Search PubMed⌕ Search

Biomedical subjects

B A Bradley

Publications and source records attributed to B A Bradley.

At least 19 recordsLinked to original sources
PubMed2004

Incidence and specificity of HLA antibodies in multitransfused patients with acquired aplastic anemia.

BACKGROUND: This study aimed to establish the prevalence and characteristics of anti-HLA in antibody acquired aplastic anemia patients following cessation of antithymocyte globulin therapy and to characterize antibody in terms of epitope specificity. STUDY DESIGN AND METHODS: One hundred and fifty multitransfused, untransplanted patients from eight European centers were investigated by serologic methods. RESULTS: Sixty-two percent were antibody positive. Eighteen HLA-Class-I-specific antibodies (15 IgG, 3 IgM) were identified in 13 patients; 13 antibodies were specific for HLA-A epitopes and 5 for HLA-B. Epitope analysis identified significant correlation between serum reactivity and amino acid substitutions associated with HLA-Class-I epitopes. An excess of antibodies to HLA-A1-associated cross-reactive groups was identified. There was no significant difference in antibody frequency in patients taking cyclosporine compared to those who were not. CONCLUSION: Data suggested a contribution from B cell memory of alloantigens introduced during pregnancy. In some cases, antibody production continued many years after the last transfusion, and although the target varied between individual patients, the antibody to HLA was focused on a few specific Class I epitopes, the majority of which mapped to the HLA-A molecule.

Adult↗
PubMed2002

In vitro expansion of cord blood does not prevent engraftment of severe combined immunodeficient repopulating cells.

This study aimed to assess the potential of human cord blood (CB) cells to engraft in the xenogenic non-obese diabetic/severe combined immunodeficient (NOD/SCID) mouse model after in vitro expansion culture. We also studied the quality of human haemopoiesis arising from the transplantation of fresh or expanded cells in this model. Cord blood CD34(+) cells were cultured for 3, 7 or 10 d with stem cell factor, Flt3, thrombopoietin, interleukin 3 (IL-3), IL-6 and granulocyte colony-stimulating factor, all at 10 ng/ml in serum-replete conditions. Transplantation of mice with fresh CB containing 3 x 10(4) CD34(+) cells and 1-2 SCID repopulating cells (SRC) resulted in a median of 7.4% (0.4%-76.8%) human engraftment. When mice received the expanded product of 1-2 SRC, the ability to repopulate NOD/SCID mice was maintained even after 10 d of in vitro culture. Serial dilution of the expanded cells suggested that in vitro expansion had increased SRC numbers two- to fourfold. Expanded SRC produced long-term culture-initiating cells, clonogenic cells and CD34(+) cells in the same proportions as fresh cells after successful engraftment. Therefore, expanded SRC were able to differentiate in the same way as fresh SRC. There was a trend towards lower levels of engraftment when d 7 cultured cells were transplanted (median engraftment 0.8%, range 0.0-24.0%) compared with 1-2 fresh SRC. Our data suggest that this is owing to reduced proliferation of cultured cells in vivo. By utilizing limiting numbers of CB SRC, we confirmed that the engraftment potential of SRC in the NOD/SCID model was preserved after in vitro expansion. Furthermore, dilution experiments strongly suggest two- to fourfold expansion of SRC in vitro. These studies are relevant for developing clinical stem cell expansion strategies.

Animals↗
PubMed2000

Does the risk of acute rejection really decrease with increasing recipient age?

In corneal transplants the risks of acute rejection and graft failure decrease with increasing recipient age, but kidney graft survival analyses tend to show the opposite effect. Why is this? Cadaveric kidney transplants performed in the UK and Republic of Ireland between 1985 and 1993 (UKTSSA database) were analysed by multifactorial methods to identify major factors affecting graft survival. In a study database that had been censured for technical failure and death with a functioning transplant, it was shown that increasing recipient age was associated with decreasing risk of graft failure at 1 year. This is consistent with the view that kidney transplants, like corneal transplants, are less likely to be acutely rejected as the age of the recipient increases.

Adolescent↗
PubMed2000

Quantitation of cyclosporine-sensitive and -resistant allospecific cytotoxic cells at birth.

In the absence of clinically relevant models of acute rejection we have attempted to develop an assay to measure cyclosporine-resistant allospecific cytotoxic cells in vitro, beginning at birth. The principle of limiting dilution analysis was applied to investigate umbilical cord bloods as responders. Responders were incubated for 1 h in different concentrations of cyclosporine and irradiated HLA mismatched stimulator cells from healthy adults added, followed by recombinant IL-2. After 7 days, responders were tested against three europium-labelled PHA blasts: stimulator, responder and third party. A significant number of cyclosporine-resistant allospecific cytotoxic cell precursors were found in cord blood indicating prior activation. They may have been primed in utero against non-inherited maternal HLA antigens. Cyclosporine-resistant allospecific cytotoxic cell precursors were demonstrated in human umbilical cord blood using a quantitative assay. These cells may influence the reaction to subsequent transplants.

Adult↗
PubMed1997

Molecular advances in the etiology and treatment of colorectal cancer.

The diagnosis and treatment of colorectal cancer remains a formidable health care problem. Colorectal cancer is the second most frequently diagnosed cancer in both men and women in Western countries and accounts for over 55,000 deaths annually in the United States alone. Cancer of the colon and rectum is eminently curable by surgical resection if identified early; however, despite our best efforts, patient survival from this disease has changed little over the past 50 years. With the advent of molecular and genetic techniques, a number of novel discoveries have been made in the last decade which have greatly expanded our understanding of the etiology and cellular mechanisms contributing to the development and subsequent progression of colorectal cancer. This review summarizes the recent molecular advances in the understanding of both familial (HNPCC and FAP) and sporadic colorectal cancers. The numerous scientific advances described in this review offer the promise of the development of novel chemotherapeutic agents, more accurate prognostic indicators and better screening techniques.

Adenocarcinoma↗
PubMed1997

Donor search or autografting in patients with acute leukaemia who lack an HLA-identical sibling? A matched-pair analysis. Acute Leukaemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation (EBMT) and the International Marrow Unrelated Search and Transplant (IMUST) Study.

One hundred and ninety-one patients with acute leukaemia who received bone marrow from HLA-A, -B and -DR identical unrelated donors and were reported to EBMT and/or IMUST, were matched with 382 patients receiving autologous bone marrow for diagnosis, age, stage of disease and year of transplantation. Transplant-related mortality (TRM) was significantly higher in recipients of unrelated marrow compared to autograft recipients, 44 +/- 4% (+/- 95% confidence interval) and 15 +/- 3% at 2 years in the two groups, respectively (P < 10(-4)). In contrast, relapse probability was lower in recipients of unrelated marrow, being 32 +/- 5% at 2 years compared to 55 +/- 3% in recipients of autografts (P < 10(-4)). Two-year leukaemia-free survival (LFS) in patients with acute lymphoblastic leukaemia was 39 +/- 5% and 32 +/- 3% in the two groups, respectively. Among patients with acute myeloid leukaemia (AML), the corresponding figures were 36 +/- 6% and 46 +/- 5% in the two groups, respectively (P = NS). In AML in first remission (CR-1), the 2-year survival was 42 +/- 10% in recipients of unrelated bone marrow, compared to 69 +/- 8% in autograft recipients (P = 0.008). When all patients with acute leukaemia were included, the 2-year LFS was 38% in recipients of unrelated marrow, compared to 37% in autograft recipients (NS). In conclusion, this retrospective analysis supports the design of a prospective randomized study in patients with high-risk/advanced acute leukaemia who lack a suitable related bone marrow donor, to ascertain which of the two strategies, if any, should be favoured.

Acute Disease↗
PubMed1997

Conclusions of the corneal transplant follow up study. Collaborating Surgeons.

AIM: On the basis of finalised data from the Corneal Transplant Follow up Study to identify and quantify factors influencing corneal graft outcome in terms of graft survival, rejection, visual acuity, and astigmatism. METHODS: Multifactorial analysis of 2777 grafts registered by the UK Transplant Support Service from July 1987 to June 1991. RESULTS: Several recipient factors influencing graft survival, rejection, and visual acuity were identified, but no donor factors. Of the operative factors amenable to change, mixed suturing was associated with reduced graft survival, and larger grafts with increased risk of rejection but better visual acuity when surviving. There was increased risk of rejection with poor matching at HLA class I antigens, but mismatched HLA-DR grafts suffered less rejection than those with zero HLA-DR mismatches. Recipient age below 10 years was associated with increased risk of both rejection and graft failure. However, whereas increasing age above 10 years was not associated with differential graft survival, it was significantly associated with decreasing risk of rejection. CONCLUSIONS: While confirming possible benefits of HLA-A and B matching, the expense and delay involved in awaiting matched HLA-DR tissue is unlikely to be justified. Other donor factors are unrelated to graft outcome following screening of tissue by eye banks. The highest rates of graft failure and rejection happen in the early postoperative period, and factors influencing visual outcome are also apparent at this stage.

Adolescent↗
PubMed1997

Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings.

PURPOSE: To compare outcomes of bone marrow transplants for leukemia from HLA-identical siblings, haploidentical HLA-mismatched relatives, and HLA-matched and mismatched unrelated donors. PATIENTS: A total of 2,055 recipients of allogeneic bone marrow transplants for chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) were entered onto the study. Transplants were performed between 1985 and 1991 and reported to the International Bone Marrow Transplant Registry (IBMTR). Donors were HLA-identical siblings (n = 1,224); haploidentical relatives mismatched for one (n = 238) or two (n = 102) HLA-A, -B, or -DR antigens; or unrelated persons who were HLA-matched (n = 383) or mismatched for one HLA-A, -B, or -DR antigen (n = 108). HLA typing was performed using serologic techniques. RESULTS: Transplant-related mortality was significantly higher after alternative donor transplants than after HLA-identical sibling transplants. Among patients with early leukemia (CML in chronic phase or acute leukemia in first remission), 3-year transplant-related mortality (+/-SE) was 21% +/- 2% after HLA-identical sibling transplants and greater than 50% after all types of alternative donor transplants studied. Among patients with early leukemia, relative risks of treatment failure (inverse of leukemia-free survival), using HLA-identical sibling transplants as the reference group, were 2.43 (P < .0001) with 1-HLA-antigen-mismatched related donors, 3.79 (P < .0001) with 2-HLA-antigen-mismatched related donors, 2.11 (P < .0001) with HLA-matched unrelated donors, and 3.33 (P < .0001) with 1-HLA-antigen-mismatched unrelated donors. For patients with more advanced leukemia, differences in treatment failure were less striking: 1-HLA-antigen-mismatched relatives, 1.22 (P = not significant [NS]); 2-HLA-antigen-mismatched relatives, 1.81 (P < .0001); HLA-matched unrelated donors, 1.39 (P = .002); and 1-HLA-antigen-mismatched unrelated donors, 1.63 (P = .002). CONCLUSION: Although transplants from alternative donors are effective in some patients with leukemia, treatment failure is higher than after HLA-identical sibling transplants. Outcome depends on leukemia state, donor-recipient relationship, and degree of HLA matching. In early leukemia, alternative donor transplants have a more than twofold increased risk of treatment failure compared with HLA-identical sibling transplants. This difference is less in advanced leukemia.

Age Factors↗
PubMed1996

Clinical and surgical factors influencing corneal graft survival, visual acuity, and astigmatism. Corneal Transplant Follow-up Study Collaborators.

PURPOSE: To quantify clinical and operative factors that influence corneal graft outcome. METHODS: A multifactorial analysis was done on 2242 corneal grafts registered by the United Kingdom Transplant Service from July 1987 to June 1991. RESULTS: There was an increased risk of graft failure in patients with preoperative diffuse and other noncentral stromal edema, less-common eye diseases, small trephine size, difference in donor and recipient sizes greater than 0.25 mm, and use of mixed continuous and interrupted sutures. Visual acuity 3 months after surgery was poorer in patients who had glaucoma and low visual acuity preoperatively, small trephine size, and combined vitreous surgery. Use of interrupted sutures resulted in higher astigmatism at 3 months. CONCLUSIONS: After allowing for the effects of recipient factors, surgical factors significantly affected corneal graft outcome. No factors that showed significant benefits for graft survival also adversely affected visual performance. Details of medical history, clinical condition, and surgical method failed to predict more than a small proportion of observed variability in visual performance of functioning grafts.

Astigmatism↗
PubMed1996

Optimal cryopreservation of human umbilical cord blood.

Cryopreservation techniques for umbilical cord blood (UCB) have been based on methods established for marrow (BM) and peripheral blood progenitor cells (PBPC) with varying degrees of success. The aim of this study was to optimise cryopreservation of UCB haemopoietic cells based on sound cryopreservation principles. UCB samples were cryopreserved with different combinations of DMSO and hydroxyethyl starch (HES) by a variety of freezing protocols. After cooling at 1 degree C/min in solutions containing 4% HES and various concentrations of DMSO there was a dramatic fall in CD34+ recovery from 85.4% (s.d. 28.4) to 12.2% (s.d. 10.0) as DMSO concentration was reduced from 5 to 2.5%. Varying HES concentration in solutions containing 5% DMSO did not have a significant effect on CD34+ cell recovery. Increasing cooling rate from 1 to 10 degrees C/min significantly reduced CD34+ recovery (P < 0.0001) while increasing DMSO concentration up to 10% had little effect (P = 0.8, two-way ANOVA). Good recovery of UCB CD34+ cells can be achieved with 5-10% DMSO at a controlled cooling rate of 1 degrees C/min. There was a significant difference (P < 0.0001) in the apparent recovery of CD34+ cells between paired aliquots thawed in the presence (recovery = 76.8%, s.d. 26.0) and absence (32.5%, s.d. 18.7) of DNase. In conclusion, conditions for cryopreserving UCB for clinical banking that yield optimal recovery of CD34+ cells have been established.

Antigens, CD34↗
PubMed1995

The predictive value of epitope analysis in highly sensitized patients awaiting renal transplantation.

The accumulation of highly sensitized patients (HSP) on renal transplant waiting lists is a problem faced by all transplant registries. We have studied the HLA class I serological reactivity of 20 random HSP and have related antibody specificity to primary amino acid sequence. In six patients we identified significant correlations (chi 2 test, r > or = 0.93) between panel reactivity and specific amino acid substitutions characteristic of HLA-A, -B, and -C public epitopes. Antibody reactivity was associated with up to three public epitopes in each patient. The 12 separate antibody specificities identified were associated with 10 residues. Seven correlated with HLA-A locus substitutions (Glu-62/Gly-65, Lys-66, Arg-114, His-114/Tyr-116/Lys-127, Thr-142/His-145 [x2], and Thr-149), two with HLA-B locus substitutions (Thr-24, Ser-24) and three with interlocus antibodies associated with either HLA-A and B (Leu-82/Arg-83 [x2]) or with HLA-B and -C substitutions (Leu-163). This information allowed us to predict HLA class I allelic products of known primary sequence that would react negatively with each HSP serum. Windows of acceptable mismatches (WAMMs) can thus be delineated with a view to crossmatch negative transplantation without the need for exhaustive serological analysis. Surprisingly we found that WAMMs for these patients included up to 80% of the 10 commonest HLA class I haplotypes in the British population with four patients being crossmatch compatible with A1,3; B7,8. These observations lead us to propose a more intelligent approach to transplanting HSP based on epitope analysis and definition of WAMMs.

Antibody Specificity↗
PubMed1995

Non-MHC antigens and their relative resistance to immunosuppression after corneal transplantation.

We have used a high responder rat model to examine the role that non-MHC antigens play in corneal graft rejection. Recipients were backcross animals derived from a cross between two inbred strains, which mimicked the human outbred population in that donor and recipient could be matched or mismatched for MHC antigens, while non-MHC mismatches were variable and unknown. All mismatched grafts and 87% of matched grafts were rejected (median survival 11 and 17 days respectively). The high incidence of rejection of matched grafts indicates that several independently segregating non-MHC genes play a role in rejection. Moreover, the immune response to matched grafts appeared resistant to immunosuppression, suggesting that matching does not permit reduced dosage of immunosuppressants. A mechanism is discussed whereby matching at the class II locus may enhance presentation of mismatched histocompatibility antigens or viral peptides derived from infected graft cells, thereby prejudicing graft survival.

Animals↗
PubMed1995

HLA-DQB1 and DQA1 matching by ambient temperature PCR-SSCP.

We have developed a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) protocol for rapid matching of DQA1 and DQB1 alleles. Electrophoresis can be performed at ambient temperature within the range 18-28 degrees C without continuous gel cooling. The method has been tested on 27 patient-potential bone marrow donor pairs for DQB1 and 31 pairs for DQA1. Bone marrow pairs were chosen to represent a broad range of common alleles based upon previous restriction fragment length polymorphism (RFLP) analysis type assignments. Samples were re-typed by PCR with sequence-specific primers (PCR-SSP) and the results compared to matching by PCR-SSCP analysis. There was a 100% correlation between PCR-SSP and PCR-SSCP analysis for DQB1, and a 97% correlation for DQA1 matching.

Base Sequence↗
PubMed1995

A survey of use of unrelated volunteer donor bone marrow transplantation at 46 centres worldwide, 1989-93. International Marrow Unrelated Search and Transplant (IMUST) Study.

Unrelated donor bone marrow transplantation is increasingly used to treat haemopoietic disorders where no HLA-identical sibling is available. The International Marrow Unrelated Search and Transplant Study has collected core data on consecutive unrelated donor BMT (UD-BMT) and HLA-identical sibling donor BMT (ID-BMT) performed in 46 participating centres world-wide between March 1989 and February 1993. Eighteen UD-BMT were performed in the first 6-month period in 14 participating centres, while in the last period there were 103 UD-BMT in 46 centres. The percentage of BMT recipients with the following diagnoses were: bone marrow failure UD-BMT 15% and ID-BMT 11%; AML 13% and 27%; ALL 18% and 17%; CML 48% and 31%; and other diseases 7% and 14%. Thirty-eight per cent of UD-BMT recipients had advanced disease compared with only 23% of ID-BMT recipients. Thirty six per cent of UD-BMT compared with 21% of ID-BMT recipients were under 16 years old. More extreme differences in pre-transplant clinical characteristics between UD and ID-BMT recipients were found when diagnosis and stage of disease were considered together. This survey indicates how UD and ID-BMT are currently used in the treatment of haematological disease; however, longer follow-up is required to assess the value of UD-BMT in the management of patients with bone marrow disorders.

Adolescent↗