Biomedical subjects

M Oudshoorn

Publications and source records attributed to M Oudshoorn.

At least 19 recordsLinked to original sources

PubMed2005

The importance of identifying a back-up donor for unrelated stem cell transplantation.

The importance of identifying a back-up donor, once a primary suitable unrelated stem cell donor has been found, is often underestimated. Transplant centres erroneously count on the unrelated volunteer donors to be willing, available and medically fit for actual donation. According to our data, which includes 502 unrelated donor work-up procedures performed for 425 Dutch patients between 1987 and 2002, one of 11 work-ups ended in the primary requested donor failing to donate. Of all donor-related cancellations (N=46), 78% of the procedures were deferred due to medical reasons and 22% due to nonmedical reasons. Most of the donors deferred for medical reasons were female (P=0.005). In 50% of the cases for which a back-up donor was already identified, the patients were transplanted with a delay of less then 2 weeks; when no back-up donor was available, the median delay increased to 18 weeks. We strongly encourage implementing a search for at least one back-up donor in the primary search. Identifying a back-up donor can save precious time and complicated logistic rescheduling.

Female↗

PubMed2005

How to improve the search for an unrelated haematopoietic stem cell donor. Faster is better than more!

Many patients do not reach haematopoietic stem cell transplantation. Shortage of unrelated donors (UDs) is still seen as the main cause. However, with a worldwide UD pool containing more than 8 million donors, it is possible that other impediments are becoming more important. We analysed 549 UD searches for Dutch patients, performed between 1987 and 2000, in order to find the reasons for failure or success to reach transplantation. Between 1996 and 2000, 59% of the patients of Northwest European origin received a graft from an UD with a median time span of 4.4 months from the start of the search. In all, 11% of the patients lacked a compatible donor, while 30% became medically unfit for transplantation. This is in contrast to the patients of non-Northwest European origin for whom UD shortage is still the most important impediment; only 32% were transplanted while 50% lacked a compatible donor. We conclude that the shortage of donors is no longer the biggest constraint in unrelated stem cell transplantation for patients of Northwest European origin. It may be more effective to optimize the chance on transplantation by making the search process more efficient.

Data Collection↗

PubMed2005

Role of NK cells in mismatched unrelated haematopoietic stem-cell transplantation: fact or fiction?

The role of alloreactive NK cells in haematopoietic stem-cell transplantation is a controversial topic. Different studies come up with different conclusions. This is mainly due to heterogeneous patient populations, differences in the sources of haematopoietic stem cells and various conditioning regimens. International collaboration is essential to reveal in which situation NK cell alloreactivity plays a role and, if so, whether it is beneficial or detrimental for patient survival.

Hematopoietic Stem Cell Transplantation↗

PubMed2004

Hematopoietic stem cell donor registry strategies for assigning search determinants and matching relationships.

Registries and cord blood banks around the world collect and store the HLA types of volunteers in order to identify matched unrelated donors for patients requiring hematopoietic stem cell transplantation. This task is complicated by the many formats in which HLA types are provided by the testing laboratories (types obtained by serology vs by DNA-based methods; high vs intermediate vs low resolution) and by the need to identify which of these diverse types are most likely to match the HLA assignments of a searching patient as closely as possible. Conversion of the assignments to 'search determinants' may be included within the algorithm used to select and prioritize a list of potentially suitable donors, either as an aid to matching or as a tool to optimize the performance of comparisons within large data files. The strategies used by registries to create search determinants are described. A set of search determinants, utilized by the National Marrow Donor Program, is provided as an example and is intended to initiate further discussion aimed at understanding the process used by each registry with the possibility of developing a standard process among registries worldwide.

Algorithms↗

PubMed2004

A special report: suggested procedures for international unrelated donor search from the donor registries and quality assurance working groups of the World Marrow Donor Association (WMDA).

This special report details the World Marrow Donor Association's recommended procedures regarding the international search for an unrelated donor for hematopoietic stem cell transplantation. The responsibilities of the national hubs, transplant center and donor registry staff are outlined for all actions associated with the preliminary search, formal search, donor confirmatory typing and final donor selection.

Hematopoietic Stem Cell Transplantation↗

PubMed2004

Isolated HLA-C mismatches in unrelated donor transplantation for CML.

HLA-incompatibility is a major factor associated with outcome of allogeneic stem cell transplantation, but little is known on the impact of isolated HLA-C mismatches. We analyzed the outcome of 114 CML patients transplanted with marrow from unrelated donors of whom 24 were mismatched for HLA-C only (9/10 match). Univariate estimates of 5-year survival (SRV) (median follow-up: 47 months) in the HLA-matched group were 68+/-12 vs 42+/-20% (P=0.03) for the patients mismatched for HLA-C only and 33+/-33% in the mismatched group (non-HLA-C single mismatches and multiple mismatches) (P=0.0004). Disease stage, GVHD-prophylaxis (T-cell depletion), CMV-status and HLA-incompatibility were the risk factors associated (all P< or =0.005) with poor outcome. In the multivariate analysis, patients mismatched for loci other than HLA-C were at high risk of an adverse outcome (death: RR, 2.9; CI, 1.6-5.4, P=0.008, transplant-related mortality (TRM): RR, 3; CI, 1.5-5.9, P=0.0015). For patients mismatched for HLA-C only, the increased risk was of borderline significance (death: RR, 1.9; CI, 1-3.9, P=0.06, TRM: RR, 2.1; CI, 1-4.5, P=0.07). In spite of their lower expression, HLA-C antigens still represent relevant transplantation barriers that should be considered when searching for an unrelated donor.

Adult↗

PubMed2004

Five newly identified HLA alleles: A0310, A2907, B4435, Cw0206, Cw0506, and confirmation of A3106, B3924, Cw0314, DRB10322, and DRB11433 alleles.

A number of HLA alleles have been newly identified. This concerns HLA-A*0310, A*2907, B*4435, Cw*0206, Cw*0506, of which Cw*0206 was found in three unrelated individuals, all B*4002 positive. Some other alleles are also presented but confirm earlier detected sequences: A*3106, Cw*0314, DRB1*0322, and DRB1*1433. Moreover, we identified B*3924 in a bone marrow transplant recipient and in five of six unrelated stem cell donors, selected for this patient. In all cases, B*3924 was found on a haplotype combining A*0201, B*3924, Cw*0701, and DRB1*1303. The observation of this extended haplotype is of importance for the selection for stem cell transplantation. Cells expressing B*3924 and B*4435 were typed by serology as B39 and B44, respectively. Cells expressing HLA-A*0310 do not express A3 but type as A-Blank.

Alleles↗

PubMed2003

Are human platelet alloantigens (HPA) minor transplantation antigens in clinical bone marrow transplantation?

The role of human platelet alloantigens (HPA) in clinical bone marrow allotransplantation was investigated. The leading hypothesis was that HPA alloepitopes act as minor histocompatibility antigens and aggravate graft-versus-host disease (GVHD). To exclude the effect of MHC disparity, only HLA identical donor-recipient pairs were entered into the study. The influence of HPA compatibility on overall survival, occurrence of relapses and haematopoietic recovery was also investigated. A total of 223 patients who received a graft from an HLA-identical sibling, genotyped for HPA -1, -2, -3, -4 and -5, were observed over a post-transplant period of 24 months following the protocol recommended by EBMT. The data from patients having received grafts from HPA compatible donors were compared to data from patients having received grafts that were mismatched in HPA allotypes in the GVH direction. Analysis of the incidence of acute and chronic (GVHD), overall survival, relapse incidence, haematopoietic recovery and some other clinical parameters did not reveal any significant difference between the HPA-matched and -mismatched groups of patients, regardless of their age. Our results give no evidence that HPA-1, -2, -3 and -5 alloantigens should be considered minor transplantation antigens in clinical bone marrow transplantation.

Adult↗

PubMed2003

The World Marrow Donor Association (WMDA): its goals and activities.

The major goal of the World Marrow Donor Association (WMDA) is to facilitate the transfer of hematopoietic cells for transplantation purposes across international borders. It also has the goal of establishing guidelines on ethical, technical, medical, and financial aspects that concern the donor and donor-cell transfer. It has a Board and five Working Groups, namely the Donor Registry Working Group, the Quality Assurance Group, the Ethic Working Group, the Finance Working Group, and the Clinical Working Group. It has three types of membership, that is, full organizational membership, nonvoting organizational membership, and individual corresponding membership. Current important projects are speeding up the search process, accreditation of registries and collecting information about severe adverse effects in donors.

Biological Specimen Banks↗

PubMed2002

[Two brothers with familial hemophagocytic lymphohistiocytosis, treated by transplantation of stem cells from a single unrelated donor].

In two Turkish brothers familial haemophagocytic lymphohistiocytosis (FHLH) was diagnosed at 3 years and 2.5 months, respectively. FHLH is a rare autosomal recessive condition with a typical clinical presentation including prolonged fever, failure to thrive, irritability and hepatosplenomegaly. Laboratory evaluations show cytopenia (at least two out of the three cell lines), hypertriglyceridaemia and hypofibrinogenaemia. A pathognomonic sign is haemophagocytosis in bone marrow or tissue biopsy. Both patients were treated with stem-cell transplants using bone marrow and peripheral blood stem cells, respectively, from one unrelated donor. They showed a good haematological recovery, with minor complications, and at follow-up after one year were free of disease. Immune suppression can induce prolonged remission in FHLH, but cure is only achieved after a successful allogeneic stem-cell transplantation. Without transplantation, the prognosis is very poor.

Bone Marrow Transplantation↗

PubMed2002

Functional versus structural matching: can the CTLp test be replaced by HLA allele typing?

Human leukocyte antigen (HLA) incompatibilities are the most important immunological barriers to bone marrow transplant success when using unrelated donors. Until recently, standards for donor selection included serological methods for HLA class I antigens and DNA-based typing for HLA class II alleles. In our center cytotoxic T-lymphocyte precursor (CTLp) assays have been an integrated part of the search selection procedure as well. More recently, DNA-based typing for HLA class I became available. This allowed us to determine the correlation of CTLp frequencies directed against incompatibilities at the HLA-A, -B, and -C locus in 211 donor-recipient pairs. HLA class I incompatibilities are significantly (p < 0.001) associated with high CTLp frequencies. Exceptions did occur, high CTLp frequencies are seen in 14% of the HLA-A, -B, and -C allele matched pairs, whereas in 7% of the pairs mismatched for HLA-A or -B a low CTLp frequency occurred. The successful outcome of transplants performed in the latter cases suggest that the CTLp test can be used as a tool to detect permissible mismatches when no fully matched donor is available. The influence of HLA-C mismatches on the CTLp outcome was less clear. Although in the majority of mismatched pairs (64%) the CTLp frequency was high, in 36% of the pairs the CTLp frequency was low. Analysis of HLA amino acid sequences was performed on the HLA-C allele mismatched group. An amino acid difference was always found at five polymorphic positions 97, 99, 113, 114, and 116 situated at the peptide binding groove in the high CTLp frequency group, whereas in the low CTLp frequency group this was observed in only 9 of 17 combinations (p < 0.001). However, this is mainly due to Cw*0303-0304 mismatches. In conclusion, although there is a highly significant correlation between the outcome of the CTLp frequency test and HLA allele class I typing, exceptions occur. It is unclear whether they are all clinically relevant but they certainly provide additional insight in allograft recognition.

Adult↗

PubMed2002

Cost analysis of HLA-identical sibling and voluntary unrelated allogeneic bone marrow and peripheral blood stem cell transplantation in adults with acute myelocytic leukaemia or acute lymphoblastic leukaemia.

Allogeneic stem cell transplantation (SCT) is one of the most expensive medical procedures. However, only a few studies to date have addressed the costs of HLA-identical sibling transplantation and only one study has reported costs of unrelated transplantation. No recent cost analysis with a proper follow-up period and donor identification expenses is available on related or voluntary matched unrelated donor (MUD) SCT for adult AML or ALL. Therefore, we calculated direct medical (hospital) costs based on 97 adults who underwent HLA-identical sibling bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT), and patients who received a graft from a MUD between 1994 and 1999. The average costs per transplanted patient were Euro 98,334 (BMT), Euro 151,754 (MUD), and Euro 98,977 (PBSCT), including donor identification expenses, 2 years follow-up and costs of patients who were not transplanted after they had been planned to receive an allograft. The majority of these costs was generated during the hospitalisation for graft infusion. For MUD transplants, nearly one-third of these costs was spent on the search for a suitable donor. For patients who were alive after 2 years, cumulative expenses were calculated to be Euro 103,509 (BMT), Euro 173,587 (MUD), and Euro 105,906 (PBSCT).

Adolescent↗

PubMed2002

Human immunodeficiency virus type 1 replication inhibition by the bidentate iron chelators CP502 and CP511 is caused by proliferation inhibition and the onset of apoptosis.

BACKGROUND: The iron chelators deferoxamine (DF) and deferiprone (CP20) have been shown to inhibit human immunodeficiency virus type 1 (HIV-1) replication in human peripheral blood lymphocytes (PBL). The orally active bidentate chelators CP502 and CP511, which also belong to the 3-hydroxypyridin-4-one family, but with higher affinities for iron than CP20, were monitored for their antiviral properties by checking for p24 antigen production and nuclear factor (NF)-kappaB activation, and their ability to induce apoptosis. MATERIALS AND METHODS: Human PBLs were isolated from HIV-1 seronegative donors and subsequently infected with HIV-1(Ba-L) for 2 h. After 5 days' incubation, HIV-1 replication was monitored by p24 antigen production. Cellular proliferation as well as caspase-3 activity were monitored in uninfected cells after a period of 5 days and after 1 day infection, respectively. NF-kappaB activity was also monitored by electromobility shift assays (EMSA) performed on nuclear extracts of Jurkat cells treated with the different chelators for 4 h. RESULTS: CP502 and CP511 decrease HIV-1 replication by decreasing cellular proliferation in a similar manner to DF and CP20. CP511 seemed to be more potent than either CP502 or CP20. Due to the reduction in cellular proliferation, there was an increase in caspase-3 activity after 24 h incubation. NF-kappaB activity was not affected by any of the chelators. CONCLUSIONS: Iron chelators with high affinities for iron, which are under development for the treatment of iron overload, could contribute to the reduction of HIV-1 replication in infected patients by cellular proliferation inhibition rather than by a direct antiviral action.

Apoptosis↗

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

The chemotherapeutic agent bleomycin in a two-drug combination with zidovudine, ritonavir or indinavir synergistically inhibits HIV Type-1 replication in peripheral blood lymphocytes.

It has been suggested that the combination of cancer chemotherapy with antiviral therapy is helpful for the containment of lymphomas in HIV-infected patients. Since we have recently shown that the nucleic acid binding chemotherapeutic agent bleomycin in itself has antiviral properties, we looked to see if there was any possible synergy with current anti-HIV agents. Combinations of zidovudine, indinavir or ritonavir with bleomycin, synergistically inhibited HIV-1(AT) replication in stimulated peripheral blood lymphocytes (combination index at 50% virus inhibition was 0.427, 0.604 and 0.535, respectively) and this synergism was not accompanied by any synergistic effects on cytotoxicity. We conclude from these data that further studies to investigate the clinical efficacy of combinations of antiviral and cancer chemotherapeutic agents are warranted in relation to viral load improvement.

Anti-HIV Agents↗

PubMed2001

Anti-HIV effect of iron chelators: different mechanisms involved.

BACKGROUND: Drugs for the treatment of AIDS have been directed to specific events in the human immunodeficiency virus (HIV-1) life cycle, aimed to stop viral replication by inhibition of reverse transcriptase or protease activity. Studies showing that oxidative stress and iron may be important in the activation of HIV-1 have focused attention on the potential therapeutic use of iron chelators. OBJECTIVES: The goal of this review is to describe several possibilities as to how iron is involved in the replication of HIV and how iron chelation may interfere in this process. STUDY DESIGN: First some physico-chemical properties of iron concerning solubility, oxidation-reduction potential, catalysis, and chelation will be discussed. In the second part, the role of iron in various biochemical systems is explained. RESULTS: Nuclear factor kappa B (NF-kappaB) activation, regulating proviral transcription, can be influenced by iron through the production of reactive oxygen species. A second route by which iron chelation could influence HIV replication, is by inhibition of DNA synthesis through inactivation of iron-dependent ribonucleotide reductase. Another strategy which can be employed in targeting iron chelators against HIV-1, is direct oxidative viral RNA/DNA attack. This could be achieved by bleomycin, a cytostatic agent with the ability to form a complex with DNA and RNA. CONCLUSION: Chelation may withhold iron from viral metabolism but on the other hand may also favor catalysis of reactive oxygen species directed to viral constituents. In combination with existing antivirals, iron chelation could add to improve the treatment of HIV-disease.

Anti-HIV Agents↗

PubMed2001

Three newly identified HLA-B alleles: B5124, B5306, B5307 and confirmation of B0809 and B*5606.

Five HLA-B sequences are described which have been detected as irregular patterns during routine molecular typing. Sequencing of HLA-B exon 2 and 3, both heterozygous and after group specific amplification, revealed three new HLA-B alleles: B*5124, B*5306 and B*5307, whereas the sequences of B*0809 and B*5606 were confirmed. Serological typing showed that B*0809 is expressed as a regular B8, B*5124 as a regular B51, B*5306 as a B51/B53-like variant and B*5606 as a B"blank"-Bw6.

Alleles↗

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↗