the salivary and lacrimal glands following D3Tx. cDNA sequencing revealed the existence of structural polymorphisms for both Stfa1 and Stfa2. Given the roles of cathepsins in Ag processing and presentation, Stfa1 and Stfa2 alleles have the potential to control susceptibility to autoimmune disease at the level of both CD4(+)CD25(+) suppressor and CD4(+)CD25(-) effector T cells.

Alleles↗
PubMed2006

The effects of age, thymectomy, and HIV Infection on alpha and beta TCR excision circles in naive T cells.

Due to homeostasis total naive T cell numbers remain fairly constant over life despite a gradual involution of the thymus. The contribution of the thymus to maintaining naive T cell pools is typically measured with TCR excision circles (TRECs) that are formed in thymocytes. The mechanisms underlying thymic involution are poorly understood. Some data suggest that thymocytes undergo fewer divisions in old (small) than young (large) thymi, and other data suggest that the number of TRECs per thymocyte is independent of age. If thymic involution were associated with a decreased number of divisions of the thymocytes, this would markedly complicate the interpretation of TREC data. To study this we develop a mathematical model in which the division rate of thymocytes decreases with increasing age. We describe the dilution of TRECs formed during the arrangement of both chains of the TCR by division of thymocytes, recent thymic emigrants, and mature naive T cells. The model behavior is complicated as TREC contents in naive T cells can increase with age due to decreased dilution in the thymus. Because our model is consistent with current data on the effects of age and thymectomy on TRECs in peripheral T cells, we conclude that aging may well affect thymocyte division, which markedly complicates the interpretation of TREC data. It is possible, but more difficult, to let the model be consistent with the rapid changes in alpha and beta TRECs observed shortly after HIV infection.

Age Factors↗
PubMed1976

Studies on recovery mechanism from rinderpest virus infection in rabbits. I. Effect of anti-thymocyte serum and thymectomy.

The role of cell-mediated immunity in recovery from rinderpest virus infection in rabbits was investigated by application of immunosuppressive procedures, i.e., treatment with anti-thymocyte serum and combined treatment with thymectomy and anti-thymocyte serum, both of which were confirmed to depress significantly cell-mediated immunity in rabbits. The immunosuppressed animals recovered in almost the normal fashion in terms of clinical signs, of virus clearance from the blood and lymphoid tissues and of repair of the lesions. It was suggested that the thymus-dependent cell-mediated immunity may not be essential in recovery from rinderpest virus infection. Possibility of participation of other recovery mechanisms was discussed.

Animals↗
PubMed1999

Video-assisted thoracoscopic thymectomy.

Video-assisted thoracoscopic surgery (VATS) provides a new, alternative approach to thymectomy and has several advantages over the other established techniques. However, even among surgeons using this approach, there are differences in the actual technique. We prefer the right approach using conventional instruments. The rationale behind our technique is discussed.

Humans↗
PubMed1999

Thymectomy and multiple sclerosis: ultrastructural study of an experimental model.

Transmission electron microscopy was performed on specimens of the thymus of rats induced for acute experimental allergic encephalomyelitis (EAE). The ultrastructural alterations of the thymus were progressive and correlated with EAE development. The thymic disorganization was due to a progressive degeneration of both epithelial cells and thymocytes. These data suggest a direct involvement of the epithelial thymic cells and thymocytes in EAE pathogenesis and may suggest the intriguing therapeutic concept of thymectomy in the management of multiple sclerosis.

Animals↗
PubMed1976

Kinetics of mononuclear phagocytes after thymectomy.

Some kinetic parameters of mononuclear phagocytes have been studied. Wistar rats were injected with 3H-thymidine. Samples of peripheral blood and peritoneal macrophages were obtained at 12, 14, 24, 36, 48, 60, and 84 hours respectively after injection. The labelling index and the mean grain count were determined. The turnover of monocytes was slowed down in the thymectomized animals. It is assumed that thymectomy had changed some biological qualities of mononuclear phagocytes and/or the humoral relations connected with the function and the regulation of mononuclear phagocytes.

Animals↗
PubMed2000

[A patient with limb-girdle type myasthenia gravis and atopic dermatitis, both of which improved after thymectomy].

We herein report a patient with myasthenia gravis (MG) and atopic dermatitis (AD). Heretofore, there have been no reports of patients with MG and AD. Nine years ago, a 25-year-old man noted muscle weakness of upper and lower extremities on physical labor, and the muscle weakness was gradually exacerbated. Two years ago, he noted acute skin eczema with itching on his hands and feet. Neurological examination revealed mild left ptosis, facial muscle weakness and proximal muscle weakness of upper and lower extremities, but no diplopia, ophthalmoplegia or dysphagia. Although anti-nicotinic acetylcholine receptor antibody was negative, edrophonium test was positive and 54% waning in the thenar muscles was observed on Harvey-Masland test. Thus, he was diagnosed as limb-girdle type MG. IgE level in his serum elevated (1,818 U/ml). After thymectomy, the muscle weakness markedly improved as well as waning in the thenar muscles (11%). Simultaneously, AD markedly improved and serum IgE level was decreased (1,245 U/ml). Thus, MG and AD in this case may be derived from some common immunological aberrancy in the thymus.

Adult↗
PubMed1975

[Effects of thymectomy on the natural bactericidal power of thymectomized mice].

T and B-dependent systems are correlated between themselves and with the macrophage system in eliciting the immune humoral response. Not all immunogens require T-B interactions to elicit the antibody response: consequently, the problem of the limits of T-dependence, with regard to different immunogen stimulations, remains open. The comparative study of the serum antibody response in mice, thymectomized at birth and in the normal ones, inferred from the values of bactericidal activity (b.a.), detected versus E. coli, S. typhi and S. albus strains did point out evident variation. Thymectomy has impaired b.a. against E. coli; it seems to have no consequence on b.a. against S. typhi; is not possible to the results of our investigation, it seems that the response to the immunogens, responsible for the so-called natural antibodies does require T-B cooperation only for some bacterial species and not for others. A higher bactericidal capacity of normal serum with regard to Gram positive as compared with Gram negative bacteria, is confirmed.

Animals↗
PubMed2000

Technique of transcervical--subxiphoid-vats "maximal" thymectomy in treatment of myasthenia gravis.

Operative technique of transcervical-subxiphoid-VATS thymectomy is described. Total sternotomy is avoided which makes the procedure less invasive without compromising its radicality. The operation is performed with aid of special device with two sternal retractors elevating the sternum from above and below and facilitating access to the mediastinum. The mediastinal pleura is incised bilaterally and exenteration of the mediastinal fat is done under control of video camera inserted through the thoracoscopic ports. Two team approach is proposed: one team, called "the cervical" team performs dissection of the neck and the superior mediastinum; the "subxiphoid" team removes the fat tissue of the anterior mediastinum. This approach makes possible reduction of the operative time to 1.5-2 h. No complications were noted in the group of 8 patients operated on by the moment of submission of the abstract.

Humans↗
PubMed2001

Thymectomy-induced deterioration of learning and memory.

Age-associated immunodeficiency and cognitive deterioration are two predominant features of the aging process, but the mutual influences between them are not clear yet. Research on the neuroendocrine immunomodulation (NIM) network indicate reciprocal interactions between the neuroendocrine and the immune systems mediated by neurotransmitters, neuropeptides, hormones and cytokines, which form an integrated network to maintain normal physiological functions of the body. An imbalance in the NIM network is believed to accelerate the aging process, in which the thymus plays an important role. We recently discovered that thymectomy in mice not only reduces the immune response, but also deteriorates learning performances. Cytokines such as interleukin-1, interleukin-6 and tumor necrosis factor, and corticosterone affect the induction of hippocampal long-term potentiation, a synaptic model of memory. Clinical studies have demonstrated that Alzheimer's patients show disordered immune function in addition to cognitive deficit, and the brain lesions of Alzheimer's patients may be associated with abnormal immune reactions occurring in the brain. With these findings, it is speculated that the disordered immune function may induce an imbalance in the NIM network, which consequently influences central cognitive function.

Aging↗