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Biomedical subjects

A H Balk

Publications and source records attributed to A H Balk.

At least 55 records · Page 3Linked to original sources
PubMed1998

Redundancy of the cytokine network in the development of rejection after clinical heart transplantation.

We used reverse transcriptase-polymerase chain reaction analysis to study the effects of anti-rejection prophylaxis with an anti-interleukin (IL)-2 receptor (IL-2R) monoclonal antibody (BT563) on the allogeneic process by analyzing intragraft IL-2, IL-4, and IL-15 mRNA expression. Analysis showed an association between rejection and intragraft IL-2 mRNA and IL-4 mRNA transcription, whereas IL-15 was constitutively expressed: IL-2, 62% (8/13) during rejection versus 23% (8/35) during immunological quiescence (P < 0.01); IL-4, 69% versus 23% (P < 0.01). BT563 therapy influenced the intragraft mRNA expression of IL-2 and IL-4 but not of IL-15. In endomyocardial biopsies (EMB) showing rejection, mRNA expression of IL-2 was detectable in 40% (2/5) during BT563 treatment versus 75% (6/8) in the absence of BT563; for IL-4, 23% versus 88%, respectively. In contrast, IL-15 mRNA transcription was not affected. Quantitative analysis in rejection EMB showed comparable IL-15 mRNA levels during and after BT563 treatment. This study demonstrates that therapeutic intervention within the IL-2-dependent T-cell activation cascade does not completely prevent rejection. Other cytokines, such as IL-15, may participate in IL-2-independent rejections.

Biopsy↗
PubMed1998

The application of human monoclonal antibodies for monitoring donor derived soluble HLA class I molecules in the serum of heart transplant recipients.

Increased levels of both donor and recipient derived HLA molecules can be found in serum and plasma of transplanted patients during rejection. Recent data suggest that levels of donor specific soluble HLA Class I (sHLA-1) correlate better with graft rejection than total sHLA Class I [1, 2]. Therefore, quantification of donor specific soluble counterparts of HLA Class I in the serum of the recipient may be a new way for non-invasive monitoring of rejection after organ transplantation. Up to now, only a limited number of mouse monoclonal antibodies (alpha HLA-A2, and alpha HLA-B7) has been used in enzyme linked immunosorbent assays (ELISAs) to detect donor specific HLA molecules in the plasma of transplant recipients. To monitor other donor-recipient combinations, we tested some of our HLA Class I specific human monoclonal antibodies, routinely used in complement dependent cytotoxicity, for their suitability in ELISA based assays. In the present model system, we used alpha HLA-A9 (BvK5C4) or alpha HLA-A3 (OK2F3) hybridoma-supernatant to set up a sHLA-A9 and sHLA-A3 specific ELISA. In a pilot study we show that these assays were sensitive enough to detect an increase of donor specific sHLA-I during rejection in the plasma of two heart transplant recipients. Use of a large set of human hybridoma's will enable monitoring most recipient/donor combinations in the near future.

Animals↗
PubMed1998

Kinetics of circulating cytotoxic T lymphocyte precursors that have a high avidity for donor antigens: correlation with the rejection status of the human cardiac allograft.

Studies on graft infiltrating cells demonstrated that accumulation of cytotoxic T lymphocytes (CTL) with high avidity for donor antigens (Ag) coincided with acute cardiac rejection. In the present study, we analyse whether such high-avidity CTL are present within the peripheral blood of cardiac transplant recipients and whether their kinetics correspond with the rejection status of the allograft. Using limiting dilution analysis (LDA), donor-specific CTL were enumerated in serial blood samples of seven patients. From each patient, 7-11 samples were obtained during the first year after transplantation and up to three samples were obtained at a later date. Enumerated donor-specific CTL were divided into CTL with high or low avidity for donor Ag, depending on their sensitivity to CD8-blocking. In contrast to the situation in the graft, the donor-specific CTL present within the peripheral blood were CTL precursors (pCTL) and not fully mature CTL (cCTL). The number of donor-specific pCTL among peripheral blood cells fluctuated irrespective of the rejection grade of the allograft, indicating that the frequency of circulating donor-specific CTL does not reflect the immunological status of the allograft. During acute cardiac rejection, 66% (median) of the circulating donor-specific pCTL had a high avidity for donor Ag. This percentage significantly exceeded pre- and postrejection values obtained during the first year post-transplantation (median, 39% and 37%, respectively). The disparity in avidity increased even further more than 1 year after transplantation, when stable engraftment was achieved. Among donor-specific pCTL in peripheral blood, those with a high avidity were absent (median, 0%). Hence the avidity of circulating donor-specific CTL might inform us about the immune status of the cardiac allograft.

Antigens↗
PubMed1998

The frequency and avidity of committed cytotoxic T lymphocytes (cCTL) for donor HLA class I and class II antigens and their relation with graft vascular disease.

Cellular immune processes may trigger the development of graft vascular disease (GVD). CD4 and CD8 cytotoxic T lymphocytes that infiltrate the allograft could play a role in the development of GVD. We studied the presence of in vivo primed or committed CTL (cCTL) and their avidity for donor HLA class I and class II antigens in graft-infiltrating lymphocyte cultures propagated from endomyocardial biopsies derived from patients with and without signs of GVD. The fraction of cCTL with high avidity for HLA class I or class II antigens was estimated by the addition of anti-CD8 or anti-CD4 MoAbs to the cytotoxic phase of the limiting dilution analysis. In the first year after transplantation no difference in the frequency of donor-specific class I cCTL between patients with and without GVD was found. Addition of anti-CD8 MoAb revealed that most cultures predominantly consisted of cCTL with low avidity for donor HLA class I antigens, irrespective of the development of GVD at 1 year after transplantation. However, in patients who did not develop GVD, the frequency of cCTL with donor HLA class II specificity was significantly higher than in patients who did develop GVD. The avidity for donor HLA class II antigens was comparable in both groups. A high frequency of donor-specific cCTL for HLA class II antigens seems to be a protective factor against the development of GVD. These cCTL might be cytotoxic for cells involved in GVD development, e.g. activated endothelium and smooth muscle cells of donor origin.

Antibodies, Monoclonal↗
PubMed1998

Heart rate variability index in congestive heart failure: relation to clinical variables and prognosis.

AIM: To evaluate the clinical and prognostic value of the heart rate variability index in patients with congestive heart failure. METHODS: Sixty-four patients with chronic congestive heart failure and sinus rhythm underwent clinical assessment, 24-h ambulatory electrocardiography and echocardiography. Patients were followed for 6 to 30 months. Cardiac death or heart transplantation constituted the primary end-point of the study. RESULTS: The heart rate variability index was related to left ventricular ejection fraction (r=0.29, P=0.02) and New York Heart Association class (P=0.01). Patients with a restrictive left ventricular filling pattern had a lower heart rate variability index compared to patients with a non-restrictive pattern (26+/-11 vs 33+/-9 units, P=0.01). Patients who died (n=11) or underwent heart transplantation (n=4) had a lower heart rate variability index compared to survivors (21+/-10 vs 33+/-9 units, P<0.0001). In multivariate survival analysis, a reduced heart rate variability index was related to survival independent of parameters of left ventricular function. CONCLUSION: The heart rate variability index provides independent information on clinical status and prognosis in patients with chronic congestive heart failure.

Aged↗
PubMed1998

No evidence for persistent enterovirus infection in patients with end-stage idiopathic dilated cardiomyopathy.

Persistence of enteroviruses in heart tissue has been implicated in the etiology of idiopathic dilated cardiomyopathy (IDC). Therefore, we determined the prevalence of enterovirus RNA in heart tissue from patients with end-stage IDC. During heart transplantation, 287 transmural biopsy specimens were aseptically collected from the explanted hearts of 38 patients with IDC and of 39 patients with cardiac failure of known cause. A nested polymerase chain reaction with general specificity for enteroviruses was used to screen for the presence of enterovirus RNA in the heart tissue samples. No enterovirus RNA was detected in any of the 287 heart biopsy specimens. These findings lead to a conclusion that enteroviruses do not persist in heart tissue from patients with end-stage IDC, nor with other heart diseases of known cause.

Adolescent↗
PubMed1998

Renal insufficiency after heart transplantation: a case-control study.

BACKGROUND: In Rotterdam 304 heart transplants have been performed since 1984. End-stage renal failure, necessitating renal replacement therapy, has developed in 24 patients (8%) after an interval of 25-121 months (median 79 months). After starting renal replacement therapy one-year survival was only 60%. Overall survival after heart transplantation, however, was favourable: 5 and 10 year survival rates of 79% and 50% respectively. METHODS: A case-control study was performed to identify possible risk factors in cases who went on to develop end-stage renal failure compared to controls. RESULTS: We found that renal failure was not limited to elderly patients with ischaemic heart disease, but also occurred in young patients having dilated cardiomyopathy. A significant rise in the serum creatinine was found in cases compared to controls as early as 3 months after transplantation. Cyclosporin dose and trough levels were not different between cases and controls. Neither were there differences in the use of calcium-antagonists or other antihypertensive drugs, allopurinol or diuretics. Rejection incidence was also similar between the two groups. CONCLUSIONS: Renal failure after heart transplantation is a long term complication of cyclosporin use that is not limited to elderly patients with ischaemic heart disease. Cyclosporin dose and trough levels in the cases were not different from patients maintaining stable good renal function, indicating that cyclosporin nephrotoxicity is the result of an individually determined susceptibility to cyclosporin. Suggestions for future strategies to prevent renal failure are given.

Adolescent↗
PubMed1998

Transmission of hepatitis B virus among heart transplant recipients during endomyocardial biopsy procedures.

BACKGROUND: The unexpected conversion to HBsAg seropositivity of three cardiac allograft recipients prompted us to conduct a multidisciplinary study to identify the source, transmission mode, and extent of the hepatitis B virus (HBV) infection among the 256 cardiac allograft recipients of our hospital. METHODS: All recipients were retrospectively screened for serum markers of HBV infection. A selected genomic region defining subtypes of the viruses involved was amplified and sequenced. An epidemiologic case-control study for possible risk factors was conducted to identify the mode of transmission. RESULTS: Eighteen additional HBV-infected patients were identified, none of whom had shown symptoms of HBV infection. The involvement of one virus (subtype ayw 3) was shown in 20 of the 21 HBV-infected patients. This virus is found in less than 10% of HBV-infected individuals in The Netherlands. The demonstration of a common source of infection, combined with results of the epidemiologic study, identified posttransplantation endomyocardial biopsy procedures as the most likely mode of transmission. However, we also found evidence of secondary virus transmission by cardiac catheterization procedures to nonallograft recipients. CONCLUSIONS: The immunosuppressive therapy practiced in these patients to prevent allograft rejection may have not only facilitated virus transmission by causing high levels of viremia but also left the spreading of HBV undetected by causing a subclinical course of the infection. These findings stress the necessity of strict hygienic precautions during intravascular diagnostic procedures and indicate that vaccination against and routine monitoring for certain bloodborne infections in cardiac allograft recipients should be considered.

Adult↗
PubMed1998

The nature of acute rejection is associated with development of graft vascular disease after clinical heart transplantation.

BACKGROUND: To determine mechanisms that trigger graft vascular disease (GVD) after heart transplantation, we studied parameters that reflect both early and late intragraft allogeneic reactions. METHOD: With reverse transcriptase-polymerase chain reaction analysis, mRNA expression of interleukin-2 (IL-2), interleukin-4, interleukin-6, interleukin-10, interferon-gamma, platelet-derived growth factor-alpha, and transforming growth factor-beta was measured in endomyocardial biopsy (EMB) specimens obtained from 34 recipients during the first acute rejection episode (n = 29) or at a comparable time after transplantation for patients without rejection (n = 5) and at time of assessment of GVD by coronary angiography at 1 year (n = 34). RESULTS: At the time of assessment of GVD, mRNA expression of IL-2, interleukin-4, and interleukin-6 were barely detectable, whereas messenger coding for interferon-gamma, interleukin-10, transforming growth factor-beta, and platelet-derived growth factor-alpha genes were constitutively expressed. Moreover, intragraft mRNA patterns of cytokines and growth factors between patients with GVD (n = 17) or without GVD (n = 17) were comparable. In contrast, during the first acute rejection episode a completely different pattern was found. Development of GVD was associated with IL-2 mRNA expression and not with the other cytokines analyzed. IL-2 mRNA was present in 77% of rejection EMB specimens obtained from patients with GVD versus 33% of the EMB specimens obtained from patients without GVD (p = 0.03) and not detectable in EMB specimens obtained from patients with no rejection. Also nonimmunologic risk factors such as longer ischemia time (median 193 vs 141 minutes; p = 0.002) and higher donor age (median 32 vs 23 years; p = 0.02) were associated with GVD. But no relation was found between these nonimmunologic risk factors and IL-2-positive acute rejections. CONCLUSIONS: Nonspecific risk factors and IL-2-positive rejections may independently trigger GVD after clinical heart transplantation.

Acute Disease↗
PubMed1997

Effect of HLA-DR-shared blood transfusion on the clinical outcome of heart transplantation.

Pretransplant blood transfusion can have a favorable effect on renal and cardiac graft survival. In a previous study, we found that HLA-DR-shared blood transfusions led to better graft survival after kidney transplantation. In the present study, we tried to confirm and extend these findings by analyzing the effects of blood transfusion on the clinical course following heart transplantation. According to a predefined protocol, cardiac allograft recipients received random blood transfusion before surgery. A beneficial effect of HLA-DR-shared blood transfusion could be observed on survival and on the number of rejection episodes. Patients who had received an HLA-mismatched transfusion had significantly more infections, and in this group, more patients died due to malignancies. To study a possible role of immunomodulating T cells, patients who had or had not received prophylactic anti-T cell therapy were analyzed separately. In both groups, a beneficial effect of HLA-DR-shared blood transfusion could be demonstrated. These results indicate that the administration of HLA-DR-matched blood transfusion before transplantation is beneficial in cardiac allograft recipients, and that regulatory T cells are either not directly involved or (partly) resistant to modulation by anti-T cell antibody therapy.

Acute Disease↗
PubMed1997

Donor-specific cytokine production by graft-infiltrating lymphocytes induces and maintains graft vascular disease in human cardiac allografts.

BACKGROUND: The development of graft vascular disease (GVD) in the allograft is a major impediment for long-term survival of heart transplant recipients. GVD may be mediated by cellular processes, in response to the transplanted heart, and regulated by cytokines. METHODS: We studied donor-specific cytokine production patterns in graft-infiltrating lymphocyte cultures propagated from endomyocardial biopsies. The biopsies were derived from patients with and without signs of GVD, as diagnosed by angiography at 1 year after heart transplantation. RESULTS: In the first year after transplantation, significantly more T-helper (Th) 1 cytokines (interleukin [IL]-2: P=0.04; interferon-gamma: P=0.01), but not Th2 (IL-4 and IL-6) cytokines, were produced by cultures of patients with GVD compared with patients without GVD. Thereafter, the Th1 cytokine levels in patients with GVD normalized to the levels of patients without GVD. Detectable levels of IL-6 were produced significantly more often (P=0.009) by cultures obtained more than 1 year after transplantation from patients with GVD. CONCLUSIONS: The results suggest that high levels of Th1 cytokines produced by graft-infiltrating lymphocytes early after transplantation may be responsible for activation of vascular endothelium, leading to the migration and proliferation of smooth muscle cells that is characteristic of GVD. IL-6, produced later after transplantation, continues this process by promoting smooth muscle cell proliferation.

Cells, Cultured↗