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Biomedical subjects

F H Claas

Publications and source records attributed to F H Claas.

At least 127 records · Page 7Linked to original sources
PubMed1994

High-affinity cytotoxic T lymphocytes after non-HLA-sharing blood transfusion--the other side of the coin.

Previously, we have shown that pretransplantation blood transfusion modulates the T cell repertoire to a great extent. Patients receiving a BT from a donor sharing one HLA haplotype with the patient (HLA-sharing BT) develop CTL nonresponsiveness against cells of the BT donor and show a selective decrease in the usage of T cell receptor V beta families. The present study has focused on the analysis of the T cell repertoire in patients receiving an HLA mismatched (non-HLA-sharing) BT. CTL precursor frequencies were measured against single class I-mismatched antigens in split-well analysis. In addition, blocking studies of CTL-target cell interaction were performed with anti-CD8 monoclonal antibodies. The results demonstrate that non-HLA-sharing BT immunizes and induces the generation of CD8 independent, high-affinity CTL against immunogenic class I-mismatched antigens. Such HLA class I antigens might become nonacceptable mismatches in subsequent organ transplantation.

Alleles↗
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

Transfusion-associated graft-versus-host disease in immunocompetent patients: a self-protective mechanism.

Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare but hazardous complication caused by transfusion of leucocyte-containing blood. It is not clear why some patients are at risk for TA-GVHD, but others are not. We studied TA-GVHD in immunocompetent individuals by looking at donor-anti-host reactivity after transfusion of leucocyte-containing blood. We tested reactivity in 62 donor-recipient combinations in vitro before and at different times after blood transfusion with mixed lymphocyte culture. One patient was studied in more detail. Reactivity of blood donors against hosts gradually decreased after blood transfusion. This decrease significantly correlated with time (p < 0.001). Studies in a single patient showed that absence of donor-host reactivity was due to host T cells that inhibited the response. These data indicate that an active mechanism exists in immunocompetent individuals which inhibits the graft-versus-host reaction of the donor against the host. This mechanism might be exploited in organ transplantation by pre-transplant blood transfer.

Cells, Cultured↗
PubMed1994

The relative radioresistance of interleukin-2 production by human peripheral blood lymphocytes: consequences for the development of a new limiting dilution assay for the enumeration of helper T lymphocyte precursor frequencies.

We describe a limiting dilution assay for the enumeration of alloreactive helper T lymphocyte precursor frequencies in human peripheral blood. The proliferation rate of the murine indicator cell line, cytotoxic T lymphoblastic line 2 (CTLL-2) induced by interleukin-2 (IL-2) culture supernatants was determined by staining with the fluorescent DNA dye propidium-iodide. Lymphocytes from healthy individuals as well as from patients with end stage kidney disease and no previous allosensitization exhibited a relative radioresistance of their IL-2 production up to gamma irradiation doses of 40-60 Gy. This differs from previous findings in the literature, showing a total inhibition of the IL-2 production in unsensitized individuals using a gamma irradiation dose of 20 Gy. The consequences of this relative radioresistance are that for a reliable stimulator cell inactivation in assays for the enumeration of helper T lymphocyte precursors gamma irradiation doses of at least 50 (-60) Gy are needed. Increasing the gamma irradiation dose for the inactivation of the stimulator cells can result in a decrease of the antigen presenting capacity of these cells.

Animals↗
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

Cytotoxic T lymphocytes against HLA-B antigens are less naive than cytotoxic T lymphocytes against HLA-A antigens.

In healthy individuals, like in highly sensitized patients, CTL precursors (CTLp) frequencies against HLA-A antigens were found to be significantly lower than CTLp frequencies against HLA-B antigens. In the present study, we tested whether not only quantitative but also qualitative differences exist between CTLs against HLA-A antigens versus HLA-B antigens. Experiments performed in the presence of antibodies against CD8 showed that CTLp directed against HLA-B antigens were significantly less inhibited by anti-CD8 compared with CTLp against HLA-A. The low anti-CD8 inhibition of the CTLp directed against HLA-B antigens may be explained by a higher affinity of the CTLp for HLA-B antigens on the target cells. CTLp directed against HLA-B antigens were also found to be less sensitive to CsA, which suggests that their high affinity is due to previous priming. A clinical relevance of these findings is suggested by the observation that matching for HLA-B antigens is of greater importance for kidney graft survival than matching for HLA-A.

Graft Rejection↗
PubMed1994

Prevention of MHC-alloimmunization by UV-B irradiation in a murine model: effects of UV dose and number of transfused cells.

The optimal dose of UV-B radiation for prevention of in vivo alloimmunization (AI) against major histocompatibility complex (MHC) antigens was investigated in a murine transfusion model. Two groups with five C57BL/6 mice (H-2b) each were transfused at weekly intervals with 1 x 10(5) or 1 x 10(6) DBA/2 (H-2d) leucocytes. Both suspensions induced anti-H-2d antibodies in all mice after the second transfusion. The minimal UV-B dose required for abolition of alloreactivity in the mixed leucocyte reaction (MLR) was 0.6 J/cm2. This dose completely prevented the onset of MHC-AI in all five mice transfused with six suspensions containing 1 x 10(5) leucocytes. In contrast, suspensions with 1 x 10(6) leucocytes and exposed to 0.6 J/cm2 induced immunization in 4/5 mice. Further increase of the dose to 1.8 or 5.4 J/cm2 did not prevent the onset of MHC-AI. The use of UV radiation for prevention of secondary MHC-AI was investigated in five mice with a primed immune system. Transfusion of suspensions with 1 x 10(5) leucocytes and irradiated at a dose of 1.8 J/cm2 did not prevent booster reactions. We conclude that the number of leucocytes per transfusion determines the efficacy of UV irradiation for the prevention of MHC-AI. For UV irradiation of human platelet concentrates (PCs) we propose to reduce the number of leucocytes by centrifugation prior to UV exposure. UV-B irradiation of PCs with high numbers of leucocytes may not be effective for prevention of alloimmunization.

Animals↗
PubMed1994

Long-term ultraviolet B-induced impairment of Langerhans cell function: an immunoelectron microscopic study.

The influence of low-dose, long-term ultraviolet B (UVB) light exposure on HLA class II-positive human epidermal Langerhans cells (LC) was studied using a sensitive immunoelectron microscopic technique for the ultrastructural assessment of HLA class II expression on LC and for quantification of these cells in situ. Six healthy Caucasian volunteers participated in the experiments and received thrice weekly UVB treatments for 4 weeks. The initial dose ranged from 30 to 50 mJ/cm2 and the total dose from 600 to 3500 mJ/cm2, depending on skin type. Suction blisters and biopsies were obtained before the start of the UVB protocol and 48 h after the last UVB irradiation, and processed for the mixed epidermal cell-lymphocyte reaction (MECLR) and electronmicroscopy, respectively. The MECLR was used as a measure of the immune response. The distribution of HLA class II molecules on LC was studied by incubating ultrathin cryosections of human skin tissue with an anti-HLA class II MoAb that was conjugated to 10 nm colloidal gold. Furthermore, the number of LC was assessed ultrastructurally, when they could be recognized by their unique cytoplasmic organelle, the Birbeck granule (BG). The UVB protocol that was employed caused a marked suppression of the MECLR responses. This UVB-induced reduction of the immune response was not paralleled by changes in HLA class II expression on LC, nor in the number of epidermal LC. These findings are further support for our hypothesis that UVB-induced immune suppression in the skin is not due to a depletion of local LC.

Histocompatibility Antigens Class II↗
PubMed1994

The development of transplant coronary artery disease after cardiac transplantation is correlated with a predominance of CD8+ T lymphocytes in endomyocardial biopsy derived T cell cultures.

Long-term survival of heart transplant recipients is limited by the development of transplant coronary artery disease (TCAD). We analysed whether the development of TCAD is correlated with the incidence of acute rejection episodes, with the formation of anti-HLA antibodies or with the composition and function of T lymphocyte cultures derived from endomyocardial biopsies. TCAD was assessed by visual analysis of annually performed coronary angiograms and defined as the presence of all vascular changes, including minor wall irregularities. One year after transplantation, 31 of the 77 patients studied had TCAD (40%). The median age and mean number of HLA mismatches in patients with or without TCAD were highly comparable. The patient groups did not differ in incidence of acute rejection episodes, nor in percentage of endomyocardial biopsies yielding T cell cultures. At 1 year after transplantation, lymphocyte cultures from 18/31 TCAD+ patients (58%) and 27/46 TCAD- patients (57%) were analysed. The TCAD+ patients had, compared with the TCAD- patients, a higher median percentage of CD8+ T cells (71% versus 25%, P = 0.06) and a lower median percentage of CD4+ T cells (4% versus 40%, P = 0.04). Similar differences were found in a longitudinal analysis of the culture results of endomyocardial biopsies (EMBs) obtained during the first year. The cytotoxic reactivity of the cultures against donor HLA class I or class II antigens was comparable in the two groups, although a difference in recognition of heart specific antigens remains possible. The fact that EMB-derived cultures from TCAD+ and TCAD- patients differed in T cell phenotype populations gives some support to the hypothesis that cellular immunological processes are involved in the development of TCAD. However, while the median values differed, the overlap of the percentages of CD8+ cells in cultures from TCAD- and TCAD+ patients shows that other factors besides CD8+ T cells also play a role.

Adolescent↗
PubMed1994

Recognition of a tissue-specific polymorphism by graft infiltrating T-cell clones isolated from a renal allograft with acute rejection.

Acute interstitial rejection is an important clinical problem after cadaver kidney transplantation. Recently we have reported that six of 17 graft-infiltrating cell (GIC) lines isolated from kidneys undergoing such rejection episodes recognize graft-derived proximal tubular cells but not lymphoid cells from the same donor. In this study we characterized the specificity of one such GIC line in more detail. From this T-cell line, 18 cytotoxic T-cell (CTL) clones were isolated. Four of these were also cytotoxic against donor lymphoid cells. Nine tissue-specific clones were selected for further analysis. They all contained CD8+ and TCR alpha/beta+ cells and cytotoxicity by these cells was class I restricted. Only proximal tubular epithelial cells (PTEC) expressing HLA-A31 (an antigen present in the donor but absent in the recipient) were recognized by all clones. There were, however, three clones that did not lyse all HLA-A31+ PTEC lines, demonstrating recognition of an HLA-A31 tissue-associated polymorphism. Thus during rejection episodes after renal transplantation GIC may recognize various tissue-derived peptides bound to a mismatched HLA molecule on the cell surface of renal parenchymal cells. These GIC are likely to contribute to the observed destruction of tubuli during episodes of acute rejection after kidney transplantation.

Adult↗
PubMed1993

Relation between skin cancer, humoral responses to human papillomaviruses, and HLA class II molecules in renal transplant recipients.

Human papillomaviruses (HPV), especially the epidermodysplasia verruciformis (EV)-associated HPV 5, 8, 14, 17, 20, and 47, are thought to play a role in the pathogenesis of some skin cancers in recipients of renal allografts. MHC class I and class II genes are involved in the cellular immune response to viral and tumor Ag. Little is known about humoral responses to HPV in recipients with and without skin cancer. We investigated the prevalence of antibodies to the early (E) protein E7 and the major capsid late (L) protein L1 of HPV 8. In addition, we studied the association of HLA class II molecules with these antibody responses. The E7 and L1 open reading frames of HPV 8 were bacterially expressed as beta-galactosidase fusion proteins, which were purified by preparative gel electrophoresis. Serum samples from 36 renal transplant recipients with and 91 recipients without skin cancer were screened for the presence of IgG and IgM antibodies to HPV 8 E7 and L1, by Western blot analysis. The detection of anti-HPV 8 L1 antibodies represents the immune response to HPV 8 and possibly other EV-associated HPV, because cross-reactivity between the representatives of this HPV subgenus can occur. The antibody responses to HLA Ag were used as controls. Recipients who had IgM antibodies but no IgG antibodies to L1 of HPV 8 (patients with no apparent class switch from IgM to IgG) had skin cancer in 50% of cases, whereas recipients who produced IgG antibodies (patients with an apparently good humoral response to L1 of HPV 8) had skin cancer in only 18% of cases. The estimated relative risk of skin cancer in recipients with no class switch, compared with the risk in those with a good humoral response, was 4.5 (95% confidence interval, 1.1 to 18.1). We found no association between the antibody response to HLA Ag and the occurrence of skin cancer. A strong linkage between the absent class switch of antibody production in response to L1 of HPV 8 and HLA-DR7 was observed (relative risk, 26.2). Renal transplant recipients who have no apparent class switch from IgM to IgG production in response to Ag encoded by L1 of HPV 8 or possibly other EV-associated HPV are at an increased risk of skin cancer. The association with HLA-DR7 indicates a genetic control of skin cancer development or regression, involving genes in the class II region of the MHC.

Amino Acid Sequence↗
PubMed1993

Influence of non-inherited maternal HLA antigens on occurrence of rheumatoid arthritis.

Many HLA-associated diseases occur in patients not carrying the putative predisposing antigen. The suggestion that this might be due to disease heterogeneity is not sufficiently supported by available data. We hypothesise that HLA-DR4-associated genetic susceptibility to rheumatoid arthritis is due to an effect of DR4 on T-cell receptor repertoire expression and that the presence of antigen in the mother is capable of producing this effect in her children, even when DR4 is not inherited by them. To investigate this possibility we HLA typed 94 rheumatoid arthritis patients and their parents and 86 control families. An increased frequency, compared with controls, of non-inherited maternal HLA-DR4 was found predominantly in the mothers of DR4-negative patients. Unexpectedly, we also found an increased frequency of non-inherited maternal HLA-DR6 and a decreased frequency of non-inherited maternal HLA-DR3 in the mothers of DR4-positive patients. The results of our analyses are consistent with our hypothesis.

Arthritis, Rheumatoid↗