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Biomedical subjects

L M Vaessen

Publications and source records attributed to L M Vaessen.

At least 55 records · Page 3Linked to original sources
PubMed1994

Differential avidity and cyclosporine sensitivity of committed donor-specific graft-infiltrating cytotoxic T cells and their precursors. Relevance for clinical cardiac graft rejection.

We have used limiting dilution analysis to study the qualitative and quantitative differences between graft-infiltrating cytotoxic T cell populations propagated from endomyocardial biopsies of heart transplant patients who experienced one or more acute rejection episodes and patients who never showed signs of rejection. Limiting dilution cultures were stimulated with autologous or donor cells both in the absence or in presence of cyclosporine and of CD8 in the cytotoxic phase. Almost all antigen-primed, committed cytotoxic T cells (cCTL) present in the graft of patients with rejections were CsA resistant. In contrast, in most patients of the nonrejector group, a substantial part of the cCTL could be inhibited by CsA. The CTL precursors (pCTL) in both groups were predominantly CsA sensitive. Addition of CD8 mAb during the cytotoxicity phase of the limiting dilution analysis was used to differentiate between CTL populations with high avidity for donor antigens and populations with low avidity. The predominant subpopulation in the graft of rejectors was a CsA-resistant cCTL with high avidity, while in the graft of most nonrejectors, cCTL with low avidity dominated. In most rejectors, CD8 mAb had only a minor influence on the pCTL frequency estimates, and thus on T cells with high avidity. CsA-sensitive pCTL with high avidity might represent an intermediate stage between the naive pCTL and mature, functional, CsA-insensitive cCTL with high avidity for donor antigens.

Antibodies, Monoclonal↗
PubMed1994

Functional and molecular characterization of graft-infiltrating T lymphocytes propagated from different biopsies derived from one heart transplant patient.

Alloreactive T lymphocytes play an important role in graft rejection. In the present study, we have analyzed the cytolytic capacity against donor cells of graft infiltrating T lymphocyte cell lines, which were propagated from various endomyocardial biopsies taken at different time points after transplantation, including during a rejection crisis. Also, T cell clones were generated from the rejection biopsy and evaluated for their cytolytic capacity and nucleotide composition of the TCR alpha and beta chains. The results of these studies revealed a strong cytolytic activity against donor cells by T cells derived from the rejection biopsy, whereas from the other biopsies, no cytolytic T cell clones could be established. The T cells that were responsible for this activity, as detected by T cell cloning and TCR gene analysis, could not been identified in earlier biopsies, indicating that these cytolytic cells were recently recruited toward the endomyocardium.

Base Sequence↗
PubMed1994

Cytomegalovirus infection and allospecific cytotoxic activity of graft-infiltrating cells after heart transplantation.

We have investigated whether cytomegalovirus (CMV) infection has an effect on donor directed cytotoxicity of graft-infiltrating cells in human heart transplants. Our study group consisted of 89 heart transplant recipients. Thirty-eight (43%) showed signs of CMV infection; in 28 of them, cytolytic activity of biopsy derived cultures could be tested during the infection. Eight patients had a primary and 20 a secondary infection. We found that during CMV infection, both primary and secondary, a significantly higher proportion of the biopsy-derived cultures showed cytotoxicity against donor HLA antigens (chi 2 test; P < 0.01 in comparison with 51 patients without infection). This was most evident in patients with both infection and acute rejection episodes when compared to patients with only one of these complications. This suggests that one process amplifies the other with regard to the up-regulation of alloreactivity within the transplanted heart. In secondary infections, only an increase of donor class I-directed cytotoxicity was found, while in primary infections cytotoxicity against donor class I and II antigens was increased (P < 0.005 vs. secondary infection).

Adolescent↗
PubMed1994

Characteristics of graft-infiltrating lymphocytes after human heart transplantation. HLA mismatches and the cellular immune response within the transplanted heart.

The influence of HLA mismatches between donor and recipient on the phenotypes, function, and specificity of T-lymphocyte cultures derived from endomyocardial biopsies was studied in 118 heart transplant recipients. In case of HLA-DR mismatches, the majority of the EMB-derived cultures were dominated by CD4+ T cells while, in patients with HLA-A and -B mismatches but without DR mismatches, CD8+ T cells comprised the predominant T-cell subset. Cytotoxicity against donor antigens was observed in 75% of the cultures. A significantly (p < 0.005) lower proportion of the cultures showed cytotoxicity against HLA-A antigens (36%) when compared with HLA-B (53%) or HLA-DR (49%). An HLA-A2 mismatch elicited a cytotoxic response that was comparable to that found against HLA-B and -DR antigens: 62% of the cultures from HLA-A2 mismatched donor-recipient combinations was reactive against A2. A higher number of A, B, or DR mismatches resulted in a higher number of cytotoxic cultures directed against these antigens. A higher number of HLA-B and -DR mismatches was associated with a lower freedom from rejection. Our data indicate that, despite the use of adequate immunosuppressive therapy, the degree of HLA matching plays a crucial role in the immune response against a transplanted heart, resulting in a significant effect on freedom from rejection.

Acute Disease↗
PubMed1994

Prophylactic therapy with OKT3 does not affect donor specific reactivity of peripheral blood lymphocytes from heart transplant recipients.

To avoid the nephrotoxic effect of high-dose cyclosporin A (CsA) immediately posttransplant, heart transplant recipients received as prophylactic therapy intravenous OKT3 for seven days instead of intravenous CsA. Patients receiving OKT3 were compared with patients receiving CsA with respect to specific proliferation and cytotoxicity of their peripheral blood mononuclear cells (PMNC) against donor antigens, at different times within three months post-transplant. No effect of the initial immunosuppressive therapy was observed on these parameters. Acute rejection did not induce a consistent effect on the relative proliferation. PMNC from patients who experienced one or more rejection episodes showed a decrease in donor specific relative proliferative response in time after transplantation, while nonrejectors did not or only slightly, independent of the initial immunosuppressive protocol. Within the group of patients not receiving OKT3, this effect of rejection reached significance. In conclusion, no effect of prophylactic OKT3 therapy compared with prophylactic CsA therapy was observed on donor reactivity of PMNC in vitro during the subsequent three to four months post-transplant.

Blood Transfusion↗
PubMed1994

In vitro and in vivo effects of BT 563, an anti-interleukin-2 receptor monoclonal antibody.

BT 563, a murine anti-IL-2R MoAb, was found to be more potent than anti-Tac in inhibiting proliferation in the mixed lymphocyte reaction. Results obtained with 33B3.1 in these experiments were similar to those with BT 563. The anti-IL-2R MoAb 2A3 was shown to be a suitable agent for monitoring the effect of BT 563 on peripheral blood. IL-2R-positive cells were not detected in peripheral blood samples from 1 h after the first dose until 8 days after the last dose. Plasma trough levels were measured in patients receiving 5 or 10 mg daily. The administration of BT 563 to allograft recipients did not lead to clinically significant side effects.

Antibodies, Monoclonal↗
PubMed1994

Discrepancy between mRNA expression and production of IL-2 and IL-4 by cultured graft infiltrating cells propagated from endomyocardial biopsies.

We studied whether acute rejection correlated with the cytokine production pattern and mRNA expression of interleukin-2 (IL-2) and interleukin-4 (IL-4) in lymphocyte cultures derived from endomyocardial biopsies (EMB) that were stimulated with B cell lines of donor origin. Unstimulated biopsy cultures neither expressed mRNA nor produced IL-2 or IL-4. All stimulated biopsy cultures contained mRNA transcripts for IL-2 and IL-4. In contrast, we found different IL-2 and IL-4 production patterns. Within the first 90 days after heart transplantation (HTx), higher levels of IL-4 were measured in cultures derived from EMB with myocytolysis than in cultures from EMB without signs of myocytolysis. More than 90 days after HTx, this phenomenon was reversed and more IL-4 was produced in cultures derived from EMB without myocytolysis. These differences were not detected for IL-2 production.

Biopsy↗
PubMed1993

Donor heart endothelial cells as targets for graft infiltrating lymphocytes after clinical cardiac transplantation.

The in vitro cytotoxic reactivity of allograft infiltrating cells cultured from endomyocardial biopsies was tested against endothelial cells (EC) isolated from the own donor heart. EC derived from pieces of atrium were found to be proper targets for graft infiltrating cytotoxic T cells from four patients. The specificity of this cytotoxicity was further analysed by cold target inhibition studies and blocking with anti-CD3, anti-CD4 or anti-CD8 monoclonal antibodies. The experiments revealed that, besides a clearly HLA directed recognition, a more heterogeneous, multispecific response can be found, which might be partially explained by the activity of EC specific T cell clones. We conclude that this system provides a valuable approach to investigate the reactivity of graft infiltrating cells against EC in relation to the clinical course of the transplantation.

Antibodies, Monoclonal↗
PubMed1993

The detection of cytotoxic T cells with high-affinity receptors for donor antigens in the transplanted heart as a prognostic factor for graft rejection.

Alloreactive T lymphocytes are the initiators and effectors of acute rejection of organ transplants, and T cells with high-affinity receptors for antigen might be especially implicated in this process. It has been shown that the cytotoxic capacity of CTL with low affinity for alloantigens can be inhibited with CD8 mAb, while high-affinity CTL are not affected. To investigate whether the presence of such high-affinity cells in human heart transplants may be predictive for acute rejection, we analyzed their frequency in cultures derived from endomyocardial biopsies in 19 patients, 9 of whom had never experienced acute rejection and 10 who had had one or more rejection episodes. IN the rejectors, already before histological signs of rejection (myocyte damage) had developed, significantly higher donor-reactive CTL frequencies were found compared with the nonrejectors (medians of 10,586 vs 1,169 reactive cells per 10(6) tested cells, P = 0.002). After CD8 inhibition, the difference between rejectors and nonrejectors was even more pronounced (P < 0.001). In patients with rejection, the number of CD8-resistant, high-affinity CTL was higher than 1000 per million cells in all cases, while in patients who had never experienced rejection this number was less than 1000. As these CTL characteristics are already present before the first histological signs of rejection have developed, this might be used as a prognostic factors.

Antibodies, Monoclonal↗
PubMed1992

Lysis of heart endothelial cells from donor origin by cardiac graft infiltrating cells.

Endothelial cells may be involved in the acute rejection of allografts. In the present study, graft infiltrating lymphoid cell lines were propagated from a heart graft at the time of histological diagnosis of rejection. The cell lines containing CD8+ cells lysed donor-derived BLCL and endothelial cells (EC) but not third party BLCL or random EC, suggesting that HLA antigens were recognized. The cell lines containing CD4+ cells only did not lyse any target cells. The lysis of EC without preincubation with gamma interferon (gIFN) indicated that the HLA antigens recognized were class I antigens. These results suggested that lysis of donor EC may be one of the mechanisms involved in rejection.

CD4-Positive T-Lymphocytes↗