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Biomedical subjects

A H Balk

Publications and source records attributed to A H Balk.

At least 19 recordsLinked to original sources
PubMed2000

Functional responses of T cells blocked by anti-CD25 antibody therapy during cardiac rejection.

BACKGROUND: Despite anti-CD25 (interleukin [IL]-2 receptor alpha chain) monoclonal antibody (mAb) therapy, rejection can still occur. T-cell activation through the IL-2 receptor beta and gamma chains by IL-2 or other growth factors may contribute to this rejection. Recently, we have demonstrated that the T-cell growth factor IL-15 was abundantly present in rejecting cardiac grafts during anti-CD25 mAb treatment. METHODS: To test whether IL-2- and IL-15-responsive T cells play an active role in rejection during anti-CD25 mAb therapy, we measured the frequency of IL-2- and IL-15-proliferative T cells in peripheral blood from treated patients during rejection (n=12). Measurements were made by limiting dilution analysis in the absence and presence of extra in vitro-added mouse anti-human CD25 mAb. RESULTS: In the absence of anti-CD25 mAb, the frequencies of peripheral T cells responding to recombinant human (rh)IL-2 and rhIL-15 from patients were lower than those measured in samples of healthy controls (n=7): median of IL-2-responding T cells 78 per 10(6) (range 31-210 per 10(6)) vs. 154 per 10(6) (122-484 per 10(6), P=0.008) and median of IL-15-responding T cells 62 per 10(6) (range 19-207 per 10(6)) vs. 129 per 10(6) (range 79-192 per 10(6), P=0.02), respectively. In the presence of extra in vitro-added anti-CD25 mAb, frequencies of IL-2-responding T cells from patients significantly decreased, although a considerable number of T cells still proliferated on rhIL-2 (median 85%, range 46-100%). In contrast, the frequencies of IL-15 T cells still responding remained stable (median 2%, range 0-50%, P<0.001). CONCLUSIONS: Treatment with anti-CD25 mAbs cannot provide complete suppression of T-cell function because significant numbers of IL-2- and IL-15-responsive T cells remain present in the peripheral blood of allograft recipients during anti-CD25 mAb treatment.

Animals↗
PubMed2000

Accuracy of dobutamine tetrofosmin myocardial perfusion imaging for the noninvasive diagnosis of transplant coronary artery stenosis.

BACKGROUND: Exercise stress myocardial perfusion scintigraphy has been used for the diagnosis of transplant coronary artery stenosis (TCAS) in cardiac allograft recipients. However, the role of pharmacologic stress myocardial perfusion imaging has not been evaluated. Aim of the study is to assess the accuracy of dobutamine stress 99m technetium tetrofosmin myocardial perfusion imaging for the diagnosis of TCAS in heart transplant recipients. PATIENTS AND METHODS: We studied 50 patients (age 56 +/- 8 year, 45 men) at a mean of 6.4 +/- 2.8 years after cardiac transplant with dobutamine (up to 40 ìg/kg/min) stress 99m technetium tetrofosmin SPECT. Resting images were acquired 24 hours after the stress study. Significant TCAS was defined as > or =50% luminal diameter stenosis by coronary angiography. RESULTS: Significant TCAS was detected in 30 patients (60%). Myocardial perfusion abnormalities (reversible and/or fixed defects) were detected in 27 of the 30 patients with and in 9 of the 20 patients without significant TCAS (sensitivity = 90%, CI 82-98, specificity = 55% CI 41-69, positive predictive value = 75%, CI 63-87, negative predictive value = 79%, CI 67-90 and accuracy = 76%, CI 64-88). Patients with multivessel TCAS had a larger stress perfusion defect score (5.6 +/- 3.1 vs 3.2 +/- 2.4, p < 0.05) compared to patients with single vessel TCAS. Among patients with abnormal perfusion who had no significant TCAS, 2 had lesions <50%, 2 had luminal irregularities and 5 had no abnormalities at angiography. Therefore specificity was 62% (8/13) in patients without any detectable angiographic abnormalities. CONCLUSIONS: Dobutamine stress tetrofosmin myocardial perfusion imaging is a highly sensitive method for the detection of TCAS in recipients of cardiac allografts. The high negative predictive value of the test indicates that patients who demonstrate normal perfusion by this method may be excluded from further invasive studies.

Aged↗
PubMed1999

[Heart transplants in infants: an estimate of need and restrictions].

The need for cardiac transplantation in children in the Netherlands can be estimated at 5-14 per year, including 1-3 in newborns. This treatment can only be successful in close cooperation with an existing programme for adult cardiac transplantation and in a centre where the surgery for congenital heart disease is performed to its complete extent. Heart transplantation should not be the primary treatment for hypoplastic left heart syndrome as the Norwood operation constitutes a good alternative. Donor shortage is a problem for children also. In the treatment of endstage heart disease in newborns, owing to ethical dilemmas, surgical treatment is not a matter of course.

Contraindications↗
PubMed1999

Potentials and limitations of the Valsalva maneuver as a method of differentiating between normal and pseudonormal left ventricular filling patterns.

Pseudonormalization of the left ventricular (LV) filling pattern complicates the Doppler echocardiographic assessment of LV diastolic function in patients with heart failure. The Valsalva maneuver is recommended as a method of differentiating between normal and pseudonormal LV filling patterns. However, neither a standardized Valsalva maneuver nor a healthy control population has been studied so far. Therefore, we studied changes in mitral flow velocities in response to a standardized Valsolva maneuver in 55 heart failure patients with LV systolic dysfunction and 35 control subjects. The study subjects were instructed to elevate their intrathoracic airway pressure to 40 mm Hg for 10 seconds. Doppler mitral flow velocities were recorded at rest and during the Valsalva maneuver. All study subjects had comparable decreases in early mitral flow velocity, but mitral flow velocity at atrial contraction increased rather than decreased in patients with a restrictive LV filling pattern. This markedly abnormal response might be useful in detecting elevated filling pressures and pseudonormal filling patterns. Furthermore, in all but 2 patients and all control subjects with an E/A ratio between 1 and 2, inversion of the E/A ratio occurred. This proves that, in contrast to previous beliefs, inversion of the E/A ratio does not differentiate between normal and pseudonormal LV filling patterns.

Blood Flow Velocity↗
PubMed1999

Anti-CD25 therapy reveals the redundancy of the intragraft cytokine network after clinical heart transplantation.

BACKGROUND: Despite blockade of the interleukin-2/interleukin 2 receptor (IL-2/IL-2R) pathway by the murine anti-CD25 (i.e., IL-2R alpha chain) monoclonal antibody BT563, cardiac rejection can still occur. In these cases, growth factors other than IL-2 may contribute to allograft rejection. We studied the expression of IL-15, a macrophage-derived cytokine associated with T-cell activation, which interacts with the beta and gamma chains of the IL-2R during rejection episodes under anti-CD25 therapy. METHODS: We measured intragraft IL-15 mRNA expression and the number of IL-15- and CD68-positive cells in posttransplantation endomyocardial biopsies (EMBs; n=45) and in nontransplanted, donor-heart specimens (n=11) by competitive template reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. RESULTS: IL-15 mRNA expression was present in the majority of posttransplantation EMB specimens (91%, 41/45) and in nontransplanted donor-heart specimens (91%, 10/11). Relative IL-15 mRNA levels were neither associated with transplantation nor with rejection status. After transplantation, the number of IL-15- and CD68-positive cells significantly increased (P<0.001), but IL-15-positive cell counts did not reflect the histological rejection grade. Anti-CD25 treatment, in contrast to its effects on the IL-2/IL-2R complex, had no influence on intragraft IL-15 mRNA and protein production. In rejection EMB specimens, during (n=5) and after (n=8) anti-CD25 therapy, no differences in relative IL-15 mRNA levels, or in IL-15- and CD68-positive cell counts, were measured. CONCLUSIONS: After heart transplantation, high numbers of IL-15- and CD68-positive cells infiltrate the graft. This phenomenon is independent of the rejection status. IL-15 remains present during blockade of the IL-2/IL-2R pathway by anti-CD25 monoclonal antibodies, and it may participate in T cell-dependent donor-directed immune responses, thereby explaining the occurrence of rejection in the absence of IL-2.

Antibodies, Monoclonal↗
PubMed1999

Intragraft platelet-derived growth factor-alpha and transforming growth factor-beta1 during the development of accelerated graft vascular disease after clinical heart transplantation.

This study was to determine whether the growth factors platelet-derived growth factor-alpha (PDGF-alpha) and transforming growth factor-beta1 (TGF-beta1) contribute to the development of graft vascular disease (GVD) after clinical heart transplantation. We analysed intragraft PDGF-alpha and TGF-beta1 messenger RNA (mRNA) expression levels by competitive template reverse transcriptase polymerase chain reaction (RT-PCR). Endomyocardial biopsies (EMB) were obtained at 1 and 9 months post-transplant from cardiac allograft recipients with (n = 11) and without (n = 11) angiographic evidence of GVD at 1 year. In 1-month EMB, comparable TGF-beta1 mRNA levels were found in patients with and without GVD at 1 year (p = 0.84, Mann-Whitney U-test). In contrast, in 9-month EMB during the development of GVD, intragraft mRNA levels of both PDGF-alpha (p = 0.08) and TGF-beta1 (p = 0.03) were higher in patients with GVD after the first year compared to patients without GVD. These results suggest that intragraft PDGF-alpha and TGF-beta1 play a role in the pathogenesis of accelerated GVD after clinical heart transplantation.

Adult↗
PubMed1999

T helper frequencies in peripheral blood reflect donor-directed reactivity in the graft after clinical heart transplantation.

We describe the usefulness of a fast (48-h) limiting dilution assay (LDA) for the enumeration of human alloreactive helper T lymphocytes (HTL) in the peripheral blood, in relation to histologically defined rejection grades after heart transplantation. HTL frequencies (HTLf) in pretransplant samples varied from patient to patient, ranging from 106 to 625 HTL/106 peripheral blood mononuclear cells (PBMC). In the first week after heart transplantation (HTx), when immunosuppression was instituted, HTLf were significant lower (range 30-190 HTL/106). The level of HTL in the first week after HTx when rejection grade was 0 or 1A (ISHLT score) was considered to be the baseline frequency. This frequency did not correlate with the number of subsequent rejection episodes. During rejection (grade 3), donor-specific HTLf were increased above their baseline frequencies (P = 0.01). Expressed as percentage of baseline frequencies, HTLf increased significantly during acute rejection (AR) compared with 1-2 weeks before rejection (P = 0.003). The increase was specific, since viral infections did not result in a rise of donor-specific HTL, while also HTLf specific for third party HLA antigens were not elevated during rejection. Monitoring HTLf in peripheral blood with a shortened (48-h) assay may serve as a non-invasive method for detecting intragraft immunological reactivity. Demonstrating absence of donor-specific reactivity may limit the number of invasive endomyocardial biopsy (EMB) procedures and allow tapering of immunosuppressive treatment.

Biological Assay↗
PubMed1999

The TNF-alpha system in heart failure and after heart transplantation: plasma protein levels, mRNA expression, soluble receptors and plasma buffer capacity.

BACKGROUND: The two soluble tumour necrosis factor (TNF) receptors (sTNF-R1, sTNF-R2) can bind TNF-alpha, which is a cytokine with cardiodepressant properties. In heart failure and after heart transplantation, the TNF-alpha system is unbalanced, due to elevated levels of sTNF receptors. AIM: To assess the activity of the TNF-alpha system in patients with heart failure and after heart transplantation. METHODS: We measured TNF-alpha mRNA expression of peripheral blood mononuclear cells, plasma levels of TNF-alpha and sTNF reverse transcriptase receptors, using polymerase chain reaction and ELISA and performed a TNF-alpha binding capacity analysis, quantitating the buffer capacity of patients' plasma. RESULTS: In 11 patients with heart failure and in 15 cardiac allograft recipients, the TNF-alpha mRNA expression was comparable to controls. This level of mRNA was not accompanied by detectable TNF-alpha plasma levels. Significantly higher sTNF receptors levels were found in patients: ( P <0.001; ANOVA). The TNF-alpha binding capacity of patients' plasma was significantly increased, which led to decreased TNF-alpha recovery ( P<0.05). Both sTNF receptors showed a linear correlation with serum creatinine (sTNF-RI: r=0.92; sTNF-R2: r=0.82, P<0.001). CONCLUSIONS: The TNF-alpha mRNA expression and plasma levels show that the 'peripheral' TNF-alpha system is not activated. The high sTNF-receptors levels and their elevated TNF-alpha binding capacity, resulting in decreased TNF-alpha bioavailability, may contribute to an immunosuppressed state in these patients.

Adult↗
PubMed1999

Cardiac peptides differ in their response to exercise. Implications for patients with heart failure in clinical practice.

AIMS: Cardiac peptides have diagnostic and prognostic value in heart failure. Their plasma concentrations, however, are sensitive to rapid changes in haemodynamics. As blood sampling under standard conditions is not feasible in clinical practice, it is important to know which peptides are most resistant to change. Therefore, the present study investigated the differences in response to exercise between atrial natriuretic peptide, N-terminal proatrial natriuretic peptide, brain natriuretic peptide and the recently identified N-terminal probrain natriuretic peptide. METHODS AND RESULTS: Fifty-two patients with chronic heart failure performed a symptom-limited graded bicycle exercise. Blood samples for determination of plasma concentrations of cardiac peptides were drawn at rest and at peak exercise. There was a significant difference in percentage increase in response to exercise between the four peptides (P<0.0001). N-terminal proatrial natriuretic peptide increased less than atrial natriuretic peptide (5+/-18% vs 59+/-58%;P<0.0001). The difference in increase between N-terminal probrain natriuretic peptide and brain natriuretic peptide was less distinct but still significant (24+/-24% vs 38+/-52%, P<0.05). CONCLUSIONS: Both N-terminal proatrial natriuretic peptide and N-terminal probrain natriuretic peptide increased less in response to exercise than their C-terminal counterparts. This implies that the circumstances under which blood sampling for measurements of N-terminal proatrial natriuretic peptide and N-terminal probrain natriuretic peptide should be performed are more favourable than the blood sampling conditions for atrial natriuretic peptide and brain natriuretic peptide.

Atrial Natriuretic Factor↗
PubMed1999

Study on microbial persistence in end-stage idiopathic dilated cardiomyopathy.

Microbial persistence may be involved in the pathogenesis of idiopathic dilated cardiomyopathy (IDC). Therefore, we evaluated the role of various cardiopathogenic microorganisms in patients with end-stage IDC. In a previous study, we did not find evidence for the persistence of enterovirus RNA in end-stage IDC. In the present study, we looked for other microorganisms that are frequently associated with heart disease, including cytomegalovirus, hepatitis B virus, hepatitis C virus, Borrelia burgdorferi, Chlamydia species, mycoplasmata, and Toxoplasma gondii. Serology, polymerase chain reaction (PCR) analysis specific for detection of microbial genomic sequences, or both investigations were performed on myocardial samples from 37 patients with end-stage IDC. PCR analysis was performed on multiple myocardial samples per patient. Thirty-nine patients with end-stage heart disease of known cause were included as controls. On the basis of our serological data and PCR analyses, we did not find any evidence that microbial persistence in the heart is involved in the end-stage disease process of IDC.

Adolescent↗
PubMed1999

Autoimmune markers are undetectable in end stage idiopathic dilated cardiomyopathy.

BACKGROUND: Autoreactive humoral and cellular immune responses may be involved in the pathogenesis of idiopathic dilated cardiomyopathy (IDC). Certain human leucocyte antigens (HLA) could also be linked to the development of IDC. AIM: To determine whether various markers of autoimmunity are present in the final phase of the disease, to substantiate the role of an autoimmune process in IDC. METHODS: 37 patients with end stage IDC were studied, together with 39 patients with end stage heart disease of known aetiology who were included for comparison. Multiple myocardial tissue samples from the explanted heart of each patient were evaluated (immuno)histologically. An indirect immunofluorescence assay was used to screen patient serum samples for the presence of heart specific autoantibodies. HLA class I and II frequencies were determined in each group and compared with HLA frequencies from healthy blood donors. RESULTS: Only scanty small mononuclear cell infiltrates were present in myocardial tissue of seven patients with IDC and of 11 patients with heart disease of known cause. The majority of these inflammatory cells were negative for T cell markers. All blood specimens were negative for heart specific autoantibodies and there was no apparent association of IDC with particular HLA phenotypes. CONCLUSIONS: These findings suggest that an active autoimmune process is not involved in the end stage of IDC.

Adolescent↗
PubMed1998

C1.7 monoclonal antibody designates high-avidity CD4+ cytotoxic T lymphocytes involved in clinical heart rejection.

BACKGROUND: It is assumed that not all donor-specific cytotoxic T lymphocytes (CTLs), but only those with a high avidity for donor antigens, can function as terminal effector cells in transplant rejection. METHODS: In the present study, we searched for markers that would exclusively designate these high-avidity CTL. RESULTS: FACS analysis of donor-specific CTL clones obtained from heart transplant patients revealed that high- and low-avidity CTL varied in their expression of p38, a surface molecule involved in signal transduction, which is stained by the antibody C1.7. High- and low-avidity CD8+ CTL and high-avidity CD4+ CTL expressed p38, whereas low-avidity CD4+ CTL did not. Noncytotoxic and naive CD4+ lymphocytes also lacked p38 surface expression. CONCLUSION: Therefore, we conclude that p38 is a marker for CD4+ lymphocytes with the potency to damage the transplanted heart. Accordingly, p38 might be used to analyze the contribution of CD4+ CTL in immune responses, such as transplant rejection.

Antibodies, Monoclonal↗
PubMed1998

Blockade of the interleukin (IL)-2/IL-2 receptor pathway with a monoclonal anti-IL-2 receptor antibody (BT563) does not prevent the development of acute heart allograft rejection in humans.

BACKGROUND: Anti-interleukin (IL)-2 receptor (IL-2R) antibodies have been used as rejection prophylaxis after organ transplantation. Despite this induction treatment, acute rejections may occur. We wondered whether these rejections developed via the IL-2/IL-2R pathway. METHODS: In a prospective trial using BT563, a murine IgG1 anti-IL-2R antibody, for rejection prophylaxis after heart transplantation, 20 patients were treated in combination with cyclosporine from the day of transplantation (group A). As a control group, 31 patients were also treated with BT563, but in these patients, cyclosporine treatment was initiated on day 3 (group B). RESULTS: Three patients from group A and two patients from group B died in the first postoperative month (of causes not related to acute rejection) and were left out of the analysis of rejection incidence. Freedom from acute rejection at 1 week after transplantation in group A (14/17; 82%) was lower than in group B (16/29; 55%), although the difference did not reach statistical significance. There was no difference in either the number of acute rejection episodes at 12 weeks or the required rejection treatments between groups A and B. Infectious complications were evenly distributed in both groups. Immunohistochemistry showed that during acute rejection, in the presence of circulating BT563, IL-2R-bearing cells were present in only one of five rejection biopsies (20%), whereas these cells were often present (6/8, or 75%) in rejections occurring in the absence of BT563. The presence of BT563 was associated with a similar difference in the mRNA expression of IL-2 (2/5 vs. 6/8). CONCLUSIONS: Apparently, despite adequate blockade of the IL-2/IL-2R pathway, patients may develop acute rejection, reflecting the redundancy of the cytokine network. The ever-present IL-15 may well be a candidate for overtaking the role of IL-2.

Adolescent↗