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Biomedical subjects

F H Claas

Publications and source records attributed to F H Claas.

At least 19 recordsLinked to original sources
PubMed2001

Immunomodulation by intrathymic injection of donor leukocytes in rhesus monkeys.

BACKGROUND: Several studies have demonstrated that intrathymic injection of donor cells into adult rodents can result in long-term allograft survival. The rationale for using the intrathymic route of donor cell administration is that in the thymic environment immature T cells are educated to discriminate between self and non-self antigens. The validity of this approach was tested in non-human primates. METHODS: The effect of the intrathymic injection of allogeneic donor cells was investigated in rhesus monkeys and compared with IV and intracutaneous administration of donor cells. Intrathymic injections were carried out without and with antithymocyte globulin. All animals received subsequently an allogeneic skin graft of the same donor and no immunosuppression post transplantation. RESULTS: Skin graft survival was slightly shorter in animals treated with IC donor cell injections (mean survival time [MST]=8.9+/-0.52) than untreated control animals (MST=10.0+/-0.44), indicating that this route caused sensitisation. Intravenous donor cell injection showed prolongation of graft survival times (MST=11.6+/-1.69). Intrathymic donor cell injection resulted in a graft survival of 9.2+/-1.44 days although addition of antithymocyte globulin slightly prolonged graft survival to 10.3+/-2.84 (not significant). Whereas the cellular responses after intrathymic and intravenous donor cell injections increased, antithymocyte globulin treated animals did not show an increased cellular response. Recipients of intrathymic donor cells showed a significantly decreased humoral anti-donor response as compared to other groups. CONCLUSIONS: Donor cell pretreatment alters the subsequent response to an allogeneic skin graft in monkeys and is dependent on the route of donor cell administration. This is also reflected in the alloantibody response and the in vitro cellular reactivity. Intrathymic administration of donor cells does not lead to prolonged skin graft acceptance.

Animals↗
PubMed2001

Pretransplant donor-specific helper T cell reactivity as a tool for tailoring the individual need for immunosuppression.

BACKGROUND: A reliable immunological assay for quantification of donor-specific alloreactivity to identify patients at risk for future allograft rejection would be a helpful tool in organ transplantation. Therefore, we questioned whether the T cell reactivity in patients measured before transplantation was predictive for the occurrence of acute rejection during the first year after kidney transplantation. METHODS: The pretransplant T cell reactivity of peripheral blood mononuclear cells to donor and third-party antigens was tested in mixed lymphocyte cultures, and to tetanus toxoid. In addition, we measured the frequency of donor and third-party reactive helper T lymphocyte precursor and cytotoxic T lymphocyte precursors using limiting dilution analysis. RESULTS: Patients who experienced acute rejection had significantly higher donor-specific mixed lymphocyte cultures responses (n=38; median stimulation index): 113 vs. 15, P=0.005) and helper T lymphocyte precursor frequency (n=37; median 194/106 vs. 62/106, P=0.009) measured before transplantation compared to patients without acute rejection. All patients with a low mixed lymphocyte culture response (stimulation index</=20; 13/13 vs. 12/25, P=0.001) and an undetectable helper T lymphocyte precursor frequency (<10/106 peripheral blood mononuclear cells; 7/7 vs. 17/30, P=0.04) before transplantation did not experience acute rejection. The donor-specific cytotoxic T lymphocyte precursor frequency (n=34; median 53/106 vs. 28/106, P=0.58) and tetanus toxoid-reactivity (n=38; median stimulation index: 53 vs.16, P=0.56) measured before transplantation did not correlate with acute rejection. No correlation between third-party reactivity and acute rejection was observed. CONCLUSIONS: From these results we conclude that despite the current HLA matching criteria, undetectable helper T lymphocyte precursor frequency and low mixed lymphocyte culture responses against donor antigens measured before transplantation are predictive for a rejection-free first posttransplant year. These in vitro assays can be used to identify patients who require less immunosuppression after transplantation.

Acute Disease↗
PubMed2001

Differential inhibitory effects of intravenous immunoglobulin preparations on HLA-alloantibodies in vitro.

BACKGROUND: Treatment of allosensitized patients with intravenously administered pooled immunoglobulin preparations (IVIG) may lead to a long-lasting reduction of anti-HLA alloantibody titers. An inhibitory response of IVIG preparations on lymphocytotoxicity is suggested to depend on IgG and to predict a successful reduction of anti-HLA alloantibodies upon the administration of high-dose IVIG in vivo. METHODS: In this study, we evaluated different IVIG preparations for their in vitro inhibitory capacity on lymphocytotoxicity and binding of anti-HLA alloantibodies to purified HLA antigens. For that purpose sera from 24 highly sensitized patients awaiting kidney transplantation and serological HLA testing reagents were used. Panel-reactive antibody (PRA) determinations using standard complement-dependent cytotoxicity testing and anti-HLA alloantibody determination by ELISA were carried out in the presence and absence of 50% (v/v) IVIG. RESULTS: The addition of IgG-containing IVIG preparations gave only a moderate inhibitory response judging from the average decrease of PRA levels (absolute DeltaPRA range: -2% to 16%), whereas the largest inhibition of lymphocytotoxicity was seen after the addition of IgM/IgA-containing IVIG preparations (absolute DeltaPRA range: 19% to 44%). For both IgG and IgM/IgA-containing IVIG preparations, the reduction of lymphocytotoxicity occurred in a dose-dependent fashion without a preference for particular anti-HLA class I antibody specificities. Significantly lower inhibitory effects on anti-HLA antibody reactivity were observed when the effects of IVIG preparations were monitored by ELISA (absolute DeltaPRA range: 7% to 22%). CONCLUSIONS: Our data suggest that the immunomodulatory capacity is largely caused by the IgM/IgA fraction of IVIG when analyzed by lymphocytotoxicity. The different effect on ELISA versus complement-dependent cytotoxicity testing suggests that interactions of IVIG with complement rather than anti-idiotypic antibodies may contribute to the inhibitory effects of IVIG in vitro.

Adjuvants, Immunologic↗
PubMed2001

Rejection of a kidney transplant does not always lead to priming of cytotoxic T cells against mismatched donor HLA class I antigens.

BACKGROUND: Previous studies showed that graft rejection is often associated with the presence of primed cytotoxic T cells (CTLs) with a high avidity for donor cells. Similar high avidity CTLs have been found in individuals who have formed IgG anti-HLA antibodies. The presence of such CTLs to a specific HLA mismatch is therefore considered to be a reflection of an activated immune system, and a contraindication for retransplantation with a donor sharing this particular HLA class I mismatch. METHODS: In our study we investigated whether patients have always primed CTLs against all individual HLA class I mismatches present on a rejected graft. Therefore, 14 patients who had undergone transplantectomy after irreversible kidney graft rejection were analyzed with respect to donor-specific CTLp frequencies and the presence or absence of high avidity CTLs directed against HLA class I mismatches present on the rejected graft. RESULTS: Patients, who have not formed anti-HLA antibodies against the donor have mainly naive CTLs. Most of the patients, that have developed IgG anti-HLA antibodies against a donor mismatch, have primed CTLs directed against that particular mismatch. However, patients with IgM anti-HLA antibodies only, and patients with IgG anti-HLA antibodies in historical sera but no IgG anti-HLA antibodies in current sera, have mainly naive CTLs against the donor HLA mismatch. CONCLUSION: Our results suggest that it is not always necessary to exclude repeated HLA class I mismatches for a subsequent transplantation. In addition to good anti-HLA antibody screening, the CTLp-assay may be a useful tool for donor-selection in retransplant candidates.

Antibodies↗
PubMed2001

Pregnancy can induce long-persisting primed CTLs specific for inherited paternal HLA antigens.

Previous studies showed that pregnancy can prime the maternal cellular immune response directed against paternal HLA antigens. Primed CTLs specific for inherited paternal HLA antigens (IPA) were found in women who had formed HLA allo antibodies, whereas naive CTLs were present in women who did not form antibodies against the paternal HLA antigens. As HLA allo antibodies may disappear in time, it is not clear which women on the waiting list for transplantation have been sensitized to paternal HLA antigens and are at risk for graft rejection if paternal HLA antigens are shared by the donor organ. The presence of primed CTLs specific for a particular antigen is considered to be a reflection of sensitization.In the present study we investigated whether these primed CTLs persist in women who had been pregnant and had formed antibodies against the inherited paternal HLA class I antigens. For this purpose 14 women who had their last pregnancy 10 years ago were analyzed with respect to IPA-specific CTLp frequencies and the presence of high avidity CTLs directed against inherited paternal HLA class I antigens. Although primed CTLs specific for IPA's were found more frequently in women with persisting alloantibodies, they still can be detected when the antibodies have disappeared. The current data show that primed CTLs directed against inherited paternal HLA antigens towards which antibodies have been formed in the past can persist for more than 10 years after pregnancy. The cellular test used in our study can be useful to detect presensitization in women with a history of pregnancy, who enter the waiting list for transplantation.

Female↗
PubMed2001

Ultraviolet-B radiation induces modulation of antigen presentation of herpes simplex virus by human epidermal cells.

Although ultraviolet (UV) B radiation is known to be immunosuppressive, there is little information regarding a relevant immunological endpoint to assess human subjects in vivo. Therefore, we have examined the effect of in vivo UV radiation on the ability of human epidermal cells (EC) to present herpes simplex virus (HSV) antigens to memory T cells. Human volunteers, who were seropositive for HSV, were exposed to one minimal erythemal dose (MED) for four consecutive days. EC, prepared from suction blister roofs, were co-cultured with autologous T cells in the presence of HSV. HSV antigen presentation by UV-exposed EC was increased compared with control, nonexposed EC. This up-regulation correlated with an influx of macrophages into the epidermis, which are considered to be associated with UV-induced tolerance. Altering the UV protocol to a sub-erythemal UV dose for four consecutive days or to a single high dose of 2 MED, resulted in suppressed HSV antigen presentation, without the influx of the UV-macrophages. One of the goals of the present study was to eventually use this HSV system to investigate sunscreen immunoprotection. A pilot study with a TiO2-containing sunscreen suggested that the endpoint for UV-induced immunosuppression presented here is promising to be used for human in vivo sunscreen immunoprotection studies.

Adult↗
PubMed2001

Permissible and immunogenic HLA-A mismatches: cytotoxic T-cell precursor frequencies reflect graft survival data.

Analysis of the in vivo immunogenicity of single HLA mismatches, in the context of a patient's own human leukocyte antigen (HLA) phenotype, has been used to define permissible and immunogenic HLA mismatches. Kidney graft survival in the case of permissible mismatches was similar to that of completely HLA matched combinations, whereas immunogenic mismatches lead to a significantly poorer graft survival. The present study tested whether such permissible and immunogenic HLA mismatches are reflected in the in vitro cytotoxic T-lymphocyte (CTL) allorepertoire. Limiting dilution experiments were performed to analyze the number of precursor CTL directed against individual HLA class I antigens. In general, the frequency of CTLp directed against permissible HLA-A antigens (n = 70, mean frequency 27 CTLp per million peripheral blood lymphocytes [PBL]) was found to be significantly lower compared with the CTLp directed against immunogenic HLA-A antigens (n = 73, mean frequency 59 CTLp per million PBL). The difference was found both in healthy individuals and a population of renal transplant candidates. These results were confirmed by a retrospective analysis of CTLp frequencies performed between partly mismatched unrelated bone marrow donors and their potential recipients. In conclusion, on the population level the permissible and immunogenic HLA-A mismatches are indeed reflected in the CTL allorepertoire. However, due to the big overlap of the CTLp frequencies in these populations, the permissible or immunogenic nature of a mismatch for a particular patient should be determined on an individual basis.

Cells, Cultured↗
PubMed2001

Modulation of the alloimmune response by blood transfusions.

Blood transfusions can induce both immune activation and immunosuppression. The former is expressed by the induction of HLA alloantibodies and T cell activation, while the latter is accompanied by enhanced graft survival in transfused versus non-transfused recipients. The immunological mechanism leading to downregulation of the alloimmune response has not yet been elucidated. Possible explanations include the induction of a Th2 response by non-professional antigen presentation by the transfused blood cells and blockage of alloreactive T cell reactivity by soluble HLA and soluble FasL in the supernatant of blood components. These mechanisms, however, do not explain the observations which have shown that the degree of HLA compatibility between the transfusion donor and patient is a determining factor. Transfusions in which the donor blood shares at least one HLA-DR antigen with the recipient induce tolerance, while fully HLA-DR mismatched transfusions lead to immunization. The importance of HLA-DR sharing suggests a central role for CD4+ regulatory T cells. In this case, indirect recognition of an allopeptide in the context of self-HLA-DR on the transfusion donor by CD4+ T cells of the recipient might be the clue to the induction of tolerance. Recent data from our laboratory in fact show that CD4+ T cells specific for an allopeptide in the context of self HLA-DR are able to downregulate the alloimmune response of autologous T cells. As these regulatory T cells produce IL-10, they may also be involved in the extension of tolerance via their modulatory effect on dendritic cells. It remains to be established whether these regulatory T cells are indeed responsible for the 'blood transfusion effect' in organ transplantation.

Blood Transfusion↗
PubMed2001

Protective and susceptible HLA polymorphisms in IgA nephropathy patients with end-stage renal failure.

Idiopathic immunoglobulin A (IgA) nephropathy is characterised by an extreme variability in clinical course, leading to end-stage renal failure in 15-20% of adults. This subgroup of patients with IgA nephropathy is usually included in the waiting lists of organ exchange organisations. The frequency of HLA-A,B,DR antigens of this subset of IgA nephropathy patients was calculated and compared to controls. The antigens HLA-B35 and DR5 were significantly increased in the patients with relative risk values of 1.385 and 1.487, respectively. The antigens HLA-B7, B8, DR2, and DR3 were found in a significantly lower frequency in the patients as compared to the controls. The relative risk (RR) values ranged between 0.695 and 0.727. Consequently, the haplotypes HLA-A1, B8, DR3, HLA-A3, B7, DR2, HLA-A2, B7, DR2 together with HLA-A1, B15, DR4, HLA-A9, B12, DR7, and HLA-A10, B18, DR2 were found to be protective with RR values ranging from 0.309 to 0.587. The only susceptible haplotype observed was HLA-A2-B5, DR5 (RR=2.990).

Gene Frequency↗
PubMed2001

Determination of the frequency of HLA antibody secreting B-lymphocytes in alloantigen sensitized individuals.

Sera from prospective transplant patients are usually screened for HLA antibodies prior to transplantation, but presently available tests do not permit quantification of the humoral alloantigen directed response. We adapted a culture system for isolated human B-lymphocytes to assay the secretion of HLA-antibodies on a single cell basis. B-cell supernatants were screened for HLA antibodies by complement dependent cytotoxicity. The assay assigns precursor frequencies for HLA-alloantibody secreting B-lymphocytes (BCPFs), and simultaneously allows for dissection of the humoral alloantigen directed response into its monoclonal components. The lymphocytes of 15 HLA-seropositive multiparous women that were used to validate the assay, were found to contain HLA-BCPFs ranging from 0 to 123 per 10(6) B-lymphocytes (mean: 43 +/- 45 per 10(6) B-lymphocytes). The HLA-specificities of antibodies in the B-cell supernatants were in agreement with serum specificities. Genuine HLA reactivity of B-cell supernatants was confirmed using an ELISA with purified HLA class I antigens. When applied to lymphocytes of patients on transplant waiting lists, the present assay may enable the unraveling of serum specificities in their components, thus supplementing HLA antibody serum screening data.

Antibody Specificity↗
PubMed2000

Beneficial effect of HLA-DR matching on the survival of corneal allografts.

BACKGROUND: Although HLA typing and matching have been used for 3 decades, that practice has been poorly implemented in corneal transplantation, mainly because of inconclusive or contradictory analytical results. Consequently, we studied the immune response of corneal transplant recipients to HLA histoincompatibilities in a large homogeneous study. METHODS: All corneal transplantations performed by a single surgeon between 1976 and 1996 were studied. HLA-AB matching was used for recipient selection. All HLA typings were performed by a single experienced laboratory. Population genetic techniques were used to assess the validity of the HLA typings. Mono- and multivariate analyses were performed to identify the factors which significantly influence the survival of corneal allografts. Simulation studies were carried out to demonstrate the effects of mis-typed donor and recipient HLA-DR typings on analytical results. RESULTS: Retransplantation, degree of vascularization, HLA-AB and DR matching, endothelial cell count, graft size, recipient gender, and storage method were identified as significant factors by our monovariate analyses. A Cox proportional hazards survival analysis model identified degree of vascularization and HLA-AB and DR matching as significant prognostic factors when all immunological rejection episodes were used, P=0.000001. When only irreversible immunological rejection episodes were used, panel reactive antibodies, retransplantation, and number of rejection events were also identified, P=0.000001. Simulation studies showed that the effects of HLA-DR matching are abrogated by poor HLA-DR typings. CONCLUSIONS: Corneal allograft recipients have a normal alloimmune response to histoincompatibilities. Demonstration of that fact requires accurate HLA typings.

Adolescent↗
PubMed2000

Permanent detrimental effect of nonimmunological factors on long-term renal graft survival: a parsimonious model of time-dependency.

PURPOSE: We attempted to model and test the pattern of effects of prognostic factors on renal graft survival during the posttransplantation time course. PATIENTS AND METHODS: Patients who received a cadaveric kidney-only transplant between January 1990 and December 1995 in Eurotransplant, who received cyclosporine as induction therapy, and who had a complete follow-up at the time of analysis were included in the study (n= 10614). An index summarizing all covariate information was calculated and used for modeling the time-dependent effects with relation to graft failure. RESULTS: The immunological factors (HLA mismatch and % panel-reactive antibody) were seen to have a slowly decreasing negative effect on renal graft survival. The cold ischemic trauma (>24 hr) exerted a permanent detrimental effect on the grafts. The use of organs obtained from old donors was associated with a constant higher risk of graft loss. CONCLUSIONS: An analysis of determinants of human allograft dysfunction should also study the interaction between the effects and time. Nonimmunological factors had a constant detrimental effect on graft failure, whereas the impact of the immunological factors--although remaining important for late graft loss--very slowly decreased. In the context of marginal transplants, clustering of unfavorable factors should be avoided to prevent late graft losses.

Adolescent↗
PubMed2000

Cross-reactive group matching does not lead to a better allocation and survival of donor kidneys.

BACKGROUND: In cadaveric renal transplantation HLA-A, -B, -DR matching of donor and recipient is beneficial for graft survival. However, allocation based on HLA matching seems to favor recipients with more frequently occurring HLA antigens. In this study we investigated whether matching on the basis of cross-reactive groups (CREGs), defined according to the United Network for Organ Sharing (UNOS), would be a good alternative for the allocation of kidneys without negatively influencing graft survival. Theoretically, this approach would provide more recipients with an immunologically well-matched donor organ. METHODS: The influence of CREG matching on graft survival was studied in univariate analyses using the Eurotransplant database. RESULTS: No beneficial effect of CREG matching was observed, whereas a significant HLA matching effect was observed in the 0 CREG mismatched donor/ recipient combinations. Only in the small subgroup with 1 MM for HLA-A, -B and 0 MM for HLA-DR, a significantly better survival was observed, when this mismatch belonged to the 0 or 1 MM CREG group versus two or more MM CREG group. However, this subgroup concerns only 8% of the transplants performed. CONCLUSIONS: In contrast to other reports, our study showed that HLA matching is by far more beneficial than CREG matching. In the homogenous Eurotransplant population, adjusting the matching criteria toward CREG matching would not lead to an improved graft survival.

Cross Reactions↗
PubMed2000

Survival of donor cells 25 years after intrauterine transfusion.

Persistence of donor leukocytes in the circulation of recipients of intrauterine transfusion (IUT) has been observed up to 5 years after birth. The aim of this study was to determine whether transfusions with nonirradiated, nonleukocyte-depleted donor blood during the fetal period resulted in long-term immunomodulation of the recipient. Twenty-four surviving IUT recipients between 1966 and 1976 were tested for autoimmune disease and autoantibodies at follow-up. Ten had sex-mismatched donors and were therefore informative for chimerism studies using fluorescence in situ hybridization (FISH). Seven female recipients could be tested for chimerism using a Y- chromosome-specific polymerase chain reaction (PCR) because they received at least 1 IUT from a male donor. Nine recipients could be studied for cytotoxic T-lymphocyte precursor (CTLp) and helper T-lymphocyte precursor (HTLp) frequencies because the original donors were available for testing. All surviving IUT recipients were in good health at the time of the examination, and routine laboratory testing revealed no abnormalities. None of the IUT recipients were chimeric as determined by FISH analysis, but Y-chromosome-specific sequences were detected by PCR in 6 of the 7 women. However, the CTLp and HTLp frequencies of the IUT recipients against the donors were comparable to those of the controls. The current study provides evidence that IUT can result in the persistence of donor cells in the recipient for a period longer than 20 years but that it is not associated with immunotolerance or with signs of chronic antigenic stimulation. (Blood. 2000;95:2709-2714)

Anemia, Hemolytic, Congenital↗
PubMed2000

High frequency of allele-specific down-regulation of HLA class I expression in uveal melanoma cell lines.

Uveal melanoma is the most common primary intra-ocular tumor in adults and has a high mortality rate due to liver metastases, for which no effective treatment is available. To investigate whether immunotherapy might be feasible in uveal melanoma, the HLA class I surface expression of 6 uveal melanoma cell lines was analyzed by flow cytometry using a broad panel of allele-specific monoclonal antibodies. To up-regulate HLA expression, cells were also cultured with IFN-alpha or -gamma. In general, expression of HLA-A alleles was high (except for cell line EOM-3) and could be further up-regulated by both IFN-alpha and -gamma. In cell line EOM-3, IFN-gamma treatment resulted in significant HLA-A expression while IFN-alpha treatment did not. Expression of HLA-B alleles was low or even negative. Variable effects were observed after IFN treatment. In 3 cell lines, expression of some HLA-B alleles could not be induced by IFN-alpha or -gamma: HLA-B44 in cell line 92-1, HLA-B15 in cell line OCM-1 and HLA-B5 in cell line MEL-202. The other B alleles of these cell lines showed enhanced expression levels upon IFN stimulation. In OMM-1 cells, IFN-alpha and -gamma increased the expression of HLA-A but did not induce expression of the 2 B alleles, indicating an HLA-B locus-specific loss. We thus found a high frequency of allele-specific and locus-specific down-regulation of HLA expression in uveal melanoma cell lines. Some of these defects were not restored by IFN-alpha or -gamma treatment. The lack of HLA expression may explain why uveal melanoma cells escape immune surveillance by cytotoxic T cells and complicate the development of immunotherapy in uveal melanoma.

Adult↗
PubMed2000

Determination of acceptable HLA mismatches in highly sensitized patients by soluble HLA class I ELISA inhibition.

BACKGROUND: Acceptable HLA mismatches for highly sensitized patients are determined so as to increase their chances of receiving transplants. The disadvantage of the current procedures is that the antibody reactivity of the patients' sera is tested against HLA antigens expressed on cells or HLA antigens isolated from cell lysates. Therefore, two (homozygous for HLA-A and -B) to four (heterozygous for HLA-A and -B) different HLA class I antigens are present in the test. This might cause reactivity toward nonacceptable mismatches to mask the determination of acceptable mismatches. METHODS: Recently we observed that the detection of soluble HLA class I antigens is inhibited by HLA-specific antibodies. In the present study, inhibition of soluble HLA-specific ELISAs (anti-soluble HLA-A2, -B7, -B12) was evaluated as a tool used to determine acceptable mismatches. The results were compared with current determination of acceptable mismatches (which is by complement-dependent cytotoxicity and/or fluorescence-activated cell sorter analysis). RESULTS: In the case of acceptable mismatches determined by conventional methods, sera from the patients were not interfering in these ELISAs, whereas in the case of nonacceptable mismatches (thus specific antibodies), significant inhibition was observed in most instances. Among the nonacceptable mismatches, the test showed significant inhibition in 20 of 24 cases, whereas among acceptable mismatches, no inhibition was observed (in eight of eight), indicating the lack of specific antibodies. CONCLUSIONS: In highly sensitized patients, the introduction of soluble HLA-specific ELISAs is of additional and confirmatory value for the determination of acceptable mismatches. The major advantage of this approach is that antibody reactivity is tested against single antigens only.

Antibodies↗