Survey - Effects of Thymectomy Professor Nick Willcox

Immunodeficiency following neonatal thymectomy in man. Clin. Exp. Immunol. 70:322-327. 1987.

 
Patients undergoing cardiac bypass operations normally have a thymectomy to facilitate cannulation of the great vessels. Laboratory indices of immune function were measured in 18 children aged 9 months to 3 years who had had a thymectomy when aged 3 months or less, and in two groups of controls individually matched for age and age at operation. Total lymphocyte numbers were similar in all three groups but thymectomized children had significantly lower numbers of T cells and T cell sub-sets than controls and showed diminished responses to phytohaemagglutinin and concanavalin A. Children who have had a thymectomy early in life represent an important group in the study of the development of the immune system in man. Although the clinical consequences of early thymectomy are unclear, evidence of impairment of parameters of immunity have been found in later infancy and routine thymectomy in paediatric cardiac surgery should be avoided.

Wells, P. R., E. Smogorzewska, and M. Barr. Division of Cardiothoracic Surgery, Childrens Hospital, Los Angeles, Calif 90027,USA.

Neonatal thymectomy: does it affect immune function? J. Thorac. Cardiovasc. Surg. 115:1041-1046. 1998.

 OBJECTIVE:

 The purpose of this study was to determine whether thymectomy in the newborn has a negative effect on immune function. METHODS: Twenty-five neonates (<30 days) who had thymectomy at congenital heart repair were prospectively studied to determine immune function. The percentage of T-cell subtypes including CD3 (all T cells), CD4 (helper T cells), and CD8 (suppressor T cells) was determined. In six patients, further testing of CD4 cells was done to determine whether they were newly formed, recent thymic emigrants (CD4, CD45, and RA+), or older educated lymphocytes (CD4, CD45, and RO+). Response to the mitogen phytohemagglutinin and to tetanus toxoid were determined, as were antibody titers to tetanus. Samples were drawn before the thymectomy, at approximately 3 months after immunization and at 1 year. Ten age-matched control patients were tested. At follow-up, parents were asked about infections. RESULTS: Prethymectomy T-cell subsets were all normal and comparable to controls. At 12 months, the percent of CD3 was significantly less than in the control group (48% +/- 3% versus 64% +/- 2% [mean +/- standard error of the mean]; p < 0.01) as was CD4 (31% +/- 2% versus 46% +/- 2% [mean +/- standard error of the mean]; p = < 0.01). CD8 did not drop. Surprisingly, the percent of CD4 that were recent thymic emigrants did not decrease significantly (50% +/- 8% versus 60% +/- 6% [mean +/- standard error of the mean]; p = not significant). Lymphocyte blastogenesis to phytohemagglutinin and tetanus toxoid and antibody to tetanus were all normal at 12 months. No patient required readmission for infection, and there were the expected number of minor infectious events (median 3; 95% confidence interval 1,4).

CONCLUSION:

 Thymectomy in neonates results in a modest but significant decrease in T-lymphocyte levels, but there is no compromise in immune function.

Machens A, Emskotter T, Busch C, Izbicki JR.  Dept of Surgery, University of Hamburg, Germany.

Postoperative infection after transsternal thymectomy for myasthenia gravis: a retrospective analysis of 125 cases. Surg Today.1998;28(8):808-10. 

The present study was conducted in an attempt to clarify the extent to which the preoperative severity of myasthenia gravis and immunosuppression favor post-operative infection. A retrospective analysis was carried out on 125 consecutive patients who had undergone transsternal thymectomy for myasthenia gravis between 1976 and 1995. The preoperative severity of myasthenia was graded by a modified version of Osserman's classification. The incidence of postoperative pneumonia among patients with Osserman's class 1, class 2, class 3, and class 4 disease were 0%, 10%, 21%, and 44%, respectively, showing a marked increase with the preoperative severity of myasthenia; however, postoperative wound infection and mediastinitis were unrelated to the preoperative severity of myasthenia. With every increment in Osserman class, there was an appreciable, though insignificant, rise in the frequency of preoperative immunosuppression. There was no significant association between postoperative infection and preoperative immunosuppression. These findings indicate that a poor preoperative clinical status has a greater impact on the risk of postoperative pneumonia than immunosuppression, and therefore, every effort should be made to decrease the preoperative severity of myasthenia. Promoting the widespread use of plasmapheresis seems particularly important for this purpose.

Myasthenia gravis. N Engl J Med 1994;330: 1797-1810.

 Complete text of article can be read HERE.

Myasthenia gravis in children: Long-term follow-up. Ann Neuro1 1983; 13: 504-10.

We report observations made on 149 patients with juvenile myasthenia gravis studied from onset of disease for as long as 40 years. Median follow-up was 17 years; minimum was 4 years. Eight other patients with congenital myasthenia gravis were studied separately. Of the juvenile myasthenic patients, 85 (57%) underwent thymectomy because of diseases severity. In juvenile myasthenia gravis, a spontaneous remission rate of 22.4 per 1,000 person-years was observed, regardless of disease duration. A remission rate of 260 per 1,000 person-years was seen during the first year after thymectomy, with a rate of 95 per 1,000 person-years during the next 2 years. Early surgery, presence of bulbar symptoms, absence of ocular signs or generalized symptoms, onset of symptoms between ages 12 and 16, and presence of other immune disease were associated with increased postoperative remission rates. Epilepsy (4 patients) and neoplasia (7 patients) were the most frequent associated nonimmune disorders; rheumatoid arthritis (5 patients), juvenile-onset diabetes mellitus (3 patients), asthma (3 patients), and thyroid disease (3 patients) were the most frequent associated immune diseases.

Thymectomy and azathioprine have no effect on the phenotype of CD4 T lymphocyte subsets in myasthenia gravis. J Neurol Neurosurg Psychiatry 1993;56: 46-51. 

The influence of thymectomy and long term immunosuppression on the phenotype of CD4 T lymphocyte subsets, which were defined by the restricted expression of CD45RA and CD45RO markers, was studied by double immunofluorescence in 29 patients in different clinical stages of generalised myasthenia gravis. In the acute stage of myasthenia, before thymectomy and immunosuppression, no differences in CD4 subsets were observed in the peripheral blood from nine patients and 21 matched controls. Four to seven weeks after thymectomy, there was a slightly decreased proportion of CD4+CD45RO+ (UCHL1+) memory cells (p < 0.05, paired t test). Patients on steroids showed a more pronounced decrease of CD4+CD45RO+ cells suggesting, in addition, a drug-related effect. CD4 subsets (CD45RA, CD45RO, and CD29 positive) in the peripheral blood compartment remained largely stable over 18 to 24 months thereafter. In addition, CD4 subsets were examined in 20 patients with myasthenia gravis who had had a thymectomy between two and 17 years before. With the exception of patients on steroids, there were no differences in CD4 subsets in patients on or off azathioprine. These data did not show any relation of CD4 T cell subsets to the clinical course of myasthenia, or significant changes due to thymectomy, or immunosuppression with azathioprine. These results also complement the authors' clinical experience that thymectomy in adults does not leave a deficit in cell-mediated immunity. The slight change associated with steroid treatment might deserve further attention.

Sempowski G, Thomasch J, Gooding M, Hale L, Edwards L, Ciafaloni E, Sanders D, Massey J, Douek D, Koup R, Haynes .Department of Medicine, Center For AIDS Research, and Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.

Effect of thymectomy on human peripheral blood T cell pools in myasthenia gravis.B. J Immunol. 2001 Feb 15;166(4):2808-17

The human thymus is required for establishment of the T cell pool in fetal life, but postnatal thymectomy does not lead to immunodeficiency in humans. Because thymectomy in humans is performed for treatment of myasthenia gravis (MG), we have studied patients with MG for effects of thymectomy on peripheral blood (PB) naive (CD45RA(+), CD62L(+)) and memory (CD45RO(+)) T cells. We have also determined the effect of thymectomy on levels of PB cells containing signal joint TCR delta excision circles (TRECs), a molecular marker of thymus emigrants that have divided few times after leaving the thymus. In 17 nonthymectomized and 26 thymectomized MG patients studied at varying times after thymectomy (1 day to 41 years), we found no significant mean difference in PB T cell TREC levels between ages 40 and 80 years. However, both thymectomized and nonthymectomized MG patients had lower PB T cell TREC levels than did age-matched normal subjects (p < 0.0001 for both). These data demonstrated that MG itself or treatment for MG decreased thymopoiesis independent of thymectomy. Next, to control for disease activity and treatment, we prospectively studied 10 MG patients before and from 27 to 517 days after thymectomy. We found that thymectomy decreased CD4 or CD8 T cell TREC concentrations most when thymopoiesis was active before thymectomy (six of six patients), but had little effect in patients when thymopoiesis was minimal (four of four patients). In contrast, there was no significant effect of thymectomy on absolute numbers of naive PB T cells. Thus, in MG, removal of a thymus with active thymopoiesis resulted in a significant fall in PB TREC(+) T cells post-thymectomy.

Effect of thymectomy on peripheral lymphocyte subsets in myasthenia gravis: selective effect on T-cells in patients with thymic atrophy. J. Immunol. 141:773. 1983. 

Myasthenia gravis (MG) is an autoimmune disease affecting nicotinic acetylcholine receptors. The clinical improvement that follows thymectomy in some myasthenic patients implicates thymic factors as well in the pathogenesis of MG. We have studied circulating immunoregulatory T cell subsets before and after thymectomy in 11 adult patients with MG. Six patients had thymic hyperplasia and five patients had atrophic thymus at the time of thymectomy. Before thymectomy, patients who subsequently were shown to have an atrophic thymus, had lower lymphocyte counts than either patients later shown to have a hyperplastic thymus (1315 +/- 143 lymphocytes/mm3 vs. 2434 +/- 350 lymphocytes/mm3, p less than 0.01), or age-matched controls (1315 +/- 143 lymphocytes/mm3 vs. 2636 +/- 589 lymphocytes/mm3, p less than 0.02). Moreover, after thymectomy, in MG patients with an atrophic thymus, there was a significant rise in lymphocyte count (from 1315 +/- 143 lymphocytes/mm3 to 2279 +/- 292 lymphocytes/mm3, p less than 0.02) beginning 3 days postthymectomy and persisting for at least 6 weeks thereafter. In comparison, patients with a hyperplastic thymus showed no change in circulating lymphocyte counts (p greater than 0.1). Enumeration of lymphocyte subsets in MG patients with an atrophic thymus demonstrated normal B cell numbers before and after thymectomy (p greater than 0.1), whereas, T cells were significantly decreased before thymectomy compared with age-matched normal subjects (859 +/- 82 T cells/mm3 vs. 2215 +/- 545 T cells/mm3, p less than 0.05), and rose to near normal levels after thymectomy (1796 +/- 294 T cells/mm3, p less than 0.02 compared with prethymectomy levels). Using monoclonal anti-T cell antibodies 3A1, OKT4, and OKT8, we found that, before thymectomy in the atrophic thymus group, 3A 1+ T cells were significantly depressed compared with postthymectomy levels (620 +/- 173 cells/mm3 vs. 1627 +/- 331 cells/mm3, p less than 0.02) as were OKT4+ cells 436 +/- 88 cells/mm3 vs. 1112 +/- 63 cells/mm3, p less than 0.001), In contrast, no significant change was seen after thymectomy in the OKT8+ cell subset (p greater than 0.1). MG patients with an atrophic thymus had decreased plasma cortisol levels postthymectomy compared with prethymectomy levels, whereas thymectomy in MG patients with a hyperplastic thymus effected no change in plasma cortisol levels. These data demonstrate in MG patients with an atrophic thymus that thymectomy has an effect on the number of circulating T cells, and in particular, on those T cells expressing antigens 3A1 and OKT4. This effect may in part be mediated by changes in plasma adrenal corticosteroid levels after thymectomy or may be due to a factor produced by atrophic thymuses in MG.

BACKGROUND: Thymectomy (Tx) is a common therapeutic option to treat myasthenia gravis (MG), but its effects on the immune system are still obscure in humans. 

OBJECTIVE: We sought to evaluate long-term immunologic effects of therapeutic Tx in patients with MG. 

METHODS: T- and B-cell subsets and T-cell repertoire were analyzed in 35 patients with MG, 16 with previous Tx (at least 8 years before), 6 with recent (<1 year) Tx, and 13 without Tx, as well as in 32 healthy subjects used as normal control subjects. Serum immunoglobulins and a variety of autoantibodies were also measured. A subsequent 3-year clinical follow-up was performed to verify the possible appearance of systemic autoimmune diseases. 

RESULTS: The long-term thymectomized (Txd) patients had mild T-cell lymphopenia and an expansion of some Vbeta families among circulating CD4+ and CD8+ T cells. They displayed a normal number of total B and CD5+ B-circulating lymphocytes, but they also displayed a polyclonal increase in serum IgM and IgG associated with the presence of high levels of a variety of organ- and nonorgan-specific autoantibodies, including anti-dsDNA and anticardiolipin, without clinical evidence of autoimmune disease. These serologic abnormalities were not detectable in both non-Txd and recently Txd patients. After 3 years, 2 long-term Txd patients had systemic lupus erythematosus and an undifferentiated connective tissue disease. 

CONCLUSIONS: The association between MG and laboratory findings of systemic autoimmune disease may be in part related to Tx rather than to MG. Tx may represent a risk for the development of systemic autoimmune disorders over years in patients with MG.

Phenotypic and functional evaluation of natural killer cells in thymectomized children. Clin. Immunol. Immunopathol. 81:277. 1996.

The purpose of this study was to determine the effect of thymectomy on the number and activity of NK cells in the peripheral blood of children submitted to thymus removal. Twenty-three children, aged 4 to 48 months at thymectomy, whose thymus was fully removed to permit access to the heart for corrective surgery, were studied. Only children thymectomized during the first year of life had a decreased number of CD2+/CD3+, CD4+/CD16- , and CD8+/CD16- T subsets and an increase in the CD16-/CD56bright+ NK subset. In addition, the CD57-/CD16+ and CD57-/D56+ subsets which are shared by T and NK cells were increased. These findings associated with a tendency to increased NK activity suggest that the human thymus is partially involved in the control of the release of circulating T cells and may negatively modulate some NK subsets, as well as NK activity, during the first year of life but not later.

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