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Biomedical subjects

T van Gelder

Publications and source records attributed to T van Gelder.

At least 73 records · Page 4Linked 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

C-reactive protein in the monitoring of acute rejection after heart transplantation.

Histological examination of endomyocardial biopsy (EMB) is the main technique for rejection surveillance after heart transplantation. This technique is elaborate, inconvenient for the patient, and not without complications. We prospectively analyzed whether the measurement of C-reactive protein (CRP), an acute phase protein that quickly rises when there is inflammation, can serve as a marker for immunological quiescence and as an indicator for withholding EMB. During a 6-month period, CRP was measured in all patients referred for EMB as part of the routine follow-up after heart transplantation. Acute rejection in patients with a follow-up of more than 1 year was rare (1/76). In the majority of cases, EMB was taken within the 1-year post-transplantation (170/246 = 69%). In 71/170 biopsies (42%), CRP was < or = 1; in the other 99/170 (58%), CRP was > or = 2. When CRP was < or = 1, acute rejection was diagnosed in 12/70 cases (17%). In contrast, acute rejection was found in 28/99 cases (28%) with CRP > or = 2 (P = 0.1). Although CRP is elevated more often in the presence of acute rejection, its sensitivity does not allow CRP to replace the routine performance of EMB for monitoring rejection after heart transplantation. We did, however, find a prognostic significance with regard to the effect of rejection treatment: in all acute rejections with a CRP < or = 3 (n = 11), steroids were effective.

Acute Disease↗
PubMed1998

The TNF-alpha system after successful living-related kidney transplantation.

The TNF-alpha system is thought to play a central role in the reduced immunity of haemodialysis patients. The imbalance between the high levels of soluble TNF receptors R1 and R2 and the low levels of immunoactive TNF-alpha results in an increased TNF-alpha buffering capacity leading to reduced immune responses. Apart from impaired renal clearance of the receptors, inefficient TNF-alpha production as a result of the uraemia may also contribute to the imbalance between this cytokine and its receptors. In patients receiving a living-related kidney transplant, renal function is nearly normalized in a very short period. This restoration of renal function may result in a state of better immunocompetence, either as a result of improved clearance of the receptors or as a result of reversal of the uraemic state. To differentiate between these two possibilities, we measured TNF-alpha protein, mRNA and the soluble TNF receptors R1 and R2 before and after successful renal transplantation. TNF-alpha mRNA was not affected by transplantation, indicating constant TNF-alpha production. The imbalance in the TNF-alpha system was markedly improved after transplantation, although normal values of the soluble receptors were not reached. One year after transplantation in stable kidney transplant recipients there was still an imbalance in the TNF-alpha system caused by persistently elevated levels of the soluble TNF-receptors. These results suggest that even after successful kidney transplantation the TNF-alpha system remains activated. However, despite immunosuppressive therapy, recipients of a living-related kidney do have a better balanced TNF-alpha system compared to haemodialysis patients.

Adult↗
PubMed1998

Donor-specific CTL frequencies in peripheral blood in relation to graft vascular disease after clinical heart transplantation.

Cellular mechanisms may play a role in the development of graft vascular disease (GVD). We previously demonstrated that GVD correlated with an increase of donor-specific T-helper 1 cytokine production by graft-infiltrating lymphocytes but not by peripheral blood mononuclear cells (PBMC). These T-helper 1 cytokines aid the generation of cytotoxic T-lymphocytes (CTL). In the present report, we investigated whether there is a relationship between the frequency of donor-specific CTL precursors (pCTL) in PBMC and the development of GVD. We tested PBMC samples of five patients with GVD and five patients without GVD in the periods 3-6 months, 1 year, and 3 years after heart transplantation. At all time points, GVD was not related to the number of pCTL. In conclusion, donor-specific cellular tests in peripheral blood could not be related to GVD. Apparently, donor-specific reactions associated with the induction of GVD can only be monitored in the graft.

Heart Transplantation↗
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 dynamical hypothesis in cognitive science.

According to the dominant computational approach in cognitive science, cognitive agents are digital computers; according to the alternative approach, they are dynamical systems. This target article attempts to articulate and support the dynamical hypothesis. The dynamical hypothesis has two major components: the nature hypothesis (cognitive agents are dynamical systems) and the knowledge hypothesis (cognitive agents can be understood dynamically). A wide range of objections to this hypothesis can be rebutted. The conclusion is that cognitive systems may well be dynamical systems, and only sustained empirical research in cognitive science will determine the extent to which that is true.

Cognition↗
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

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

Losartan, an angiotensin-II receptor antagonist, reduces hematocrits in kidney transplant recipients with posttransplant erythrocytosis.

BACKGROUND: Posttransplant erythrocytosis (PTE) occurs in 10-15% of patients with a well-functioning kidney transplant and is associated with increased morbidity. Although the mechanism of PTE is unknown, PTE responds to inhibitors of ACE (ACE-i) in most cases. ACE converts angiotensin I to angiotensin II and is a metabolizer of a number of other peptides. METHODS: Because ACE-i frequently show side effects we wanted to elucidate the pathway by which ACE-i mediate their effect in PTE. Therefore, we treated eight patients (five with newly diagnosed PTE, two with PTE unresponsive to ACE-i, and one with PTE responsive to ACE-i, which had to be withdrawn due to side effects) with 50 mg of the type 1 angiotensin II receptor antagonist losartan for at least 14 weeks. RESULTS: Hematocrit values in the two patients who were unresponsive to ACE-i did not change significantly. In contrast, hematocrits decreased in all the other six patients from 0.53+/-0.02 to 0.44+/-0.02 after 14 weeks of treatment with losartan (mean +/- SE; P<0.005, paired t test). Graft function, cyclosporine concentration, and leukocyte and platelet count remained stable. The serum potassium level rose in one patient from 6.0 to 6.8 mmol/L but remained stable in all other patients. CONCLUSIONS: We conclude that blockade of the type 1 angiotensin II receptor is safe and effective in treating PTE.

Angiotensin Receptor Antagonists↗
PubMed1997

Mycophenolate mofetil and prednisone as maintenance treatment after kidney transplantation.

BACKGROUND: Hemolytic uremic syndrome (HUS) is an infrequent but severe complication of kidney transplantation. Cyclosporine-induced microangiopathy may be the causative factor in allograft recipients with HUS. In transplant recipients with HUS, discontinuation of cyclosporine is generally advised. This often leads to loss of the graft. METHODS: An adult kidney transplant recipient developed HUS in the third week after transplantation. Maintenance immunosuppression was changed to mycophenolate mofetil and prednisone after cyclosporine was discontinued. RESULTS: The change in immunosuppressive therapy led to remission of the HUS and stable graft function. CONCLUSIONS: In transplant recipients receiving cyclosporine who suffer from HUS, the possibility of conversion from cyclosporine to mycophenolate mofetil should be considered. As this case shows, complete remission of HUS and maintenance of the graft are possible.

Female↗