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(Circulation. 1995;91:20-22.)
© 1995 American Heart Association, Inc.
Articles |
T Lymphocyte Activation in Stable Angina Pectoris and After Percutaneous Transluminal Coronary Angioplasty
From the Coronary Care Unit, Cardiovascular Division (A.B., S.S.) and the Hematological Institute (B.S.), Cellular Immunology Unit, Beilinson Medical Center, Petah Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Israel.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Inflammatory reactions have an important part in atherosclerosis. Smooth muscle cells, endothelial cells, monocytes, and T lymphocytes are actively involved. The purpose of this study was to assess whether T lymphocytes are activated in patients with stable angina pectoris who are candidates for a percutaneous transluminal coronary angioplasty (PTCA) and the influence of PTCA on this process.
Methods and Results Twenty-four patients participated in the study. All were 40- to 60-year-old men, and all but one underwent successful PTCA. Blood samples were taken 1 day before PTCA and 1 week, 1 month, and 2 months after. Two groups of patients were detected: group A, 11 patients who had high levels of soluble interleukin-2 receptor (sIL-2R) before PTCA that decreased toward normal during the follow-up period in most of them; and group B, 13 patients who did not have elevated sIL-2R levels before PTCA and in whom sIL-2R levels did not change after the procedure. Group C consisted of 15 healthy men whose sIL-2R levels were in the normal range (control subjects).
Conclusions (1) T lymphocytes are activated in stable angina patients. (2) The level of sIL-2R can be a reliable laboratory marker for follow-up of patients after PTCA, especially those with high sIL-2R levels before the procedure.
Key Words: lymphocytes • angina • interleukin
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Studies of human plaque specimens have shown that T lymphocytes and macrophages are present in all types of lesions, from fatty streaks to advanced plaques, and it is therefore likely that they are involved throughout the pathogenesis of atherosclerosis.1 The presence of T lymphocytes in a tissue does not necessarily imply that an immune response is taking place, and it is important to classify the extent of activation of the T cells in the plaques.2 The expression of interleukin-2 receptor (IL-2R) is of central importance for autocrine growth stimulation after T-cell activation by an antigen,3 and by measuring the soluble interleukin-2 receptor (sIL-2R) level we can evaluate the activation of T lymphocytes. Patients with unstable angina have an increased expression of granulocyte and monocyte CD11b/CD18 adhesion receptors, indicating that an inflammatory reaction takes place within their coronary tree.4 Thrombin formation in unstable angina patients is caused by the expression of tissue-like activity by monocytes activated by lymphocytes that are triggered by unknown factors.5
The aims of the present study were to investigate (1) T-lymphocyte activation and involvement in stable angina patients and (2) T-lymphocyte behavior after percutaneous transluminal coronary angioplasty (PTCA) and whether the sIL-2R level can be a reliable laboratory marker for follow-up after PTCA.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Study Population
Twenty-four men 40 to 60 years old were enrolled; all presented for elective PTCA of one coronary artery and had a stable angina pectoris syndrome with a positive thallium stress test. Patients were excluded from the study if they had enzymatic, clinical, or ECG evidence of myocardial infarction, had clinical evidence of recent infections, or were suffering from diabetes mellitus, immunological disorders, or a neoplastic disease. Patients were also excluded if they had undergone invasive surgical procedures in the month preceding the study. They were treated with aspirin, nitrates, and calcium channel blockers; none received heparin. Blood samples were taken 1 day before PTCA and 1 week, 1 month, and 2 months after. Twenty milliliters of fasting blood was drawn at 8 AM according to the schedule described. The blood was allowed to coagulate, and then the serum was removed and tested in duplicate for sIL-2R levels by a "sandwich" double-epitope ELISA.6
Statistical Analysis
The analysis of data with observation
over time was done by
the MANOVA test with repeated measures.
Coronary Angiography
Coronary angiography was performed by
Judkins' technique. The
occurrence and severity of coronary angiographic lesions were evaluated
from at least three projections. The decision to perform a PTCA was
based on the angiographic findings, the patient's clinical condition,
and the thallium stress test.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Characteristics of patients and control subjects are shown in the Table
. Group A consisted of 11 patients with high sIL-2R
levels, which decreased toward normal in 9 patients after PTCA. In 2
patients in group A, sIL-2R level did not decrease. One of these had a
failed PTCA, and the other suffered from recurrent chest pain and
restenosis, which was reopened; after the second PTCA, the sIL-2R level
decreased toward normal, and the patient felt well. A statistically
significant difference was found (by MANOVA) between the day before
PTCA and 30 and 60 days after.
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Group B consisted of 13 patients with normal sIL-2R levels during the
follow-up period. In group B, there was no difference in sIL-2R levels
between 30 and 60 days of follow-up (Table
).
Group C consisted of 15 healthy volunteers, all men 40 to 60 years old (control subjects).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Our results indicate that about half the patients with stable angina who present for PTCA because of significant stenosis have high sIL-2R levels, a sign of activated T lymphocyte involvement in the atherosclerotic process. Our results also indicate that there is a tendency for the sIL-2R level to decrease after PTCA in these patients, which could indicate that the T lymphocytes return to an "unactivated state" after successful PTCA.
T-cell adhesion to activated endothelium has been demonstrated in
vivo and in vitro.2 7 T cells of both the helper
(CD4+) and cytotoxic/suppressor (CD8+)
subtypes
have been detected in human atheromas and have been shown to be
immunologically activated.8 The first direct evidence for
this activation was the class II histocompatibility antigen expression
on the surface of the smooth muscle cells adjacent to the T lymphocytes
in the lesions. This HLA expression is induced by interferon-
, a
product of activated T cells and natural killer cells. Since natural
killer cells were not found in complicated plaques, the only remaining
source of interferon- is the adjacent activated T cells.
Additionally, high levels of IL-2R are a hallmark of activated T
cells.2 The presence of activated T lymphocytes in the
atherosclerotic plaque suggests a local immune response, and it has
been postulated that such a response may be directed against local
antigens in the plaque. Recent molecular genetic studies have
demonstrated that these T cells are heterogeneous in terms of their
immunological specificities.8 It is therefore possible
that only a small proportion of plaque T cells respond to local
antigens.
As mentioned earlier, the expression of IL-2R is of central importance
of autocrine growth stimulation after T-cell activation by
antigens.3 Hansson et al2 showed that sIL-2R
expression codistributed with T cells, and not macrophages or B cells,
in the plaque. Assuming that sIL-2R are expressed only by T cells in
the plaque, the frequency of positive T lymphocytes would be of the
same magnitude as that found in autoimmune conditions, such as
rheumatoid arthritis, thyroiditis, and multiple
sclerosis.9 10 11 It has been observed
that activated
lymphocytes lose the sIL-2R after a few days but retain other signs of
a continuing activation process,12 such as the expression
of HLA-DR and virus-like agent-1 on the surface of activated T cells
that were isolated from plaques.13 Activated T lymphocytes
secrete growth factors and cytokines that may affect other cell types
and the process of atherosclerosis. It was demonstrated that smooth
muscle cells are sensitive to interferon- (secreted by T cells) and
respond by inhibition of proliferation and by expression of class II
HLA antigens.14
The decrease in sIL-2R level after PTCA could be explained by the decrease in the mass of T cells in and around the atherosclerotic plaque, a mechanical destruction that lowers the number of activated T lymphocytes.
Conclusions
Our study supports the hypothesis that T
lymphocytes are activated
and involved in atherosclerosis in at least half the patients with
stable angina pectoris. Previous reports have hypothesized that the
flare-ups of unstable angina represent acute transient
inflammatory state caused by lymphocyte activation (intermittently)
triggered in response to unknown factors5 ; however, it
seems to us that the same basic process takes place in patients with
stable angina pectoris. Levels of sIL-2R after PTCA, measured in
patients with high levels before the procedure, may serve as a marker
of restenosis or failed PTCA.
There could be several explanations for our finding that some patients with stable angina demonstrate active T-lymphocyte involvement, while others are "silent" immunologically. (1) There could be several stages of growth and development of the atherosclerotic plaque. It might be that some stages are more T lymphocyte dependent and aggressive, whereas others are stable, without any development and growth. The latter would involve no T-cell activation and thus would be a "silent" immunological process. (2) There could be several mechanisms involved in atherosclerosis, with only some of them being T lymphocyte dependent. Group B patients could represent patients with well-organized atherosclerotic plaque with no active immunological activity in or around it, which thus continues to be "silent" immunologically after PTCA.
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Footnotes |
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Reprint requests to B. Shohat, PhD, Cellular Immunology Unit, Hematological Institute, Beilinson Medical Center, Petah Tiqva 49100, Israel.
Received July 7, 1994; accepted November 1, 1994.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
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1. Hansson GK. Immune and inflammatory mechanisms in the development of atherosclerosis. Br Heart J. 1993;69(suppl):S38-S41.
2. Hansson GK, Holm J, Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol. 1989;135:169-175. [Abstract]
3.
Waldman TA. The structure, function, and expression of
interleukin-2 receptors on normal and malignant lymphocytes.
Science. 1986;232:727-732.
4.
Mazzone A, De Servi S, Ricevuti G, Mazzucchelli I,
Fossati G, Pasotti D, Bramucci E, Angoli L, Marsico F, Specchia G,
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Serneri GN, Abbate R, Gorri AM, Attanasio N, Martini F,
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6. Rubin LA, Nelson DL. The soluble interleukin-2 receptor: biology, function, and clinical application. Ann Intern Med. 1990;113:619-627.
7. Berman JW, Caldron TM. The role of endothelial cell adhesion molecules in the development of atherosclerosis. Cardiovasc Pathol. 1992;1:17-28.
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Hansson GK, Jonasson L, Holm J, Clowes NN, Clowes AW. Gamma
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