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Biomedical subjects

E W Petersdorf

Publications and source records attributed to E W Petersdorf.

At least 19 recordsLinked to original sources
PubMed2003

Tissue typing in support of unrelated hematopoietic cell transplantation.

The success of unrelated hematopoietic cell transplantation (HCT) for the treatment of hematologic malignancies has closely paralleled development of robust typing methods for comprehensive and precise donor-recipient matching. The application of molecular methods in clinical research has led to a more complete understanding of the immunogenetic barriers involving host-vs-graft (HVG) and graft-vs-host (GVH) reactions. Along with the development of less toxic transplant regimens, advances in the prevention and treatment of graft-vs-host disease (GVHD) and in the supportive care of the transplant recipient, improved HLA matching of potential unrelated donors has led to clinical results that begin to compare favorably with that of HLA-identical sibling transplants.

Alleles↗
PubMed2002

Identification of a novel HLA-B*07 allele--HLA-B*0726.

We describe here, the identification of a novel HLA-B*07 allele named HLA-B*0726. This allele was found in a Caucasian individual serologically typed as HLA-B7, B35. Novel DNA probe patterns for the HLA-B*07 allele were found using HLA-B specific reverse sequence-specific oligonucleotide probe (SSOP) and sequence-specific primer (SSP) typing. DNA sequencing demonstrated the presence of a new HLA-B*07 sequence variant encoding a single nucleotide substitution from a G to a T at nucleotide 539 in exon 3. This results in an amino acid substitution from arginine to leucine at residue 156 in exon 3.

Alleles↗
PubMed2002

Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation.

We retrospectively analyzed the relationship between busulfan average steady-state plasma concentration (C(SS)) and graft rejection in 53 children receiving busulfan/cyclophosphamide (BU/CY) preparative regimens prior to hematopoietic stem cell transplantation (HSCT). Patients received a total oral busulfan dose of 11 to 28 mg/kg followed by a total cyclophosphamide dose of 120 to 335 mg/kg in preparation for allogeneic grafts (HLA-matched or HLA partially matched sibling, parent or unrelated donor). Graft rejection occurred in eight (15%) patients. Busulfan C(SS) (P = 0.0024) was the only statistically significant predictor of rejection on univariate logistic regression analysis, with the risk of rejection decreasing with an increase in busulfan C(SS). Severe (grade 3 or 4) regimen-related toxicity (RRT) occurred in four patients. Ten patients (19%) had a busulfan C(SS) higher than 900 ng/ml, one of whom had severe RRT. Higher and variable doses of cyclophosphamide may explain the lack of a relationship between busulfan C(SS) and RRT in children. It may be possible to improve the outcome of HSCT in pediatric patients receiving the BU/CY regimen through optimization of busulfan C(SS) and better definition of the contribution of activated cyclophosphamide metabolites to toxicity.

Adolescent↗
PubMed2001

Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation.

BACKGROUND: Successful engraftment of hematopoietic stem cells from unrelated donors is influenced by disparities between the donor and recipient for HLA-A, B, and C alleles. Disparities between HLA sequence polymorphisms that are serologically detectable are termed antigen mismatches, whereas those that can be identified only by DNA-based typing methods are termed allele mismatches. Whether both kinds of polymorphisms are important in transplantation is not known. We tested the hypothesis that allele mismatches that are detectable only at the DNA level are less immunogenic than those that are serologically detectable and thereby are associated with a lower risk of graft failure after hematopoietic-cell transplantation METHODS: We used DNA sequencing to define the HLA-A, B, and C alleles in 471 patients who received bone marrow from unrelated donors for the treatment of chronic myeloid leukemia after myeloablative conditioning therapy. The odds ratios for graft failure were determined for recipients of transplants from donors with a single class I allele mismatch, a single class I antigen mismatch, or two or more class I mismatches, as compared with those with no mismatch RESULTS: A single HLA allele mismatch did not increase the risk of graft failure, whereas a single antigen mismatch significantly increased the risk. The risk was also increased if the recipient was HLA homozygous at the mismatched class I locus or if the donor had two or more class I mismatches CONCLUSIONS: HLA class I antigen mismatches that are serologically detectable confer an enhanced risk of graft failure after hematopoietic-cell transplantation. Transplants from donors with a single class I allele mismatch that is not serologically detectable may be used without an increased risk of graft failure.

Genes, MHC Class I↗
PubMed2001

Effect of HLA class II gene disparity on clinical outcome in unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia: the US National Marrow Donor Program Experience.

The clinical importance of HLA class II gene disparity in unrelated stem cell transplantation is not entirely known. The impact was evaluated of matching donors and recipients for HLA-DR, HLA-DQ, and HLA-DP genes on clinical outcome after stem cell transplantation for chronic myeloid leukemia (CML) performed between 1988 and 1997. HLA-DRB1, -DQA1, -DQB1, -DPA1, and -DPB1 alleles were identified in 831 transplant pairs using a combination of sequence-specific oligonucleotide probes, sequence-specific priming, and sequencing methods. Among the 831 pairs, 696 (84%) were HLA-A and -B serologically matched; of these, 565 (81%) were also matched for HLA-DRB1. HLA-DRB1 matching correlated with significantly improved survival (relative risk [RR], 1.29 [95% confidence interval (CI), 1.02-1.64; P =.04]) independently of HLA-DQA1 or HLA-DQB1 (RR, 1.01 [95% CI, 0.81-1.26; P =.94]) and HLA-DPA1 or HLA-DPB1 (RR, 1.11 [95% CI, 0.84-1.48; P =.46]). Single-locus HLA-DQ or HLA-DP disparity was not associated with significantly poorer survival. For patients who underwent transplantation in the first chronic phase (CP) from HLA-A, B matched donors, the presence of DRB1 allele mismatching was independently associated with increased incidence of grades III-IV acute graft-versus-host disease (GVHD). No significant associations of class II allele mismatching with risk for delayed engraftment or chronic GVHD disease were detected. This study clearly demonstrates the importance of precise matching of HLA-DRB1 alleles for successful transplantation. Furthermore, a good-risk population of patients whose transplantations were performed in the first CP of disease from HLA-A, B, DRB1 matched unrelated donors can be shown to have superior survival.

Alleles↗
PubMed2001

The biological significance of HLA-DP gene variation in haematopoietic cell transplantation.

Although it has been over 25 years since HLA-DP was mapped to the major histocompatibility complex (MHC), its biological functions remain ill-defined. We sought to test the hypothesis that HLA-DP functions in a manner similar to that of other class II genes by measuring the risk of clinically severe grades III-IV acute graft-vs.-host disease (GVHD) associated with recipient HLA-DP disparity after haematopoietic cell transplantation. HLA-DPB1 exon 2 was sequenced in 205 patients who underwent transplantation from HLA-A, -B, -C, -DRB1 and -DQB1 allele-matched unrelated donors. HLA-DPB1 mismatched recipients experienced a significantly increased risk of acute GVHD compared with HLA-DP-identical transplants. Patients who were mismatched for a single HLA-DPB1 allele had an odds ratio (OR) of 1.0 (0.5, 2.2; P = 0.99) and patients who were mismatched for two alleles had an OR of 2.2 (1.0, 4.9; P = 0.06) for developing acute GVHD. Compared with matched and single-allele mismatched transplants, patients who were mismatched for two DPB1 alleles had an OR of 2.2 (1.2, 4.1; P = 0.01). HLA-DP plays an important role in the alloimmune response. A threshold effect of multiple HLA-DP disparities is evident in determining the risk of acute GVHD after haematopoietic cell transplantation from unrelated donors.

Adolescent↗
PubMed2001

Generation of HLA-C-specific cytotoxic T cells in association with marrow graft rejection: analysis of alloimmunity by T-cell cloning and testing of T-cell-receptor rearrangements.

Peripheral blood mononuclear cells from a patient who rejected a T-cell-depleted marrow graft showed spontaneous cytotoxic activity specific for HLA-Cw4 and HLA-B35 alloantigens of the donor. T-cell-receptor complementarity-determining region 3 length distributions in a blood sample obtained at the time of rejection generally showed distortions in only 1 or 2 peaks, indicating that recipient T cells with a broad repertoire of antigen receptors survived the pretransplantation conditioning regimen. An HLA-Cw4-specific, CD8 T-cell clone was recovered from a blood sample after rejection. The T-cell-receptor-B gene rearrangement expressed by this clone was not readily detectable in other blood samples drawn before or after the transplantation, indicating that this clone was only 1 of many recipient-derived T cells that recognized HLA alloantigens of the donor. These results demonstrate the role of the HLA-C locus in T-cell-mediated alloimmune responses and add to emerging evidence that indicates the need to evaluate HLA-C compatibility in selecting hematopoietic stem cell donors for patients who have an increased risk of rejection.

Adult↗
PubMed2001

Trends in transplantation of hematopoietic stem cells from unrelated donors.

Transplants of hematopoietic stem cells from unrelated donors have become feasible for patients with a growing variety of hematologic disorders. The probability of finding a suitable donor has increased because of the expansion of the network of registries containing more than seven million HLA-typed donors worldwide. The selection of compatible donors has become more effective, thanks to the discovery of new HLA alleles and the development of precise and efficient HLA typing methods using DNA technology. Improved methods for transplantation may provide the opportunity to further decrease treatment-related toxicity and improve survival.

Animals↗
PubMed2000

Unrelated donor marrow transplantation for acute myeloid leukemia: an update of the Seattle experience.

Between 1985 and 1998, 161 patients with primary acute myeloid leukemia (AML) received T-replete bone marrow transplantation (BMT) from unrelated donors in Seattle. Median age was 30 (range 1-55) years. Conditioning for BMT consisted of cyclophosphamide and total body irradiation in 154 (96%) cases and graft-versus-host disease prophylaxis was the standard methotrexate and cyclosporine combination in 134 (83%) cases. Median post-transplant follow-up was 2.9 years. Leukemia-free survival (LFS) at 5 years was 50+/-12% for transplants during first complete remission (n = 16), 28+/-8% during second CR (n = 40), 27+/-17% during subsequent CR (n = 8), 7+/-3% during relapse (n = 81) and 19+/-10% during primary induction failure (n = 16). The cumulative incidences of relapse were 19%, 23%, 25%, 44% and 63%, for the five groups, respectively. Transplantation during remission, a marrow cell dose above 3.5 x 10(8)/kg, and cytomegalovirus seronegative status before BMT in both patient and donor were favorable prognostic factors. Adults in any CR who received a marrow cell dose above 3.5 x 10(8)/mg had a LFS of 54+/-9% at 5 years. These data extend our previous findings on the association between a high marrow cell dose and improved survival and support the use of unrelated donor BMT for treatment of patients with high risk AML when a family match is not available.

Acute Disease↗
PubMed2000

Improving availability and safety of unrelated donor transplants.

Transplants of hematopoietic stem cells from unrelated donors have become feasible for a growing population of patients with hematologic malignancy. More than 2,000 patients with acute and chronic leukemia, lymphoma, myeloma, and myelodysplasia are transplanted each year worldwide using marrow or blood stem cells from unrelated volunteers. Many patients have achieved complete immunologic tolerance and have become long-term survivors. The probability of finding a suitable donor has increased, because of the expansion of the network of registries containing more than 5 million HLA-typed donors worldwide. The selection of compatible donors has become more effective, thanks to the discovery of new HLA alleles and the development of precise and efficient HLA typing methods using DNA technology. Prophylaxis of viral and fungal infections has decreased morbidity and improved survival. The availability of more selective immunosuppressive agents provides the opportunity to decrease treatment-related toxicity and graft-versus-host disease.

Graft vs Host Disease↗