A positive crossmatch and treatment with IvIg.
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HLA Antigens↗
Biomedical subjects
Gerhard Opelz
Publications and source records attributed to Gerhard Opelz.
Longitudinal analysis of T-helper cell phenotypes in renal-transplant recipients undergoing growth hormone therapy.
BACKGROUND: Treatment with recombinant human growth hormone (rhGH) in growth-retarded children after renal transplantation is effective, but there have been concerns regarding the safety of rhGH because of its possible immunomodulatory actions. We therefore evaluated the immune phenotypes of pediatric renal-transplant recipients and controls in response to rhGH with regard to a possible shift toward a T-helper (TH)1-type response. METHODS: Intracellular cytokines, activation markers, costimulatory, and adhesion molecules were studied in 13 children after renal transplantation (Tx+GH). Children with chronic renal failure (CRF+GH, n=11) before and under rhGH therapy and pediatric renal-transplant recipients without rhGH therapy (Tx, n=33) served as controls. Measurements were performed by four-color flow cytometry before and 4, 12, 18 and 24 weeks after initiation of rhGH therapy. RESULTS: Under baseline conditions, Tx+GH patients did not differ from Tx patients. During rhGH therapy in children with transplants, interleukin (IL)-2 production increased threefold at 4 weeks, and IL-4 and IL-13 increased by 70% at 12 weeks. All three cytokines returned to baseline after 18 weeks. No patient experienced rejection. In CRF+GH patients, baseline values for all investigated cytokines were higher than in patients with transplants but did not change in response to rhGH therapy. CONCLUSION: Our data indicates that rhGH therapy in stable, pediatric renal-transplant recipients has a mild and transient immunostimulatory effect in vivo. Immunosuppression and graft function in patients with transplants undergoing rhGH treatment should therefore carefully be monitored.
Adolescent↗
Regulation of human auto- and alloreactive T cells by indoleamine 2,3-dioxygenase (IDO)-producing dendritic cells: too much ado about IDO?
Although dendritic cells (DCs) strongly stimulate the immune response, they can also induce unresponsiveness. Recently, a human monocyte-derived DC subpopulation was described that constitutively expresses indoleamine 2,3-dioxygenase (IDO). These DCs were defined as nonadherent CD123+/CC chemokine receptor 6+ (CCR6+) cells that suppress the allogeneic T-cell response. In the present study, we generated nonadherent, mature DCs from human blood monocytes. As expected, in addition to the classic markers, these cells expressed CD123 and CCR6. Reverse transcription-polymerase chain reaction (RT-PCR), however, did not show IDO gene transcription, nor did we detect enzymatic IDO activity. Treating the cells with interferon-gamma (IFN-gamma) resulted in significant IDO production. Subsequently, we studied the regulatory properties of IDO-producing DCs on autologous and allogeneic T-cell responses. Neither OKT3-stimulated T cells of healthy donors nor myelin basic protein (MBP)-specific T cells of patients with multiple sclerosis (MS) were suppressed by autologous IDO DCs. However, whereas IDO(neg) DCs supported further stimulation of preactivated MBP-specific T cells of an MS patient, IDO(pos) DCs had lost this capacity. The allogeneic T-cell response was only marginally suppressed by IDO DCs. Our findings show that nonadherent CD123+/CCR6+ human DCs do not constitutively express IDO, and, even if they express the enzyme after IFN-gamma treatment, they possess only limited T-cell regulatory function.
Antineoplastic Agents↗
Immunological relevance of CREG matching in cadaver kidney transplantation.
BACKGROUND: On the basis of cross-reactive antibodies that react with different human leukocyte antigens (HLA) with shared epitopes, HLA-A and -B antigens can be assigned to cross-reactive groups (CREG). In the context of renal transplantation, it has been reported that matching for CREG results in improved graft outcome and reduces the requirement for rejection treatment. Because CREG matching also improves the equity of kidney distribution to ethnic minorities, a CREG-based cadaver kidney allocation policy was introduced in the United States a few years ago. METHODS: The authors reexamined the immunologic relevance of matching according to CREG using the data of the international Collaborative Transplant Study. A total of 91,917 patients who received a first cadaver kidney transplant between 1991 and 2002 formed the basis of this analysis. RESULTS: The authors found that the underlying impact of matching for HLA antigens accounts entirely for the observed positive effect of CREG matching. For patients with a particular HLA antigen match grade, matching for CREG had no advantageous effect on graft outcome or rejection treatment. An immunologic basis for CREG matching could thus not be found in this large analysis of cadaver kidney transplants. CONCLUSIONS: The findings indicate that CREG matching for kidney allocation is conceptually flawed from an immunologic viewpoint.
Cadaver↗
Generation of tolerogenic dendritic cells by treatment with mitomycin C: inhibition of allogeneic T-cell response is mediated by downregulation of ICAM-1, CD80, and CD86.
BACKGROUND: Deliberately generated tolerogenic dendritic cells (DC) might be a useful tool for induction of donor-specific tolerance in transplantation. In this article, the authors study the effect of mitomycin C (MMC)-treated DC on rat T cells and delineate the mechanism of their conversion into tolerogenic cells. METHODS: The influence of MMC treatment on the capacity of DC to activate allogeneic T cells was tested in vitro, and the expression of cell surface molecules was studied by flow cytometry. RESULTS: MMC-treated DC lose their allostimulatory capacity, and this cannot be attributed to cell death or release of MMC. Interestingly, suppressed T cells cannot be restimulated, indicating that MMC-treated DC induce tolerance. MMC treatment selectively decreases adhesion (intercellular adhesion molecule [ICAM]-1) and co-stimulatory (CD80, CD86) molecules. Functional blocking of these molecules with specific antibodies confers to DC the same T-cell-suppressive properties as treatment with MMC. CONCLUSIONS: MMC treatment converts rat DC into tolerogenic cells. This mechanism is mediated by decrease of ICAM-1, CD80, and CD86.
Alkylating Agents↗
Serial peripheral blood interleukin-18 and perforin gene expression measurements for prediction of acute kidney graft rejection.
BACKGROUND: We and others have shown that expression of the cytotoxic T-lymphocyte effector gene perforin in the peripheral blood is a strong predictor of acute rejection in the early posttransplant period. In the present study we investigated whether interleukin (IL)-18, an immunostimulatory gene that up-regulates perforin-dependent cytotoxicity and promotes tissue damage through other noncytotoxic T-lymphocyte mechanisms alone or in combination with perforin gene expression, may serve as a better predictor of renal allograft rejection in the first weeks after transplantation. METHODS: Peripheral blood was collected twice weekly, and gene expression was measured using real-time polymerase chain reaction. RESULTS: Recipients with acute rejection (n = 17) showed higher levels of perforin and IL-18 transcript on days 5 to 7, 8 to 10, and 11 to 13, compared with patients without rejection (n = 37, P < 0.01 in all cases). Rejection diagnosis using gene expression criteria was possible 1 to 32 days before traditional diagnosis (median 11 days). High specificity was associated with IL-18 expression (72%-93%), and high sensitivity was associated with perforin expression (63%-90%). Positive predictive value was optimized (78%-100%) by using combined up-regulation in both genes as a diagnostic criterion (double-positive). Using high expression in "either or both" genes as a diagnostic criterion yielded high sensitivity (82%-91%) and negative predictive value (91%-96%). CONCLUSIONS: Our data indicate that combined perforin and IL-18 gene expression measurements are useful tools for the recognition of graft rejection in its earliest stages. Serial measurements could be implemented as a monitoring system to identify patients at higher risk of rejection, making them candidates for biopsy or prophylactic increases in immunosuppression.
Acute Disease↗
Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation.
Immunosuppression after organ transplantation is an acknowledged risk factor for skin cancer and lymphoma. We examined whether there was also an excess of leukemia in patients after transplantation and whether this might be related to a particular immunosuppressive treatment. Data from more than 170 000 patients indicated that organ transplantation is associated with a significantly increased risk for acute myeloid leukemia (AML). AML was more frequent after heart transplantation and lung transplantation than after kidney transplantation and was associated with immunosuppression by azathioprine, a thiopurine prodrug. Cellular resistance to thiopurines is associated with DNA mismatch repair (MMR) deficiency. We demonstrate that thiopurine treatment of human cells in vitro selects variants with defective MMR. Consistent with a similar selection in patient bone marrow, in 7 of 7 patients, transplant-related AML/myelodysplastic syndrome (MDS) exhibited the microsatellite instability (MSI) that is diagnostic for defective MMR. Because MSI occurs infrequently in de novo AML, we conclude that the selective proliferation of MMR-defective, azathioprine-resistant myeloid cells may contribute significantly to the development of AML/MDS in patients who have received organ transplants. Identifying azathioprine as a risk factor for AML/MDS suggests that discontinuing the use of azathioprine as an immunosuppressant might reduce the incidence of posttransplantation AML/MDS.
Acute Disease↗
Critical evaluation of the amino acid triplet-epitope matching concept in cadaver kidney transplantation.
BACKGROUND: A computer-based approach for determining human leukocyte antigen (HLA) compatibility between kidney donors and recipients on the basis of differences of amino acid sequences as motifs for immunogenic epitopes was proposed by Duquesnoy et al. The HLAMatchmaker algorithm focuses on HLA class I polymorphisms of serologically defined antigens encoded by the HLA-A and -B loci. HLA phenotypic mismatches that represent only a few mismatches at the amino acid triplet level are held to be not or only mildly immunogenic. This approach was proposed as being especially suitable for the allocation of donor kidneys to highly sensitized patients. METHODS: We reexamined this attractive concept using the data of the Collaborative Transplant Study. Intra- and interlocus comparisons for HLA-A and -B were performed according to the original HLAMatchmaker algorithm. To exclude the influence of HLA-DR, only transplants with no HLA-DR mismatch were considered. Patients who had one HLA-A and one HLA-B antigen mismatch were separated into subgroups, depending on the number of triplet mismatches as calculated by the HLAMatchmaker software. Separate analyses were performed for first transplants, retransplants, and patients with a panel-reactive antibody activity of 50% or more. A total of 16,997 white patients matched for HLA-DR who received a cadaver kidney transplant between 1991 and 2001 formed the basis of this analysis. RESULTS: Application of the HLAMatchmaker method could not be shown to result in any statistically significant effect on graft survival. CONCLUSIONS: The HLAMatchmaker concept is theoretically attractive; however, it could not be shown to yield useful results in this analysis. Serologic HLA typing appears to provide an insufficient basis for applying epitope matching in clinical kidney transplantation.
Algorithms↗
Dissociation of CD4(+) cell counts from viral load and association with immune complexes in HIV(+) hemophilia patients.
OBJECTIVE: We have postulated that the host autoimmune response regulates and mediates CD4 depletion during HIV infection by opsonization of circulating CD4(+) lymphocytes carrying autoreactive immune complexes (IC) consisting of complement-fixing IgM and IgG, and during advanced stages of HIV disease of IgM/ IgG/gp120 complexes. In this retrospective study, we investigated whether HIV causes CD4 depletion by direct cytotoxicity or indirectly by induction of a host autoimmune response. PATIENTS AND METHODS: In 1996, 12 HIV(+) hemophilia patients were converted to highly active antiretroviral therapy (HAART), while 10 other patients were maintained on conventional antiretroviral treatment and another 11 patients refused to be treated with antiretroviral drugs. The host immune response of these 33 HIV(+) patients was studied during the periods of minimum viral replication (Interval 1), subsequent rise in viral replication with strong replication dynamic (Interval 2), and maximum viral replication (Interval 3). The patients were categorized into three groups according to viral load (VL). Group A: patients with low level VL (n=10) showed a modest increase from <80 to <4 log 10 HIV-1 RNA copies per milliliter plasma during the observation period; Group B: patients with medium level VL (n=12) showed a stronger increase from <80 to >4 log 10 copies per milliliter plasma; and Group C: patients with high level VL (n=11) consistently had a median of >4 log 10 copies per milliliter plasma, during Intervals 1-3, with the exception of one patient who during Interval 2 had 4800 copies per milliliter. Blood lymphocyte subpopulations, proportions of CD4(+) blood lymphocytes coated with IgM, IgG, C3d and/or gp120, in vitro responses to mitogens and pooled allogeneic stimulator cells, as well as numbers of HIV-1 RNA copies per milliliter plasma were measured. RESULTS: Sequential analysis of VL, IC load on CD4(+) blood lymphocytes and CD4 counts showed that an increasing VL was not associated with CD4 depletion, when the proportion of IC-coated circulating CD4(+) blood lymphocytes remained stable. When, CD4 counts and IC load were analyzed during corresponding intervals of retroviral replication in the three patient groups, a higher VL was associated with lower CD4 counts only when the IC load (IgG or gp120/IgG) on CD4(+) lymphocytes was higher as well. CONCLUSION: These data suggest that HIV regulates and mediates CD4 depletion in part by the induction of autoreactive ICs against CD4(+) lymphocytes, especially complement-fixing autoreactive IgG and gp120/IgG complexes.
CD4 Antigens↗
Risks of allogeneic hand transplantation.
A patient undergoing allogeneic hand transplantation needs lifelong immunosuppression with the risk of serious side effects, including life-threatening disease. The question remains: does the eventual improvement in function justify the risk? To answer this question, we try to assess the risks based on a large body of cumulative data derived from more 200,000 kidney transplants using the Collaborative Transplantation Study (CTS). Only selective data which apply to a patient population aged between 15-40 years were used (n = 58,310). Data are compared to the literature references and show superiority with respect to patient numbers, statistics, actuality, and methodology. The CTS data show that the incidence of de novo malignancies is lower than previously reported. The risk of developing any form of cancer is approximately 3%, of developing a skin cancer 1.1%, and of developing a lymphoma 0.58% within 5 years after transplantation. The risk of suffering from a cataract is 11% after 5 years, which is also lower than previously reported. Although the incidence of side effects (particularly malignant disease) is likely to be lower than previously thought, the risk-benefit question must be answered by each hand surgeon for each individual patient.
Adolescent↗
Pathway of apoptosis induced in Jurkat T lymphoblasts by anti-HLA class I antibodies.
We demonstrated recently that human leukocyte antigen (HLA) class I human monoclonal antibodies (mAbs) are able to induce apoptosis of resting human lymphocytes as well as Jurkat lymphoblastic T cells. We now analyzed the signaling pathway involved in apoptosis mediated by human HLA class I allele-specific mAb OK2F3 and mouse monomorphic mAb W6/32. An inhibitor of a broad spectrum of caspases had only a moderate inhibiting effect, and an inhibitor of caspase 3 failed to inhibit HLA class I-mediated apoptosis. Although caspase 3 activation was not observed, internucleosomal DNA fragmentation was found in half of the apoptotic cells. Importantly, the mitochondrio-nuclear redistribution of apoptosis inducing factor (AIF), a caspase-independent mitochondrial death effector, was detected after 1 hour of treatment with human anti-HLA mAb and was associated with large-scale DNA fragmentation, whereas the release of cytochrome c, which is responsible for caspase-dependent internucleosomal fragmentation, followed AIF translocation and occurred after 2 hours. Our results indicate that apoptosis mediated through HLA class I molecules represents a unique mechanism of cell death in Jurkat T lymphoblasts that involves two parallel pathways, one caspase-independent and the other caspase-dependent. This study clarifies the precise mechanism of anti-HLA antibody-induced apoptosis which might have clinical implications.
Animals↗
Good kidney transplant outcome in recipients with presensitization against HLA class II but not HLA class I.
It is a matter of debate whether pretransplant anti-human leukocyte antigen (HLA) class II antibodies contribute to the increased graft rejection rate found in presensitized recipients. We investigated the influence of preformed anti-HLA class II antibodies on graft survival in 5949 cadaver kidney transplants. Pretransplant recipient sera were tested in enzyme-linked immunosorbent assay (ELISA) for immunoglobulin (Ig)G-anti-HLA class I and IgG-anti-HLA class II antibodies. A total of 672 recipients with antibodies against HLA class II but not against HLA class I had a 3-year graft survival rate of 80 +/- 2%, identical to the 80 +/- 1% rate in 4561 recipients who were negative for anti-HLA class I and II (p = NS). Graft survival was significantly lower in 365 recipients who were positive for both anti-HLA class I and II (65 +/- 3%, p < 0.0001). Compatibility for HLA-A+B+DR influenced graft survival significantly in anti-HLA class I- and II-positive recipients (p = 0.0016), whereas no significant HLA effect was found in patients with antibodies directed against only class I or II. Surprisingly, not even incompatibility for HLA class II antigens of the DR locus caused a significant impairment of graft survival in anti-class II-positive recipients. We conclude that the risk associated with sensitization against HLA class II in the absence of sensitization against HLA class I is negligible.
Antilymphocyte Serum↗
Lymphomas after solid organ transplantation: a collaborative transplant study report.
We used the Collaborative Transplant Study database to analyze the incidence, risk, and impact of malignant lymphomas in approximately 200,000 organ transplant recipients. Over a 10-year period, the risk in renal transplant recipients was 11.8-fold higher than that in a matched nontransplanted population (p<0.0001). The majority of lymphomas were diagnosed after the first post-transplant year. Heart-lung transplants showed the highest relative risk (RR 239.5) among different types of organ transplants. In kidney recipients, immunosuppression with cyclosporine did not confer added risk compared with azathioprine/steroid treatment, whereas treatment with FK506 increased the risk approximately twofold. Induction therapy with OKT3 or ATG, but not with anti-IL2 receptor antibodies, increased the risk of lymphoma during the first year. Antirejection therapy with OKT3 or ATG also increased the risk. First-year mortality in renal and heart transplant patients with lymphoma was approximately 40% and 50%, respectively, and showed no improvement in recent years. A pattern of preferential localization to the vicinity of the transplant was noted, and the prognosis of the patient was related to localization. This study highlights the continuing risk for lymphoma with time post-transplantation, the contribution of immunosuppression to increased risk, and continuing poor outcomes in patients with post-transplant lymphoma.
Adolescent↗
Malignancy in renal transplantation.
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Humans↗
Reduction of skeletal muscle injury in composite tissue allotransplantation by heat stress preconditioning.
Ischemia-reperfusion injury is a dominant factor limiting tissue survival in any microsurgical tissue transplantation, a fact that also applies to allogeneic hand transplantation. The clinical experience of the 12 human hand transplantations indicates that shorter ischemia times result in reduced tissue damage and, ultimately, in better hand function. Heat stress preconditioning and the accompanying up-regulation of the heat shock protein 72 have been shown to reduce the ischemia-reperfusion injury following ischemia of various organs, including organ transplantation. The aim of this study was to reduce the ischemia-reperfusion injury in a model of composite tissue allotransplantation. Allogeneic hind limb transplantations were performed from Lewis (donor) to Brown-Norway rats. Donor rats in group A (n = 10) received a prior heat shock whereas rats in group B (n = 10) did not receive any prior heat shock. Group C served as a control group without transplantation. The transplantations were performed 24 hours after the heat shock, at which time the heat shock protein 72 was shown to be up-regulated. The outcome was evaluated 24 hours after transplantation by nitroblue tetrazolium staining and wet-to-dry weight ratio of muscle slices (anterior tibial muscle). The nitroblue tetrazolium staining showed a significant reduction of necrotic muscle in group A (prior heat shock) (p = 0.005). The wet-to-dry ratio was significantly reduced in group A (prior heat shock), indicating less muscle edema and less tissue damage (p = 0.05). Heat shock preconditioning 24 hours before an ischemic event leads to an up-regulation of heat shock protein 72 in muscle and to a tissue protection reducing ischemia-reperfusion injury in composite tissue transplantation.
Animals↗
Cytomegalovirus prophylaxis and graft outcome in solid organ transplantation: a collaborative transplant study report.
We investigated relationships between cytomegalovirus (CMV) seropairing and CMV prophylaxis on graft outcome in recipients of solid organ transplants. Transplants carried out from 1985 to 2002 and reported to the Collaborative Transplant Study were analyzed. In cadaver kidney recipients, CMV prophylaxis was significantly associated with improved graft survival only in the seronegative-recipient/seropositive-donor combination (at 3 years: 79.4% with prophylaxis vs. 73.5% without prophylaxis; RR 0.80, p < 0.0001). Among patients who had a functioning graft at 1 year, significantly fewer patients who received CMV prophylaxis received rejection treatment in the preceding year (26.3%), compared with patients who did not receive prophylaxis (32.4%) (p = 0.0001), suggesting an inhibitory effect of CMV prophylaxis on acute rejection. Significant improvements in graft survival after CMV prophylaxis were found also in CMV-negative recipients of CMV-positive heart, and lung or heart-lung transplants, but not liver transplants. The age of the recipient had a differential effect on graft and patient survival after CMV prophylaxis. Use of antilymphocyte antibodies or mycophenolate mofetil was not associated with an enhanced CMV effect on graft outcome. These results may contribute to a better understanding of the influence of pretransplant CMV serology on the effect of CMV prophylaxis.
Adolescent↗
Relevance of IL10, TGFbeta1, TNFalpha, and IL4Ralpha gene polymorphisms in kidney transplantation: a collaborative transplant study report.
Single nucleotide polymorphisms (SNPs) of cytokine genes have been shown to influence cytokine plasma levels. Cytokines are important mediators during organ graft rejection. It was reported that certain cytokine genotypes are associated with improved kidney graft survival. In the present study, SNPs within the IL10 promoter gene, the first exon of the TGFbeta1 gene, the TNFalpha promoter gene, and the IL4Ralpha gene were analyzed in 2298 first and 1901 repeat cadaver kidney recipients. We found no significant effect on the survival rate of first grafts. Among retransplants, we observed that recipients who were homozygous for the high TNFalpha producer genotype -308 A had a significantly lower graft survival rate than patients who were carriers of the low producer genotype -308 G (at 3 years: 63.0% vs. 79.5%; pcorrected = 0.0116). The results of this large-scale study suggest that IL10, TGFbeta1, TNFalpha, and IL4Ralpha cytokine genotypes do not affect the survival of primary kidney grafts. The outcome of retransplants appears to be affected by TNFalpha genotypes only.
Cadaver↗
One thousand renal transplants in Belfast (1968-1998).
The first kidney transplant was performed in Belfast in 1968. During the next 30 years 1,000 transplants were undertaken at this unit. Data were analysed on 937 cadaveric transplants, 815 first and 122 regrafts. There were 63 living transplants. Long-term follow-up was achieved for all grafts except one live transplant. All recipients had follow-up of at least 5 years. One- and 5-year graft survival rates were 78.9% and 65.0% for first cadaveric grafts, 83.6% and 66.4% for regrafts and 85.7% and 68.3% for living transplants. Nine of 41 transplants performed more than 30 years ago are still functioning. Multivariate analysis determined risk factors for graft survival as recipient age, donor age, HLA-A mismatching, HLA cytotoxic antibody level and year of transplant. A conservative regime regarding the use of immunosuppression, HLA matching and crossmatching has proved successful in accomplishing good graft survival at this unit.
Adolescent↗