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Biomedical subjects

L A Baxter-Lowe

Publications and source records attributed to L A Baxter-Lowe.

At least 19 recordsLinked to original sources
PubMed2006

Antibody-mediated rejection of a pancreas allograft.

The role of antibody-mediated rejection (AMR) in pancreas transplantation is poorly understood. Here, we report on a patient who developed AMR of his pancreas allograft after receiving a simultaneous pancreas-kidney transplant. Pre-operative enhanced cytotoxicity and flow cytometry T-cell crossmatches were negative; B-cell crossmatches were not performed as per institutional protocol. The patient's post-operative course was significant for elevated serum amylase levels and development of hyperglycemia approximately 1 month after transplantation. A pancreatic biopsy at this time showed no cellular infiltrate but strong immunofluorescent staining for C4d in the interacinar capillaries. Analysis of the patient's serum identified donor-specific HLA-DR alloantibodies. He received intravenous immunoglobulin (IVIg), rituximab and plasmapheresis, and his pancreatic function normalized. We conclude that clinically significant AMR can develop in a pancreas allograft and recommend that pancreatic biopsies be assessed for C4d deposition if the patient has risk factors for AMR and/or the pathologic evidence for cell-mediated rejection is underwhelming.

Adult↗
PubMed2003

New HLA haplotype frequency reference standards: high-resolution and large sample typing of HLA DR-DQ haplotypes in a sample of European Americans.

A collaborative study involving a large sample of European Americans was typed for the histocompatibility loci of the HLA DR-DQ region and subjected to intensive typing validation measures in order to accurately determine haplotype composition and frequency. The resulting tables have immediate application to HLA typing and allogeneic transplantation. The loci within the DR-DQ region are especially valuable for such an undertaking because of their tight linkage and high linkage disequilibrium. The 3798 haplotypes, derived from 1899 unrelated individuals, had a total of 75 distinct DRB1-DQA1-DQB1 haplotypes. The frequency distribution of the haplotypes was right skewed with haplotypes occurring at a frequency of less than 1% numbering 59 and yet constituting less than 12% of the total sample. Given DRB1 typing, it was possible to infer the exact DQA1 and DQB1 composition of a haplotype with high confidence (>90% likelihood) in 21 of the 35 high-resolution DRB1 alleles present in the sample. Of the DRB1 alleles without high reliability for DQ haplotype inference, only *0401, *0701 and *1302 were common, the remaining 11 DRB1 alleles constituting less than 5% of the total sample. This approach failed for the 13 serologically equivalent DR alleles in which only 33% of DQ haplotypes could be reliably inferred. The 36 DQA1-DQB1 haplotypes present in the total sample conformed to the known pattern of permissible heterodimers. Four DQA1-DQB1 haplotypes, all rare, are reported here for the first time. The haplotype frequency tables are suitable as a reference standard for HLA typing of the DR and DQ loci in European Americans.

Gene Frequency↗
PubMed2002

Non-invasive determination of the paternal HLA haplotype of a fetus using kinetic PCR to detect fetal microchimerism in maternal plasma.

Knowledge of fetal HLA type can be important if cord blood (CB) is being considered as a stem cell source for transplantation. The feasibility of determining the paternally inherited HLA haplotype of a fetus was explored through analysis of fetal DNA in the maternal circulation. A 5-year-old child with relapsed acute leukemia was a candidate for transplantation. The HLA type of the fetal sibling was needed to assist with evaluation of this potential cord blood donor. DNA was isolated from maternal plasma and whole blood. Kinetic PCR using sequence-specific primers for paternal HLA-A, -B, and -DRB1 alleles was performed. Alleles corresponding to one paternal haplotype were detectable in plasma, but not in whole blood. Alleles from the alternative haplotype were not detectable. This demonstrated that the fetus shared at least one haplotype with the patient and therefore arrangements were made to bank the CB. The maternal haplotype of the fetus could not be determined in the presence of maternal DNA. The prenatal fetal typing was confirmed by typing the newborn's CB. This rapid non-invasive technique may facilitate the selection of CB units for banking based on needed HLA types.

Acute Disease↗
PubMed2001

Influence of pretransplant pregnancy on survival of renal allografts from living donors.

BACKGROUND: The presence of a small number of cells of donor origin in organ transplant recipients (microchimerism) may influence allograft survival and may induce tolerance. Postpartum women may be microchimeric to offspring hematopoietic cells up to 27 years. We hypothesized that mothers receiving renal allografts from offspring would have better graft survival compared with either fathers receiving allografts from offspring, or mothers receiving allografts from nonoffspring donors. METHODS: We analyzed 1803 living related kidney transplants from the UNOS database performed between January 1, 1990, and December 31, 1995, for mothers and fathers who received grafts from offspring with one haplotype match. We also compared these mothers with parous females receiving a kidney from nonoffspring donors (spouse and other biologically related or unrelated family members). A multivariate logistic regression method was used to analyze the effect of donor type, as well as other recipient, donor, and transplant characteristics, on graft and patient survival. RESULTS: Mothers receiving one haplotype-matched offspring renal allografts did not have better graft survival at 1 or 3 years posttransplant compared with fathers receiving similar grafts. There was also no difference in graft or patient survival between mothers receiving kidney grafts from either offspring or nonoffspring donors. Graft survival in mothers with multiple pregnancies was poorer than those with a single pregnancy. CONCLUSIONS: It is possible that persistent microchimerism of fetal cells in maternal circulation may, for some mothers, cause a detectable improvement in graft or patient survival. Comparison of female and male recipients from the UNOS database did not reveal any differences in outcomes. If mothers are tolerant to their offspring, our results indicate that this microchimerism may not improve renal allograft or patient survival in offspring donor to maternal recipient combinations. Lastly, more sensitive pretransplant cross-match assays may need to be implemented in multiparous women, given our results.

Adult↗
PubMed2000

The extent of HLA class II allele level disparity in unrelated bone marrow transplantation: analysis of 1259 National Marrow Donor Program donor-recipient pairs.

A comprehensive analysis of the HLA-D region loci, DRB1, DRB3, DRB5, DQA1, DQB1, DPA1 and DPB1, was performed to determine allelic diversity and underlying HLA disparity in 1259 bone marrow recipients and their unrelated donors transplanted through the National Marrow Donor Program. Although 43.0% of DRB1 alleles known to exist at the beginning of the study were found in this predominantly Caucasian transplant population, a few alleles predominated at each locus. In recipients, 67.1% of DRB1 alleles identified were one or two of six common DRB1 alleles. Only 118 (9.4%) donor-recipient pairs were matched for all alleles of DRB1, DQA1, DQB1, DPA1 and DPB1. While 79.4% of the pairs were matched for DRB1, only 13.2% were matched for DPB1 alleles. Almost 66% of pairs differed by more than one allele mismatch and 59.0% differed at more than one HLA-D locus. DQB1 was matched in 85.9% of DRB1-matched pairs. In contrast, only 13.9% of the pairs matched for DRB1, DQA1 and DQB1 were also matched for DPA1 and DPB1. This database, highlighting the underlying HLA disparity within the pairs, forms the foundation of an ongoing study to establish the relationship between HLA matching and successful outcome in unrelated allogeneic stem cell transplant.

Alleles↗
PubMed1998

Successful unrelated marrow transplantation for patients over the age of 40 with chronic myelogenous leukemia.

Some older patients (> or =40 years) with chronic myelogenous leukemia (CML) who lack human leukocyte antigen (HLA)-identical sibling donors are not offered unrelated marrow transplantation because of concerns over excessive regimen-related toxicity, in particular due to graft-vs.-host disease (GVHD). The purpose of this study was to determine the efficacy and toxicity of unrelated marrow transplantation in older CML patients using a regimen designed to minimize the severity of GVHD. Thirty-one consecutive patients over the age of 40 with CML received unrelated marrow transplants between January 1988 and June 1997. Twenty-one patients were transplanted in chronic phase while ten were transplanted in the accelerated phase of their disease. Fifteen patients received transplants from phenotypically matched donors while 16 received marrow grafts from donors who were mismatched at one HLA locus. GVHD prophylaxis consisted of ex vivo T cell depletion of the donor marrow graft plus posttransplant cyclosporine administration. Durable engraftment was achieved in 29 of 31 patients (94%). The probability of developing grades II-IV or severe grades III-IV acute GVHD was 39.2 and 7.1%, respectively. There was no difference in the incidence of grades II-IV acute GVHD between patients transplanted with marrow grafts from phenotypically matched (38.1%) vs. those transplanted from mismatched unrelated donors (40%, p = 0.99). The 2-year probability of relapse for the entire population was 29.4%. Relapse was significantly higher for patients transplanted in accelerated phase (60%) than for those in chronic phase (13.8%, p = 0.027). The 2-year probability of overall survival and disease-free survival for the entire cohort was 56 and 45%, respectively. There was no significant difference in survival or disease-free survival for patients receiving phenotypically matched vs. mismatched marrow grafts. Immunological reconstitution for this cohort was compared with a younger (<40 years) patient population that had been similarly transplanted over the same time period. Immune function as assessed by total T cell, B cell, NK cell, and T cell subset reconstitution posttransplant was quantitatively equivalent in the two groups with most parameters normalizing within 18 months of transplant. We conclude that CML patients over the age of 40 who have either phenotypically matched or one antigen-mismatched unrelated donors can successfully undergo allogeneic marrow transplantation. T cell depletion of the marrow graft may be advantageous in these older patients by reducing GVHD severity, particularly in those patients transplanted with HLA-disparate marrow grafts.

Adult↗
PubMed1998

Cord Blood Transplantation Study (COBLT): cord blood bank standard operating procedures.

In 1995, the National Heart Lung and Blood Institute (NHLBI) solicited requests for a proposal (RFP) entitled "Transplant Centers for Clinical Research on Transplantation of Umbilical Cord Stem and Progenitor Cells." Three banks, six transplant centers, and one medical coordinating center (MCC) (Table 1) were funded with the overall goal of banking cord blood units (CBU) using a single manual of operations. Furthermore, the clinical protocols to evaluate the transplant outcome for adult and pediatric recipients of these well-characterized CBU would be analyzed in a uniform fashion. Because of the intense interest of the transplantation community in the policies and procedures for cord blood collection and processing, the principal investigators of the cord blood banks (CBB) and NHLBI elected to submit for publication the rationale and an abridged, but detailed, version of the standard operating procedures (SOP) developed between October 1996 and July 1998 prior to the initiation of the clinical protocols to be performed with these CBU. As the SOP will be refined over time, the complete SOP and subsequent amendments will be published and continually updated on the websites from the MCC-The EMMES Corporation (www.EMMES.com). All forms referred to in this document may be obtained from the EMMES website. It is hoped that the publication of this document will lay down a framework that will not only facilitate the development of other CBB but also help us more rapidly define what constitutes an "acceptable" CBU product.

Adult↗
PubMed1997

Association of donor-derived host-reactive cytolytic and helper T cells with outcome following alternative donor T cell-depleted bone marrow transplantation.

Recipients of marrow from alternative donors (unrelated or HLA-mismatched related donors) have a higher incidence of post-transplant complications compared to recipients of marrow from HLA-identical siblings. HLA disparity undetected by routine typing techniques has been suggested as one cause for the increased complications observed. Limiting dilution analysis (LDA) of donor-derived, host-reactive T cell precursor frequency prior to transplant has been proposed as a surrogate indicator of underlying HLA disparity which might be used to predict transplant outcome and aid in donor selection. We compared results of LDA of host-reactive IL-2 producing helper T lymphocytes (HTLp) and/or cytolytic T lymphocytes (CTLp) in 77 alternative marrow donor/recipient pairs with transplant outcome using univariate and multivariate analysis. All donor grafts were depleted ex vivo of mature T cells. Median patient age was 15 years (1-53). Donor selection was based on serologic typing for HLA class I and high resolution oligotyping for HLA-DRB1-DRB5, and HLA-DQB1. HLA-A and HLA-B locus antigens were retrospectively defined by one dimensional isoelectric focusing (IEF). Cox proportional hazards regression models were used to assess the impact of frequency and estimated cell dose of CTLp and HTLp on outcome. The CTLp assay was most sensitive to HLA-A and HLA-B locus disparity detected by serology or IEF. The HTLp assay detected class I disparity but was most strongly reactive in the presence of HLA-DRB1 disparity. Univariate analysis indicated a significant association of CTLp frequency and dose with severe (grades 3-4) acute graft-versus-host disease (GVHD), and of CTLp dose with chronic GVHD. Both assays were associated with survival and neither assay was associated with relapse. After adjustment for other significant covariables including known HLA disparity, the association of CTLp with acute GVHD was lost, however, CTLp frequency and CTLp dose remained associated with survival and HTLp frequency was associated with chronic GVHD. These data support the hypothesis that post-BMT complications may be influenced not only by T cell dose but by the alloreactive potential of the cells infused. LDA of alloreactive potential was useful in detecting disparity and in predicting survival or chronic GVHD in recipients of alternative donor TCD marrow grafts.

Adolescent↗
PubMed1996

DRB1*1316: evolutionary and functional implications of a novel polymorphism at codon 86.

HLA-DRB1 molecules contain extensive polymorphism localized to specific functional regions of the antigen binding site (ABS). Position 86 of HLA-DRB1 molecules modulates a hydrophobic pocket in the ABS which acts as a peptide anchoring site [1]. We report the nucleotide sequence of HLA-DRB1*1316 which is identical to HLA-DRB1*1301 and *1302 except at codon 86. The novel allele encodes aspartate rather than valine or glycine at position 86. Val86 and Gly86 have been exclusively observed in thousands of oligotyped specimens; thus Asp86 is a rare polymorphism which is significant with respect to hypotheses concerning evolution and structure-function relationships of HLA-DRB1 molecules.

Alleles↗
PubMed1996

Unrelated donor bone marrow transplantation to treat severe aplastic anaemia in children and young adults.

Alternative donor bone marrow transplantation (BMT) to treat severe aplastic anaemia (SAA) in children and young adults has been complicated by high rates of graft rejection and severe graft-versus-host disease (GVHD). We hypothesized that increased immunosuppression combined with T-cell depletion of the marrow graft would enable successful use of unrelated donor BMT in this disease. Preconditioning consisted of cytosine arabinoside, cyclophosphamide, and total body irradiation (TBI). T-cell depletion was with the anti-CD3 antibody T10B9. GVHD prophylaxis consisted of cyclosporine A. 28 previously transfused patients were transplanted. Nine donor/recipient pairs were HLA matched. As of 1 January 1996, 15/28 (54%) patients are alive, transfusion independent and well with a range of follow-up of 13 months to 8 years (median 2.75 years). Fatalities include all three patients with nonengraftment and all three patients with grade III/IV GVHD. Other fatalities were due to infections or therapy-related toxicity. The incidence >or= grade II acute GVHD was 28%. These data show that in children with SAA who have failed immunosuppression, unrelated donor BMT offers a reasonable hope of long-term survival.

Adolescent↗
PubMed1996

Large-scale DRB and DQB1 oligonucleotide typing for the NMDP registry: progress report from year 2.

DNA typing of HLA class II alleles of the DRB1/3/4/5 and DQB1 loci using sequence-specific oligonucleotide probes and polymerase chain reaction amplified DNA has been used for the large-scale typing of donors for the National Marrow Donor Program unrelated donor registry. The results of quality control analysis for the second year of the project (10/1/939/30/94) show the typing continues to be highly accurate, specific, and reliable. The average percent of correctly classified HLA oligotypes (groups of alleles defined by a hybridization pattern with a panel of sequence-specific oligonucleotide probes) based on 9,244 DRB1 and 7,244 DQB1 assignments was 99.8% (range 99.4%100.0%) for DRB1/DRB3/DRB4/DRB5 and 99.8% (range 99.6%100.0%) for DQB1. This level of accuracy is particularly remarkable because the 4,636 DRB quality control samples were tested blindly and could not be distinguished from 57,580 donor samples tested at the same time by the laboratories.

Alleles↗
PubMed1996

Sequenase sequence profiles used for HLA-DPB1 sequencing-based typing.

Sequencing-based HLA typing (SBT) is a PCR based high resolution HLA typing method in which polymorphic regions of the gene are sequenced and directly used for typing. Currently, for class II SBT, alleles are identified by comparison of the exon 2 sequence with their corresponding allele sequence library. Routine SBT requires reliable identification of heterozygosity, and automated assignment of the alleles. In sequencing strategies different enzymes can be used for primer extension. The most characteristic difference between sequences obtained by two protocols using Sequenaseregistered, or Taq-cycle sequencing, respectively, is a difference in incorporation of nucleotides in the primer extension leading to different sequence profiles. In Taq-cycling sequencing variable nucleotide incorporation results in irregular, but reproducible peak patterns, whereas Sequenase incorporates nucleotides in nearly equal amounts, resulting in more even peak patterns. In a previously published multi-center study we evaluated HLA-DPB1 SBT using Taq-cycle sequencing, and showed that typing can reliably be performed, considering the specific sequence profiles. In this study the applicability of Sequenase for HLA-DPB1 SBT was tested. A panel of samples were typed by SBT at five test sites which participate in the Sequencing Based Typing component of the 12th International Histocompatibility Workshop. The panel represents the existing polymorphism at all known polymorphic positions of exon 2, both in homozygous and heterozygous combinations. The assignment of homozygosity and heterozygosity was validated by Multi-Sequence Analysis, performing cluster analysis of chromatographic data of all sequences at each position. Sequence characteristics were examined and considered for appropriate assignment. Data reveals that Sequenase sequencing can also reliably be used for HLA-DPB1 typing.

Bacteriophage T7↗