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Biomedical subjects

A Fuller

Publications and source records attributed to A Fuller.

At least 19 recordsLinked to original sources
PubMed2006

Cytokine profiles during carrageenan-induced inflammatory hyperalgesia in rat muscle and hind paw.

UNLABELLED: It is not known if a cytokine cascade develops during muscle inflammation and whether cytokines contribute to muscle inflammatory pain. We measured plasma and tissue cytokine concentrations, and behavioral responses to noxious mechanical stimuli, after inducing inflammation in the gastrocnemius muscle and the hind paw of rats. Tissue and plasma samples were taken 3, 6, or 24 h after carrageenan or saline injection into one of the 2 sites. Tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and cytokine-induced neutrophil chemoattractant 1 (CINC-1) concentrations were measured. Hyperalgesia was present 3 h after carrageenan injection into the hind paw and muscle. The TNF-alpha was elevated significantly in the inflamed hind paw tissue (P < .001) but not in inflamed muscle tissue. IL-1beta was elevated 6 h after carrageenan injection in the hind paw tissue but only 24 h in the muscle tissue (P < .001). The IL-6 was elevated 3 h after injection in the hind paw tissue but only after 6 h in the muscle tissue (P < .01). The CINC-1 in plasma, muscle, and hind paw was elevated from 3 h to 24 h after carrageenan injection (P < .01). The release of IL-1beta and IL-6, known to mediate hyperalgesia elsewhere, is delayed in muscle inflammation compared with cutaneous inflammation, whereas TNF-alpha is not elevated during muscle inflammation. PERSPECTIVE: The quality and mechanisms of muscle pain are different from that of cutaneous pain. So too is the pattern of cytokine release during inflammation. Inhibiting TNF-alpha is unlikely to be effective in managing inflammatory muscle pain, but other cytokines, notably IL-1beta and CINC-1, may prove useful therapeutic targets.

Animals↗
PubMed2005

Pre- and post-engraftment bloodstream infection rates and associated mortality in allogeneic hematopoietic stem cell transplant recipients.

We report on bloodstream infection (BSI) rates, risk factors, and outcome in a cohort of 298 adult and pediatric hematopoietic stem cell transplantation (HSCT) recipients at Memorial Sloan-Kettering Hospital from September 1999 through June 2003. Methods. Prospective surveillance study. BSI rates are reported per 10,000 HSCT days. Date of engraftment is defined as the first of at least 3 consecutive dates of absolute neutrophil count >500/mm(3) after stem cell infusion. BSI severity grades: severe (intravenous antibiotics), life threatening (sepsis), or fatal (caused or contributed to death). Results. The incidence of pre- and post-engraftment BSI was 22% and 19.5%, respectively. Pre-engraftment highest rates were observed for viridans streptococci (58), Enterobacteriaceae (39), and Enterococcus faecium (34). Post-engraftment rates ranged from 0.2 to 2.9 without any predominant pathogen. In multivariate analyses, pre-engraftment BSI was associated with diagnosis of chronic myelogenous leukemia, age >18 years and peripheral blood stem cell graft; post-engraftment BSI was associated with acute graft-versus-host disease, neutropenia, and liver or kidney dysfunction. Attributable mortality was 12.5% and 1.7% for pre- and post-engraftment BSI, respectively. BSI fatality rates were 24% for viridans streptococci, 8% for E. faecium, 11% for Staphylococcus aureus, and 67% for Candida. Conclusions. Pre-engraftment BSI, especially by viridans streptococci and E. faecium, was associated with substantial attributable mortality. Post-engraftment BSI was a marker of post-transplant complications and rarely the primary cause of death.

Adolescent↗
PubMed2005

Thermoregulatory, motor, behavioural, and nociceptive responses of rats to 3 long-acting neuroleptics.

We investigated physiological effects of intramuscular injections of the following 3 long-acting neuroleptics commonly used in wildlife management: haloperidol (0.05, 0.1, and 0.5 mg/kg body mass), zuclopenthixol acetate (0.5, 1, and 5 mg/kg), and perphenazine enanthate (1, 3, and 10 mg/kg), in a rat model. Body temperature and cage activity were measured by intra-abdominal telemeters. Nociceptive responses were assessed by challenges to noxious heat and pressure. Haloperidol (0.5 mg/kg) produced a significant nocturnal hypothermia (p < 0.05) and decreased nighttime cage activity and food intake. Zuclopenthixol (5 mg/kg) significantly decreased nighttime body temperature and cage activity and, at 1 mg/kg and 5 mg/kg, significantly decreased food intake 5-17 h after injection (p < 0.05). Perphenazine (10 mg/kg) significantly decreased nighttime body temperature and cage activity and, at all doses, significantly decreased food intake 5-17 h after injection (p < 0.05). Significant analgesic activity was evident in rats given 5 mg/kg zuclopenthixol up to 40 h after injection, and 10 mg/kg perphenazine from 48 to 96 h after injection (p < 0.0001). Zuclopenthixol (5 mg/kg) and perphenazine (10 mg/kg) had significant antihyperalgesic activities at 16 h postinjection and 24-48 h postinjection, respectively (p < 0.0001). Haloperidol had no significant antinociceptive activity at doses tested. Motor function was impaired in rats given 0.5 mg/kg haloperidol, 5 mg/kg zuclopenthixol and 10 mg/kg perphenazine. Effects of long-acting neuroleptics on body temperature, feeding, and activity were short-lasted and should not preclude their use in wildlife. Antinociceptive actions were longer-lasting, but were nonspecific, and we recommend additional analgesics for painful procedures during wildlife management.

Analgesics↗
PubMed2005

Rofecoxib and tramadol do not attenuate delayed-onset muscle soreness or ischaemic pain in human volunteers.

We assessed the effect of rofecoxib, a cyclo-oxygenase-2 inhibitor, and tramadol, a centrally acting analgesic, on both delayed-onset muscle soreness (DOMS) and experimentally induced ischaemic pain. We induced DOMS in 10 male and 5 female healthy volunteers by downhill running for 30 min at a 12% decline and a speed of 9 km x h(-1). We also induced ischaemic pain by finger movements with an arterial tourniquet around the arm. In a randomized, double-blind crossover format, we administered rofecoxib (50 mg, daily), tramadol (50 mg, 3 times per day), and a placebo (orally for 3 days), starting immediately after exercise. A 100 mm visual analogue scale (VAS) and McGill pain questionnaire were used to describe muscle soreness and ischaemic forearm pain 24 h after the exercise. The pressure pain threshold (PPT) in the thigh and ischaemic pain tolerance in the forearm were measured before exercise and 24 and 72 h after exercise. PPT decreased 24 h after exercise, compared with pre-exercise values (ANOVA, p < 0.05), but neither drug had any significant effect on the PPT. Neither rofecoxib nor tramadol had any effect on time of ischaemia tolerated or amount of finger activity during ischaemia. The VAS and pain-rating index, for both muscle soreness and experimental ischaemic pain, were not affected significantly by either drug. Both DOMS and ischaemic pain share peripheral and central mechanisms, yet neither are attenuated by rofecoxib or tramadol.

Adult↗
PubMed2004

Chlamydia pneumoniae in HIV-infected patients and controls assessed by a novel whole blood interferon-gamma assay, serology and PCR.

Chlamydia pneumoniae seropositivity is associated with cardiovascular disease and HIV infection. Cell-mediated immune responses are important for control of C. pneumoniae, and such responses may be impaired in HIV-infected patients. An assay for detection of interferon (IFN)-gamma in whole blood stimulated with C. pneumoniae antigen was developed and studied in HIV-infected patients and uninfected controls. Among 34 HIV-infected patients, none had an IFN-gamma response to C. pneumoniae antigen, compared with five of 32 healthy controls (p < 0.001). Fewer HIV-infected individuals elicited a serum IgG response when tested with a commercial enzyme immunoassay (p 0.009), but this was not so for serum IgA (p 0.12). Additionally, the IFN-gamma and antibody assays showed a trend towards a bivariate response in normal controls. This indicates that cellular and antibody responses against C. pneumoniae may be mutually exclusive, with potential implications for the role of this organism in the genesis of cardiovascular disease in both immunocompetent and HIV-infected populations.

Adult↗
PubMed2003

A phase II trial of three sequential doublets for the treatment of advanced müllerian malignancies.

OBJECTIVES: In an effort to improve the results of primary chemotherapy for müllerian malignancies a novel chemotherapy program was piloted that delivered three sequential chemotherapy doublets. The primary endpoints were surgically defined response rates and evaluation of toxicity. METHODS: After primary cytoreductive surgery patients were treated with three sequential doublets including three initial cycles of carboplatin and paclitaxel (doublet 1) and then two cycles of cisplatin (day 1) and gemcitabine (days 1 and 8; doublet 2), and finally two cycles of doxorubicin (day 1) and topotecan (days 3,4, and 5; doublet 3). Cycles 4 through 7 were given with G-CSF (Neupogen) support at a dose of 5 mcg/kg/day. After therapy, all women were clinically staged and evaluated by second-look laparoscopy/laparotomy (SLO) if clinical staging was negative for residual disease. RESULTS: A total of 49 eligible patients were enrolled with a median age of 52 (SD 9). Forty-four women had either ovarian cancer or primary peritoneal carcinoma with 3 women diagnosed with fallopian tube carcinoma and 2 with papillary serous carcinoma of the uterus. Eighty-four percent of patients had stage IIIc/IV tumors, with 29% having >1 cm residual disease after primary cytoreductive surgery. Thirty-nine of 49 (80%) patients completed therapy. A total of 283 cycles of chemotherapy were delivered with acceptable toxicities. There were no toxic deaths. Five women were withdrawn from trial (3 for Taxol hypersensitivity, 1 for gemcitabine pulmonary hypersensitivity, and 1 for serious line infection). Neutropenia, typically without fever, was relatively frequent in the first doublet. Nausea and thrombocytopenia were the predominant toxicities in doublet 2. Thirty-nine women completed all cycles of treatment. Thirty-six women had restaging results consistent with a clinical complete response (CR) and underwent SLO. The pathologic CR rate of the patients undergoing SLO was 38%. CONCLUSIONS: Treatment with this sequential doublet regimen is feasible with a 38% pathologic CR rate.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Cluster randomised controlled trial to compare three methods of promoting secondary prevention of coronary heart disease in primary care.

OBJECTIVE: To assess the effectiveness of three different methods of promoting secondary prevention of coronary heart disease in primary care. DESIGN: Pragmatic, unblinded, cluster randomised controlled trial. SETTING: Warwickshire. SUBJECTS: 21 general practices received intervention; outcome measured in 1906 patients aged 55-75 years with established coronary heart disease. INTERVENTIONS: Audit of notes with summary feedback to primary health care team (audit group); assistance with setting up a disease register and systematic recall of patients to general practitioner (GP recall group); assistance with setting up a disease register and systematic recall of patients to a nurse led clinic (nurse recall group). MAIN OUTCOME MEASURES: At 18 months' follow up: adequate assessment (defined) of 3 risk factors (blood pressure, cholesterol, and smoking status); prescribing of hypotensive agents, lipid lowering drugs, and antiplatelet drugs; blood pressure, serum cholesterol level, and plasma cotinine levels. RESULTS: Adequate assessment of all 3 risk factors was much more common in the nurse and GP recall groups (85%, 76%) than the audit group (52%). The advantage in the nurse recall compared with the audit group was 33% (95% confidence interval 19% to 46%); in the GP recall group compared with the audit group 23% (10% to 36%), and in the nurse recall group compared with the GP recall group 9% (-3% to 22%). However, these differences in assessment were not reflected in clinical outcomes. Mean blood pressure (148/80, 147/81, 148/81 mm Hg), total cholesterol (5.4, 5.5, 5.5 mmol/l), and cotinine levels (% probable smokers 17%, 16%, 19%) varied little between the nurse recall, GP recall, and audit groups respectively, as did prescribing of hypotensive and lipid lowering agents. Prescribing of antiplatelet drugs was higher in the nurse recall group (85%) than the GP recall or audit groups (80%, 74%). After adjustment for baseline levels, the advantage in the nurse recall group compared with the audit group was 10% (3% to 17%), in the nurse recall group compared with the GP recall group 8% (1% to 15%) and in the GP recall group compared with the audit group 2% (-6% to 10%). CONCLUSIONS: Setting up a register and recall system improved patient assessment at 18 months' follow up but was not consistently better than audit alone in improving treatment or risk factor levels. Understanding the reasons for this is the key next step in improving the quality of care of patients with coronary heart disease.

Aged↗
PubMed2001

Miniature data loggers for remote measurement of body temperature in medium-sized rodents.

We have investigated the use of miniature temperature data loggers for the recording of abdominal temperature in laboratory animals, using the guinea pig as a model. The data loggers, which are small (16cm(3)), light (20g) and have a battery life of +/-5 years, recorded both the normal abdominal temperature of guinea pigs, and their febrile response to an intramuscular injection of 50µg/kg lipopolysaccharide (E. coli) every 5min for the duration of the experiment (21 days), to a resolution of at least 0.05 degrees C. No calibration shifts or loss of data occurred during the study period. However, despite their small size and versatility, we found that the loggers were suited for use only in guinea pigs with a body mass of approximately 600g or greater. In smaller animals, the loggers caused peritonitis.

Journal Article↗
PubMed2001

Single-donor platelets reduce the risk of septic platelet transfusion reactions.

BACKGROUND: Septic platelet transfusion reactions (SPTRs) are the most common, serious risk of transfusion. Because SPTRs result from donor skin flora or asymptomatic bacteremia, the use of single-donor platelets (SDPs) has been proposed to reduce the risk of SPTRs from the risks with pools of platelet concentrates (PCs). STUDY DESIGN AND METHODS: Beginning in 1986, all febrile transfusion reactions were evaluated by culture of the platelet bag. Confirmed SPTRs were identified by isolation of the same bacteria from the bag and the patient's blood or by positive Gram's stain of the bag that confirmed a positive platelet culture. In 1987, a program to minimize PC use in favor of SDP use was initiated as a means of reducing SPTRs. RESULTS: In 12 years, the use of SDPs increased from 51.7 percent to 99.4 percent of all platelet transfusions at one institution. SPTRs fell from three events in 1 year to the current rate of one event per year. The incidence of SPTRs decreased from 1 in 4,818 transfusions to 1 in 15,098 transfusions. The rate of SPTRs due to PCs was 5.39 times higher than that of SPTRs due to SDPs (95% CI, 1.89,12.9). CONCLUSION: The use of SDPs is a simple means of reducing SPTRs. Other measures such as sterilization will be required to eliminate all SPTRs.

Adult↗
PubMed2001

Referral of patients with a family history of breast/ovarian cancer--GPs' knowledge and expectations.

BACKGROUND: Primary care is expected to play a significant role in the management of patients with genetic problems. Currently, this particularly involves patients with a family history of cancer. If GPs are to exercise their gatekeeper role efficiently in this area, they must be able to evaluate genetic risk and make appropriate referral decisions. OBJECTIVES: The aim of this study was to examine GPs' ability to assess risk and to make appropriate referral decisions for women with a family history of breast/ovarian cancer, and to determine their expectations of a referral to secondary care. METHOD: A questionnaire survey was carried out of the 282 GP principals working within Bedfordshire Health Authority. GPs were asked to make decisions for six simulated cases of women presenting with a family history of breast or ovarian cancer. RESULTS: A total of 164 (58%) GPs returned completed questionnaires. Across the six family histories, the percentage of GPs making an appropriate risk assessment ranged from 21% [95% confidence interval (CI) 14-27%] to 63% (95% CI 56-71%), and an appropriate referral decision ranged from 40% (95% CI 32-48%) to 80% (95% CI 73-86%). Regardless of their accuracy of risk assessment, most GPs were consistent in deciding not to refer low risk women and to refer moderate and high risk women (range 71-85% of GPs for the six family histories). Only 43 (26%, 95% CI 20-33%) of GPs knew the three most important criteria for risk assessment. CONCLUSIONS: GPs require more help and education to enable them to perform their gatekeeper role satisfactorily when assessing patients with a family history of breast/ovarian cancer.

Adult↗
PubMed2001

Rectal temperature measurement results in artifactual evidence of selective brain cooling.

Selective brain cooling (SBC) is defined as a brain temperature cooler than the temperature of arterial blood from the trunk. Surrogate measures of arterial blood temperature have been used in many published studies on SBC. The use of a surrogate for arterial blood temperature has the potential to confound proper identification of SBC. We have measured brain, carotid blood, and rectal temperatures in conscious sheep exposed to 40, 22, and 5 degrees C. Rectal temperature was consistently higher than arterial blood temperature. Brain temperature was consistently cooler than rectal temperature during all exposures. Brain temperature only fell below carotid blood temperature during the final few hours of 40 degrees C exposure and not at all during the 5 degrees C exposure. Consequently, using rectal temperature as a surrogate for arterial blood temperature does not provide a reliable indication of the status of the SBC effector. We also show that rapid suppression of SBC can result if the animals are disturbed.

Animals↗
PubMed2000

Effects of nitric oxide synthase inhibitors on the febrile response to lipopolysaccharide and muramyl dipeptide in guinea pigs.

We investigated the effect of N-nitro-L-arginine methyl ester (L-NAME), an unspecific nitric oxide synthase (NOS) inhibitor, and aminoguanidine, a relatively selective inhibitor of the inducible NOS enzyme, on both gram-negative lipopolysaccharide (LPS) and gram-positive muramyl dipeptide (MDP) fever in guinea pigs. Intraperitoneal injection of either 10 mg/kg L-NAME or 25 mg/kg aminoguanidine inhibited the febrile response to an intramuscular injection of 50 microg/kg MDP. However, LPS fever (20 microg/kg) was inhibited only by L-NAME. The development of LPS fever may therefore occur independently of the synthesis of nitric oxide by the inducible NOS enzyme, while MDP fever may involve synthesis of nitric oxide by both the inducible and the constitutively expressed NOS enzymes.

Abdomen↗
PubMed2000

Efficacy and hematologic toxicity of salvage chemotherapy following stem cell-supported high-dose chemotherapy in women with recurrent ovarian cancer.

OBJECTIVE: The objective of this study was to determine the efficacy and hematologic toxicity of salvage chemotherapy in patients with recurrent ovarian cancer following high-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT). METHODS: A retrospective analysis of 19 Massachusetts General Hospital case records of women with relapsed ovarian cancer following PBSCT was conducted. RESULTS: Between February 1996 and September 1998, 24 women with ovarian cancer were treated with PBSCT. Nine patients were treated with an upfront PBSCT regimen to consolidate first-line chemotherapy and 15 patients were treated with PBSCT after a median of two lines (range: 1-3) of prior chemotherapy. Sixteen patients presented with relapsed disease at a median of 230 days post-PBSCT and 3 patients had persistent disease through high-dose chemotherapy. Each of these 19 patients has been treated with salvage chemotherapy following PBSCT. Patients received one of six different first-line salvage chemotherapy regimens. Sixteen of nineteen patients are alive a median of 383 days (range: 156-868) after relapse following PBSCT. Three patients died of progressive disease at a median of 284 days (range: 224-648) after post-PBSCT relapse. Six patients achieved a complete response, four patients had a partial response, three patients had stable disease, and six patients had progressive disease in response to first-line salvage chemotherapy. Seven patients experienced grade III/IV neutropenia, and three patients experienced grade III/IV thrombocytopenia. CONCLUSIONS: We conclude that in a patient population selected for chemotherapy sensitive and low-volume disease prior to PBSCT, patients with recurrent tumor appear to respond to salvage chemotherapy, and associated hematologic toxicity is acceptable and manageable.

Adult↗
PubMed2000

Association between polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers.

Central dopaminergic reward pathways give rise to dependence and are activated by nicotine. Allelic variants in genes involved in dopamine metabolism may therefore influence the amount of tobacco consumed by smokers. We developed assays for polymorphisms in dopamine beta-hydroxylase (DBH), monoamine oxidase (MAO) and catechol O-methyl transferase (COMT) using the polymerase chain reaction with sequence specific primers (PCR-SSP). We then typed 225 cigarette smokers to assess whether genotype was related to the number of cigarettes smoked a day. Smokers with DBH 1368 GG genotype smoked fewer cigarettes than those with GA/AA [mean difference -2.9 cigarettes, 95% confidence interval (CI) -5.5, -0.4; P = 0.022]. The effect reached statistical significance in women (-3.8, 95% CI -6.4, -1.0, P = 0.007) but not in men (-1.5, 95% CI -6.0, 3.0, P = 0.498). Overall, the effect was greater when analysis was confined to Caucasians (-3.8, 95% CI -6.6, -1.1, P = 0.007). Smokers with MAO-A 1460 TT/TO smoked more cigarettes than those with CC/CT/CO (2.9, 95% CI 0.6, 5.1, P = 0.013). Within each sex group, the trend was similar but not statistically significant (difference for men 2.9, 95% CI -1.0, 6.7; for women 2.0, 95% CI -0.7, 4.8). The effect of the allele was greater in smokers with a high body mass index (> 26) (difference 5.1, 95% CI 1.4, 8.8, P = 0.008). More heavy smokers (> 20 a day) had the DBH 1368A allele when compared to light smokers (< 10 a day). (Relative risk 2.3, 95% CI 1.1, 5.0, P = 0.024.) The trend for increasing prevalence of the DBH A allele in heavy smokers was greater when analysis was restricted to Caucasians (relative risk 3.2, 95% CI 1.3, 8.2, P = 0.004). Conversely, heavy smokers were less likely to have the MAO-A 1460C allele (relative risk 0.3, 95% CI 0.1, 0.7, P = 0.012). Variations in DBH and MAO predict whether a person is a heavy smoker and how many cigarettes they consume. Our results support the view that these enzymes help to determine a smoker's requirement for nicotine and may explain why some people are predisposed to tobacco addiction and why some find it very difficult to stop smoking. This finding has important implications for smoking prevention and offers potential for developing patient-specific therapy for smoking cessation.

Adult↗
PubMed2000

Absence of selective brain cooling in free-ranging zebras in their natural habitat.

We used implanted miniature data loggers to measure brain and arterial blood temperatures in three free-ranging zebras (Equus burchelli) in their natural habitat, every 5 min for 9 days. The animals experienced globe temperatures exceeding 40 C, and radiant heat load of about 1000 W m-2. Arterial blood exhibited a moderate amplitude (1.7 C) nychthemeral rhythm, with an acrophase at 19.00 h and a nadir late in the morning, at 10.00 h. Brain temperature consistently exceeded blood temperature, on average by 0.2-0.4 C, and changes in brain temperature closely tracked changes in blood temperature. There was no evidence of selective brain cooling, even during the hyperthermia which followed surgery or that associated with intense, short-duration exercise. The relationship between brain and arterial blood temperatures in free-ranging zebras was unlike that reported for horses in the laboratory. Our results do not support the view that mammals lacking a carotid rete can achieve selective brain cooling.

Animals↗
PubMed1999

Repeat donor HLA-DR mismatches in renal transplantation: is the increased failure rate caused by noncytotoxic HLA-DR alloantibodies?

INTRODUCTION: Data from the UCLA/UNOS and Collaborative Transplant Studies Registries indicate that mismatched HLA-DR alloantigens expressed on a former donor renal allograft should not be repeated because of significantly poorer long-term survival. METHODS: Retransplant candidates waiting for another renal allograft were screened for HLA class II alloantibodies (aAb) using direct complement-dependent cytotoxicity and several sensitive aAb binding assays. RESULTS: When screened by complement-dependent cytotoxicity, 46% of the patients were aAb negative. In contrast, using aAb binding assays, 90% of the patients had HLA-DR aAb specific for previous HLA-DR allograft mismatches. Most important, no directly cytotoxic HLA-DR antibody was detected in 9 of 27 patients. CONCLUSION: Our studies suggest that crossing the same HLA-DR mismatch in a subsequent transplant may result in poorer survival due to underlying donor-specific HLA-DR aAb. If confirmed in a retrospective study of retransplant patients, B cell donor cross-matches using antiglobulin complement-dependent cytotoxicity or flow cytometry would appear essential if this barrier were to be crossed.

Antibody Specificity↗
PubMed1999

The humoral immune response against an HLA class I allodeterminant correlates with the HLA-DR phenotype of the responder.

BACKGROUND: The genetic basis for control of alloantibody responses against foreign HLA histocompatibility antigens has never been delineated. The most likely postulate would be that HLA class II alloantigens of the host regulate the response through their ability to present processed HLA allopeptide fragments for the cognate interaction between CD4+ T lymphocytes and B lymphocytes that leads to IgG antibody synthesis. METHODS: We have analyzed our allosensitized transplant patient population with regard to humoral responsiveness to a serologically defined public HLA class I epitope, Bw4. Peptides representing the linear sequence of the Bw4 epitope (amino acids 74-86) and the alternative Bw6 epitope were synthesized and assayed for binding to a panel of HLA homozygous lymphoblastoid B cells using a quantitative fluorescence binding assay. RESULTS: We found that 73% of patients who have produced a HLA-Bw4-specific alloantibody express either the HLA-DRB1*01 or HLA-DRB1*03 alloantigen; 19% of the remaining responders expressed HLA-DRB1*04. Analysis of the United Network for Organ Sharing Transplant Registry indicated that the survival of cadaver renal allografts mismatched for Bw4 was significantly compromised in sensitized DRB1*01+ or DRB1*03+ recipients (P<0.01). In vitro, the Bw4 peptide bound strongly to DRB1*01+ and DRB1*03+ lymphoblastoid B cells; no similar binding was observed with Bw6 peptide. These findings were confirmed using murine fibroblast lines transfected with HLA-DR alpha/beta genes and by solid-phase enzyme-linked immunosorbent assay using purified HLA-DR alloantigen. CONCLUSIONS: We conclude that there are at least two human Ir genes, HLA-DRB1*01 and HLA-DRB1*03, that confer a high risk for both humoral allosensitization and renal allograft failure in situations of HLA-Bw4 incompatibility. These findings may be of future benefit in devising new antigen matching strategies for reducing the risk of humoral HLA allosensitization and chronic allograft rejection.

Antibody Formation↗