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Biomedical subjects

F H Claas

Publications and source records attributed to F H Claas.

At least 91 records · Page 5Linked to original sources
PubMed1997

The avidity, not the mere presence, of primed cytotoxic T-lymphocytes for donor human leukocyte class II antigens determines their clinical relevance after heart transplantation.

BACKGROUND: To analyze the relevance of CD4-positive cytotoxic T-lymphocytes (CTL) in clinical heart rejection, we studied the frequency and avidity of donor human leukocyte antigen class II-specific CTL present within the graft during a rejection episode and during a period without rejection. METHODS: For this analysis endomyocardial biopsies of heart transplant recipients were cultured to obtain graft-infiltrating lymphocytes (GIL). GIL cultures exhibiting donor class II-directed cytotoxicity were considered for this study. With limiting dilution analysis, the frequency of donor class II-specific CTL that had been primed by donor antigens in vivo (designated cCTL) was determined in GIL cultures established from endomyocardial biopsies taken during a rejection episode (n = 10) or during a period without rejection (n = 11). Addition of anti-CD4 to the limiting dilution analysis revealed the fraction of donor class II-specific cCTL having a high avidity for donor antigen. RESULTS: During a rejection episode, 196 (median) donor class II-specific cCTL/106 GIL were present. In a period without rejection, the frequency of donor class II-specific cCTL was not significantly different (median = 330/10(6); p = 0.1). Addition of anti-CD4, however, revealed that donor class II-specific cCTL with a high avidity for donor antigen are predominant during a rejection episode (median = 100%) but are in minority during a period without rejection (median = 35%; p < 0.0001). CONCLUSIONS: These results suggest that graft-infiltrating CD4+ CTL can mediate heart rejection provided they have a high avidity for donor antigen.

Antibody Affinity↗
PubMed1996

Schistosoma mansoni excretory circulating cathodic antigen shares Lewis-x epitopes with a human granulocyte surface antigen and evokes host antibodies mediating complement-dependent lysis of granulocytes.

Parasitic worms of the genus Schistosoma excrete relatively large amounts of immunogenic glycoproteins (circulating cathodic antigen [CCA]) that contain polysaccharide side chains with the trisaccharide Lewis-x (L(ex)) as a repeating unit. These carbohydrates evoke high titers of specific IgM antibodies that cross-react with the repeating L(ex) units on the surface of granulocytes. Consequently this might lead, in the presence of complement, to lysis of the granulocytes. In the present study, this hypothesis was investigated using anti-CCA mouse monoclonal antibodies (MoAbs) and polyclonal antibodies purified from sera of infected humans. By flow cytometry, it was demonstrated that the mouse MoAbs directed against CCA strongly recognized the granulocytes. It could also be shown that these MoAbs, as well as anti-CCA IgM antibodies purified from infected human sera, caused lysis of granulocytes in a complement-dependent cytotoxicity assay. Sera from healthy controls or from patients with other helminth infections resulted in negligible granulocytotoxicity. These in vitro observed phenomena may explain the mild to moderate neutropenia that occurs in schistosomiasis patients.

Animals↗
PubMed1996

In vitro sensitivity to prednisolone may predict kidney rejection after steroid withdrawal.

A maintenance immunosuppressive regimen of cyclosporine and steroids after renal transplantation has proven to be a successful policy to obtain long-term graft survival. However, serious side-effects are associated with this therapy; these include an increased risk for infections, cancer, and cardiovascular morbidity and mortality. Therefore, this pilot study was conducted to investigate the possibility of reducing the immunosuppressive load after transplantation. To this end, we tried to develop an in vitro assay to predict graft rejection after withdrawing steroids from the immunosuppressive therapy. Patients who had stable renal function at least one year after transplantation were randomly divided into a group that continued to receive standard immunosuppression of cyclosporine and steroids and a group to be withdrawn from steroid therapy, the latter group being the subject of the present study. Patients withdrawn from steroids were monitored closely and when a biopsy-proven rejection occurred, steroid treatment was reestablished. Blood was collected from patients preceding steroid withdrawal and at fixed time points thereafter. In case of suspected rejection, blood was also taken before biopsy, before steroid treatment was reestablished. In the in vitro limiting dilution analysis-assays cytotoxic T lymphocyte precursor frequencies directed against kidney donor HLA-antigens were determined, in the absence or presence of cyclosporine and several concentrations of prednisolone and the combination of these agents. Confirming earlier results, we found that the number of cyclosporine-resistant cytotoxic T lymphocytes increased prior to a rejection crisis, while they did not change or even decreased in patients who retained normal graft function after steroid withdrawal. More importantly, the results show that 10(-7) M prednisolone in vitro differentially affected donor-specific cytotoxic T lymphocyte precursor frequencies in patients who experienced a rejection crisis after steroid withdrawal, compared with those who remained to do well. This heterogeneity could be detected before the start of steroid withdrawal. Therefore, we conclude that the present data justify a prospective clinical trial to investigate the possible application of this in vitro assay to predict for which patients steroid withdrawal might be considered.

Adult↗
PubMed1996

Association between specific HLA combinations and probability of kidney allograft loss: the taboo concept.

BACKGROUND: HLA matching improves the outcome of cadaveric renal transplantation. However, many allografts function well even in the presence of one or more HLA mismatches, which raises the question of whether some mismatches are better recognised by the recipient's immune system than others. We aimed to identify mismatched HLA donor-recipient combinations that were associated with increased graft loss. METHODS: We selected 2877 first, unrelated renal transplants with a single HLA A, B, or DR mismatch, undertaken between 1982 and 1992, from the Eurotransplant database. To enhance statistical power the analysis was restricted to mismatches of an HLA antigen that occurred in 100 or more donors. 1342 transplants met this criterion and were grouped into a definition set (n = 873) and a validation set (n = 469). In the definition set, we studied further only those recipient HLA antigens that occurred in at least 30 cases within each donor antigen mismatch subset. By a Cox proportional hazards model, donor-recipient combinations that led to significantly higher graft loss than in the whole group were defined. Such combinations were classified as taboo; the remaining combinations were classified as indifferent. FINDINGS: 106 individual recipient antigens were found at least 30 times with a corresponding donor mismatch in the definition set; 11 of the 106 had a significant effect on graft survival. Seven combinations were classified as taboo. Taboo combinations, confirmed as such in the validation set, were associated with graft survival of 81% at one year and 50% at 5 years, significantly lower than the rates in the group with indifferent combinations (89% and 69%; p = 0.04) or among 1190 recipients with no mismatches (89% and 72%; p = 0.03). The findings were substantiated by a multivariate analysis that included the effect of patient immunisation, cold ischaemia time, age, and sex. INTERPRETATION: Mismatched donor antigens are differentially recognised depending on the HLA phenotype of the recipient. The findings may have important clinical consequences for graft survival after transplantation.

Cadaver↗
PubMed1996

The outcome of kidney grafts from multiorgan donors and kidney only donors.

From 1988 to 1994, 15356 renal cadaveric transplantations have been performed within the Eurotransplant area (Austria, Belgium, Germany, Luxembourg and The Netherlands); 8746 kidneys were obtained from multiorgan donors and 6610 from kidney only donors. To evaluate the impact of the procurement policy, multiorgan donor (MOD) versus kidney only donor (KOD), on renal graft survival, an observational study has been performed. Multivariate analysis using Cox's proportional hazards model served to quantify the role of the procurement policy on renal graft survival after adjustment for other prognostic factors. The kidneys obtained from MODs had a significantly better graft survival at 1, 3, and 5 years after transplantation than the kidneys obtained from KODs (85%, 75%, and 58% versus 78%, 68%, and 46% (P=0.0001). In the Cox model, patients transplanted with a KOD kidney had a 1.28 times higher risk of losing their graft than patients transplanted with a MOD kidney. This benefit in graft survival for MOD kidneys could not be explained by the fact that the MODs were younger and male, and that UW was used as preservation solution. A plausible explanation is that MODs, on average, because of the nonrenal transplants, are better supervised. We expect that optimal donor management will contribute to a better outcome of all renal grafts.

Adenosine↗
PubMed1996

Pregnancy can induce priming of cytotoxic T lymphocytes specific for paternal HLA antigens that is associated with antibody formation.

Some transplant centers consider paternal HLA antigens as unacceptable mismatches for mothers awaiting kidney transplantation. It is feared that a pregnancy may cause priming of the maternal immune response directed toward paternal HLA antigens. Should a woman receive an organ from a donor who shares those paternal HLA antigens, the risk of graft rejection might be increased. It is known that some women, as a consequence of pregnancy, develop antibodies specific for paternal HLA antigens. The purpose of the present study was to investigate whether a pregnancy can also prime the cellular immune response and whether this occurs in all cases. Frequencies of maternal cytotoxic T lymphocytes directed to paternal HLA antigens were evaluated in limiting dilution analysis assays and compared with those directed to third-party HLA antigens. Differentiation between naive and in vivo primed cytotoxic T lymphocytes was made by performing these assays in the absence and presence of anti-CD8, respectively. No difference in the frequency nor sensitivity to blocking by anti-CD8 was found when maternal cytotoxic T lymphocytes directed toward paternal HLA antigens were compared with those against third-party HLA antigens. However, more heterogeneous responses were detected against paternal HLA antigens. Therefore, paternal antigens that had been inherited by children were analyzed separately from the paternal antigens that had not been inherited. Furthermore, the presence of pregnancy-induced HLA antibodies was taken into consideration. Naive cytotoxic T lymphocyte responses were detected against paternal antigens that had never been inherited and those that had been inherited but had not induced antibody formation. In contrast, inherited paternal antigens that had induced HLA-specific antibodies in the mother gave rise to elevated cytotoxic T lymphocyte precursor frequencies, as compared with the response to third-party antigens. Also, the cytotoxic T lymphocytes were found to be more resistant to inhibition by anti-CD8, suggesting that these cells had been primed in vivo. These results suggest that not all paternal HLA antigens have to be considered as unacceptable mismatches. Only those individuals who share a paternal HLA antigen against which a mother has formed HLA-specific alloantibodies should be excluded from organ donation.

Adult↗
PubMed1996

Progressive accumulation of CTL with high avidity for donor antigens during the development of acute cardiac rejection.

To study the importance of cytotoxic T lymphocytes (CTL) with high avidity for donor antigens (Ag) in the development of acute cardiac allograft rejection, their appearance within the graft in relation to rejection was analyzed. For this study, donor directed CTL propagated from sequentially taken endomyocardial biopsies (EMB) were enumerated by limiting dilution analysis (LDA). Subsequentially, the fraction of these CTL having high avidity for donor Ag was determined by addition of a CD8 monoclonal antibody (mAb) to the cytotoxic phase of the LDA. Analysis of 37 EMB cultures obtained from 11 heart transplant (HTx) patients before, during, or after they experienced rejection, revealed the kinetics of donor specific CTL in relation to rejection for HTx patients in general. For 5 individual recipients, a more detailed analysis was performed. The kinetics found for individual patients confirmed the pattern found for the total group of HTx recipients tested. Frequencies of donor specific precursor CTL (pCTL) as well as of in vivo primed donor reactive CTL (committed CTL or cCTL) increased towards rejection and decreased after successful rejection therapy. More than 2 weeks before rejection was diagnosed, only a small fraction of the graft infiltrating donor specific pCTL and cCTL had high avidity for donor Ag (median = 35% and 11%, respectively). Within 2 weeks preceding rejection, this fraction increased gradually (median = 52% and 55%, respectively) and became dominant during rejection (median = 87% and 78%, respectively). After successful rejection therapy, a decrease to basal levels (median = 18% and 24%, respectively) was observed. Conclusively, intragraft accumulation of high avidity, donor specific pCTL and cCTL may cause transplant rejection.

Acute Disease↗
PubMed1996

Human heart endothelial-cell-restricted allorecognition.

We studied the reactivity of cardiac graft-infiltrating cells, cultured from endomyocardial biopsy specimens, toward heart endothelial cells (Hec). In two cases, Hec derived from the specific donor heart or Hec compatible with the donor were lysed, but not the syngeneic B cell line. A vessel-derived endothelial cell line was not lysed. Panel studies suggest that the epitopes recognized are, in one case, a Hec-specific peptide presented in the context of HLA-Bw41 and, in the other case, a Hec-specific peptide presented by a subtype of HLA-B44. In conclusion, we showed that cardiac graft-infiltrating cells cultured from endomyocardial biopsy specimens can exhibit cytotoxic reactivity specifically directed against HLA-peptide complexes on Hec.

Cell Line↗
PubMed1996

Peripheral monitoring of direct and indirect alloantigen presentation pathways in clinical heart transplant recipients.

It has been reported that the response to alloantigens presented by the direct and indirect pathway may be of differential relevance after human kidney transplantation. Accordingly, we monitored these routes in peripheral blood mononuclear cells (PBMC) of heart transplant patients from before transplantation and up to 2 years thereafter in an attempt to find a correlation with the clinical status of the patients. Both before and after transplantation, comparable proportions of PBMC samples reacted in mixed lymphocyte culture to nondepleted donor spleen cells (direct route), but never to donor cells depleted for antigen-presenting cells (indirect route). In contrast, the latter route could easily be activated by a nominal antigen and persisted after transplantation, although the proportion of PBMC samples responding was significantly suppressed, irrespective of the occurrence of rejection. Consequently, complete removal of antigen-presenting cells from the stimulator population in a mixed lymphocyte culture with PBMC as responder is not a suitable tool for measuring indirect presentation of alloantigens, and therefore not relevant for monitoring the immunological status of heart transplant recipients.

Antigen Presentation↗
PubMed1996

Culture of graft-infiltrating cells from cryopreserved endomyocardial biopsies.

Graft-infiltrating cells can be cultured from fresh endomyocardial biopsies (EMB) taken after heart transplantation to determine their growth patterns, phenotypic composition, and functional characteristics for clinical or scientific purposes. In this study we investigated whether graft-infiltrating cells can also be cultured successfully after cryopreservation of these EMB. Three different cryopreservation methods were used. One method gave successful growth in 100% of the cases (n = 6): The biopsy fragments were preincubated in 10% vol/vol dimethyl sulfoxide during 5 min at 0 degree C, frozen to -70 degrees C at approximately 1 degree C per minute, and subsequently immersed and stored in liquid nitrogen. Thawing was performed rapidly in water at 37 degrees C. In addition, the effect of cryopreservation on cell surface phenotype and donor-specific cytotoxicity of these graft-infiltrating cells was analyzed. When compared to cultures of nonfrozen control biopsies, both qualities remained constant in most cases, although a variation in CD4+/CD8+ cell ratio was observed in 33% of these cultures. However, when nonfrozen fragments of size-matched biopsies were cultured separately, a similar variation in phenotype was noted, indicating that this phenomenon can be attributed to sampling variation and not to the cryopreservation procedure. The present findings suggest that it is no longer required to culture fresh (nonfrozen) post-transplant EMB to propagate graft-infiltrating cells: Culturing can be limited to cryopreserved EMB that are selected retrospectively, depending on actual clinical or scientific interests. Besides greatly facilitating the long-term monitoring of heart transplant recipients, this also means a substantial decrease in cost and work load for laboratories involved in heart transplantation.

Biopsy↗
PubMed1996

Evidence that cyclosporin A prevents clinical cardiac allograft rejection by blocking both direct and indirect antigen presentation pathways.

Monitoring for the responses to alloantigens presented either by the direct or the indirect presentation pathway have been reported to be of clinical value after kidney transplantation. Amongst others, the level of these responses may be dependent on the immunosuppressive treatment. We studied both presentation routes in peripheral blood mononuclear cells (PBMC) of cardiac transplant patients, who experienced episodes of rejection, and related them to the in vivo cyclosporin A (CsA) levels in plasma. PBMC of the recipients were stimulated with irradiated donor cells to determine the direct presentation pathway. As a method for the activation of the immune response via the indirect pathway, PBMC were stimulated with tetanus toxoid. Both immune responses increased when CsA levels inadvertently decreased to inadequate concentrations and histological rejection was diagnosed. After clinical heart transplantation, CsA may prevent rejection by blocking both the direct and the indirect antigen presentation pathway.

Antigen Presentation↗
PubMed1996

Inverted V delta 1/V delta 2 ratio within the T cell receptor (TCR)-gamma delta T cell population in peripheral blood of heart transplant recipients.

We investigated the levels of TCR-gamma delta T cells and their subpopulations V delta 1 and V delta 2 in the peripheral blood lymphocytes (PBL) of 28 heart transplant (HTx) patients. Patients (n = 10) receiving cyclosporin A (CsA) for treatment of a nephrotic syndrome (NS) and 10 healthy individuals served as controls. There was no difference in levels of TCR-gamma delta T cells between the different groups. However, an elevated proportion of V delta 1+ gamma delta T cells was found in the PBL of HTx patients, especially when these cells were present in their graft-infiltrating lymphocyte (GIL) cultures. V delta 1+ gamma delta T cells of HTx patients showed normal expression of CD45RO and lacked the activation markers CD25 and HLA-DR. After expanding in IL-2-containing medium, PBL cultures of HTx patients more often were dominated by V delta 1 cells than PBL cultures of controls, in which V delta 2 cells were predominantly grown. The aberrant composition of the TCR-gamma delta population in HTx patients was not a result of immunosuppressive medication, since the proportion V delta 1+ gamma delta T cells was normal in the PBL of the NS patients receiving a similar dose of CsA. It is postulated that long-term antigenic stimulation by the graft, at low level, might be responsible for the altered composition of the gamma delta pool in the HTx patients. Since no donor HLA-specific gamma delta T cells have been detected, other ligands, such as heat shock proteins, may be involved.

Adolescent↗
PubMed1996

Chronic sun exposure and age are inversely associated with nevi in adult renal transplant recipients.

In 126 adult renal transplant recipients who had survived their transplantation for at least 8 years, we determined whether numbers of nevi and the presence of clinically atypical nevi were related to chronic sun exposure. On the basis of a skin examination, three groups were defined: patients with at least one clinically a typical nevus; patients with only clinically normal nevi: and patients without any nevi. The prevalence odds ratio of having any clinically atypical nevi as compared to having only clinically normal nevi was calculated in a logistic model, in relation to gender, skin type, age, sun exposure, and number of keratotic skin lesions present. Similarly, the prevalence odds ratio of having 30 or more nevi compared to fewer than 30 nevi was calculated. We found an inverse association between chronic sun exposure and age with numbers of nevi in adult renal transplant recipients. The presence of clinically atypical nevi was also inversely associated with chronic sun exposure, but this association disappeared after adjustment for age. We did not observe an association of nevi with the number of keratotic skin lesions, nor with humoral immune responses against human papillomavirus and the presence of certain HLA antigens, which are factors associated with nonmelanoma skin cancer in renal transplant recipients. Chronic sun exposure and age appeared to be strong determinants for decreased numbers of nevi in adult renal transplant recipients. Infection with human papillomaviruses does not appear to play an important role.

Adult↗
PubMed1996

Immune mechanisms leading to drug-induced blood dyscrasias.

Drug-induced blood dyscrasias may be due to toxicity of the drug, inborn errors of metabolism or immunological reactions. In the latter case, drug-induced antibodies are directed to specific target cells, such as platelets (thrombocytopenia) or granulocytes (agranulocytosis). Some of these immune mechanisms are based on the physical interaction between drug, antibody and target cells. A particular drug may bind to the surface of the blood cell which, as a carrier of the drug, will be destroyed as part of the immune reaction to the drug (hapten mechanism). Other drugs will form immune complexes with drug-specific antibodies. These immune complexes will bind to certain blood cells and destroy them as innocent bystanders (immune complex mechanism). In vitro assays are described which enable the offending drug to be detected by mimicking these immune mechanisms using patient serum, platelets or granulocytes, and the suspected drug. The diagnostic value of these in vitro assays is discussed.

Antibodies↗