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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
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↗
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

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

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↗
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↗
PubMed1997

Kinetics of IL-2 and IL-4 mRNA and protein production by graft-infiltrating lymphocytes responsible for rejection after clinical heart transplantation.

During cardiac rejection we studied the kinetics of IL-2 and IL-4 mRNA and subsequent protein production by in vivo primed graft-infiltrating lymphocytes (GIL), using semiquantitative RT-PCR and ELISA. Following in vitro stimulation with either donor or third-party antigens, mRNA expression of IL-2 and IL-4 were already detectable 1-2 h after stimulation, while their protein production could be measured from 4 h onwards at least until 48 h. At both the mRNA and protein level, we measured a donor-specific signal for IL-2 and for IL-4 production (p = 0.02), while the relative donor-specific IL-2 mRNA level was significantly higher than the relative IL-4 mRNA level (p = 0.002). These observations suggest that after in vitro challenge with donor antigens, GIL obtained from rejecting cardiac allografts predominantly produce IL-2 mRNA and protein.

Biopsy↗
PubMed1997

The avidity of allospecific cytotoxic T lymphocytes (CTL) determines their cytokine production profile.

Donor-specific CTL present within the cardiac allograft during a rejection episode are distinct from those that populate the cardiac allograft in the absence of rejection. Whereas the former generally have a high avidity for donor cells, the latter mainly have a low avidity for donor cells. This observation made us reason that high-avidity CTL are implicated in transplant rejection, whereas low-avidity CTL are not. In the present study, we analyse whether both CTL subsets were distinct with respect to their IL-2, IL-4, IL-6 and interferon-gamma (IFN-gamma) secretion pattern. CTL clones with either a high or a low avidity for donor antigens were stimulated with donor cells, third party cells, or immobilized anti-CD3 MoAb and the amount of cytokine released was measured. High- and low-avidity CTL clones were found to differ with respect to their IFN-gamma production profile. Stimulation with donor cells resulted in IFN-gamma secretion by high-avidity CTL clones, but not by low-avidity CTL clones. CD3 stimulation, in contrast, led to secretion of equivalent amounts of IFN-gamma by both CTL subsets. These observations indicate that low-avidity CTL are fully capable of producing IFN-gamma, but, in contrast to high avidity CTL, fail to do so when they encounter donor cells. As IFN-gamma favours the occurrence of transplant rejection, this observation emphasizes the relevance of high-avidity CTL in the rejection process. Additionally, the data show that the cytokine production profile of CTL depends on the nature of the stimulus.

Antibodies, Monoclonal↗
PubMed1997

Effect of adopting a new histological grading system of acute rejection after heart transplantation.

BACKGROUND: Treatment policy of acute rejection after heart transplantation has been changed after adopting the ISHLT endomyocardial biopsy grading system in 1991. OBJECTIVE: To determine the effect of this policy change on clinical outcome after transplantation. METHODS: The outcome of 147 patients who had a transplant before (early group, median follow up 96 months) and 114 patients who had a transplant after (late group, median follow up 41 months) the introduction of the ISHLT biopsy grading system was studied retrospectively. Initially "moderate rejection" according to Billingham's conventional criteria was treated. From January 1991 grade 3A and higher was considered to require intensification of immunosuppression. RESULTS: There were some differences between the two groups: recipients (50 v 44 years) as well as donors (28 v 24 years) were older in the "late group" and more patients of this group received early anti-T cell prophylaxis (92% v 56%). Despite more extensive use of early prophylaxis more rejection episodes were diagnosed (2.4 v 1.4) and considerably more courses of rejection treatment were instituted in the late compared with the early group (3.2 v 1.5). There were no deaths because of rejection in the late group, however, more infections occurred within the first year (mean 1.8 v 1.4) and more non-skin malignancies within the first 41 months were diagnosed (8 of 57 v 6 of 147, 95% CIs of difference includes 0). The incidence of graft vascular disease in the late group has been comparable to the early group until now. CONCLUSION: The interpretation of the ISHLT grading system resulted in lowering of the threshold for the diagnosis of rejection thereby increasing the number of rejections and subsequently the immunosuppressive load and its complications.

Acute Disease↗
PubMed1997

Cytotoxicity of graft-derived lymphocytes: specific for donor heart endothelial cells?

BACKGROUND: Previously, we showed that lymphocytes cultured from cardiac allografts can lyse lymphoid cell lines from donor origin. Because endothelial cell form the first allogeneic barrier to be encountered in vivo, the reactivity of graft-infiltrating cells against donor heart-derived endothelial cells (DoHEC) may be more relevant for understanding the clinical course after heart transplantation. METHODS: Endomyocardial biopsies (EMB) were taken at different times after transplantation, both during acute rejection and during quiescence. Lymphocytes cultured from these EMB were assayed for cell-mediated cytotoxicity in a 4-hour chromium 51 release test by use of target panels of different cell types derived from donor or third party. Cell specificity was investigated by addition of a tenfold excess of unlabelled target cells to 51Cr-labeled DoHEC. RESULTS: These experiments show that DoHEC can be lysed by lymphocytes derived from EMB. Antigens that were recognized on DoHEC were often donor human leukocyte antigen class I antigens. Some cultures in addition recognized alloantigens present only on DoHEC and not on donor-derived B cells as suggested by lack of or partial inhibition of DoHEC lysis by addition of excess competitor B cells. Endothelial cell-specific reactivity was unequivocally identified after limiting dilution of EMB-derived cultures. CONCLUSION: We conclude that not only DoHEC-reactive but also DoHEC-specific cells are present among the cardiac graft infiltrating cells.

CD8-Positive T-Lymphocytes↗
PubMed1997

The avidity, not the mere presence, of primed cytotoxic T-lymphocytes for donor human leukocyte class II antigens determines their clinical relevance after heart transplantation.

BACKGROUND: To analyze the relevance of CD4-positive cytotoxic T-lymphocytes (CTL) in clinical heart rejection, we studied the frequency and avidity of donor human leukocyte antigen class II-specific CTL present within the graft during a rejection episode and during a period without rejection. METHODS: For this analysis endomyocardial biopsies of heart transplant recipients were cultured to obtain graft-infiltrating lymphocytes (GIL). GIL cultures exhibiting donor class II-directed cytotoxicity were considered for this study. With limiting dilution analysis, the frequency of donor class II-specific CTL that had been primed by donor antigens in vivo (designated cCTL) was determined in GIL cultures established from endomyocardial biopsies taken during a rejection episode (n = 10) or during a period without rejection (n = 11). Addition of anti-CD4 to the limiting dilution analysis revealed the fraction of donor class II-specific cCTL having a high avidity for donor antigen. RESULTS: During a rejection episode, 196 (median) donor class II-specific cCTL/106 GIL were present. In a period without rejection, the frequency of donor class II-specific cCTL was not significantly different (median = 330/10(6); p = 0.1). Addition of anti-CD4, however, revealed that donor class II-specific cCTL with a high avidity for donor antigen are predominant during a rejection episode (median = 100%) but are in minority during a period without rejection (median = 35%; p < 0.0001). CONCLUSIONS: These results suggest that graft-infiltrating CD4+ CTL can mediate heart rejection provided they have a high avidity for donor antigen.

Antibody Affinity↗
PubMed1996

Progressive accumulation of CTL with high avidity for donor antigens during the development of acute cardiac rejection.

To study the importance of cytotoxic T lymphocytes (CTL) with high avidity for donor antigens (Ag) in the development of acute cardiac allograft rejection, their appearance within the graft in relation to rejection was analyzed. For this study, donor directed CTL propagated from sequentially taken endomyocardial biopsies (EMB) were enumerated by limiting dilution analysis (LDA). Subsequentially, the fraction of these CTL having high avidity for donor Ag was determined by addition of a CD8 monoclonal antibody (mAb) to the cytotoxic phase of the LDA. Analysis of 37 EMB cultures obtained from 11 heart transplant (HTx) patients before, during, or after they experienced rejection, revealed the kinetics of donor specific CTL in relation to rejection for HTx patients in general. For 5 individual recipients, a more detailed analysis was performed. The kinetics found for individual patients confirmed the pattern found for the total group of HTx recipients tested. Frequencies of donor specific precursor CTL (pCTL) as well as of in vivo primed donor reactive CTL (committed CTL or cCTL) increased towards rejection and decreased after successful rejection therapy. More than 2 weeks before rejection was diagnosed, only a small fraction of the graft infiltrating donor specific pCTL and cCTL had high avidity for donor Ag (median = 35% and 11%, respectively). Within 2 weeks preceding rejection, this fraction increased gradually (median = 52% and 55%, respectively) and became dominant during rejection (median = 87% and 78%, respectively). After successful rejection therapy, a decrease to basal levels (median = 18% and 24%, respectively) was observed. Conclusively, intragraft accumulation of high avidity, donor specific pCTL and cCTL may cause transplant rejection.

Acute Disease↗
PubMed1996

Human heart endothelial-cell-restricted allorecognition.

We studied the reactivity of cardiac graft-infiltrating cells, cultured from endomyocardial biopsy specimens, toward heart endothelial cells (Hec). In two cases, Hec derived from the specific donor heart or Hec compatible with the donor were lysed, but not the syngeneic B cell line. A vessel-derived endothelial cell line was not lysed. Panel studies suggest that the epitopes recognized are, in one case, a Hec-specific peptide presented in the context of HLA-Bw41 and, in the other case, a Hec-specific peptide presented by a subtype of HLA-B44. In conclusion, we showed that cardiac graft-infiltrating cells cultured from endomyocardial biopsy specimens can exhibit cytotoxic reactivity specifically directed against HLA-peptide complexes on Hec.

Cell Line↗
PubMed1996

A randomized trial comparing safety and efficacy of OKT3 and a monoclonal anti-interleukin-2 receptor antibody (BT563) in the prevention of acute rejection after heart transplantation.

In a prospective randomized trial, BT563, a murine IgG, anti-interleukin-2 receptor antibody, was compared with OKT3 for use as an early rejection prophylaxis after heart transplantation. Patients received either BT563 (n=31) or OKT3 (n=29) during the first 7 days after transplantation; cyclosporine was started on day 3. Median follow-up was 34 months. A cytokine release syndrome occurred in the majority of patients of the OKT3-treated group but in none of the BT563 recipients. The mean duration of electrical stimulation of the heart in the BT563 group was longer than in the OKT3 group (5.1 vs. 2.1 days). In both groups, one patient required insertion of a permanent pacemaker. Freedom from acute rejection at 3 months was not significantly different between the two groups (BT563: 5/29, 17%; OKT3: 6/29, 21%). In the BT563 group, however, rejection tended to occur earlier after transplantation. There was no difference in the overall incidence of rejection. The incidence of infectious complications was evenly distributed in both groups. Malignancies occurred in two patients, both in the OKT3 group. In conclusion, the use of this anti-interleukin-2 receptor monoclonal antibody in heart transplant recipients is safe and devoid of the side effects that accompany the use of OKT3. OKT3 and BT563 result in a similar freedom from rejection at 3 and 12 months after heart transplantation.

Adolescent↗