Polymorphic and monomorphic HLA-DR determinants on human hematopoietic progenitor cells

The expression of monomorphic Ia-like antigens and polymorphic (allotypic) HLA-DR determinants on CFU-GM, BFU-E, CFU-E, and CFU-GEMM was studied in bone marrow and peripheral blood cells from normal healthy individuals. Using various polyclonal and monoclonal anti-Ia- like antibodies, the presence of HLA-DR backbone antigens was shown on all hematopoietic progenitor cells (HPC) studied, both in complement- dependent cytotoxicity assays and in fluorescence-activated cell sorting (FACS). The expression of allotypic determinants was demonstrated on all HPCs, using the HLA-DR typing sera anti-HLA-DR1, 2, 3, 4, 5, and 7. The Class II antigen MT-2 was also shown on all HPCs, using both monoclonal and alloantisera, whereas the MB-1 (DC-1) determinant could not be demonstrated on HPCs. This might open the possibility of removing MB-1-positive malignant cells from the graft in autologous bone marrow transplantation.     

Natural interferon-alpha versus its combination with 6-methyl- prednisolone in the therapy of type II mixed cryoglobulinemia: a long- term, randomized, controlled study

Type II mixed cryoglobulinemia (MC) is an often progressive vasculitis characterized by circulating cold-precipitable proteins that usually consists of polyclonal IgG and monoclonal IgM kappa with rheumatoid factor (RF) activity. Its etiology is unknown, although recent evidence strongly suggests that hepatitis C virus (HCV) plays a major role. Plasmapheresis, corticosteroids, and cytotoxic drugs have been used in the therapy of MC patients. Recently, favorable results with recombinant interferon-alpha (rIFN alpha) have been reported. To further assess its effectiveness, we studied the effects of natural human interferon-alpha (nIFN alpha), alone and in combination with 6- methyl-prednisolone (PDN), in a prospective, randomized, controlled trial in patients with symptomatic MC. Sixty-five patients were enrolled onto the trial, 52 (80%) of whom presented serum anti-HCV antibodies and specific genomic RNA sequences. Fifteen patients received nIFN alpha (3 MU) intramuscularly (IM) three times weekly, whereas 17 patients also received 16 mg/d of PDN orally on non-IFN days. Moreover, 18 patients received 16 mg/d of PDN only, and 15 were untreated. Treatment was discontinued after 1 year and patients were monitored for 8 to 17 months (mean, 13). A complete response was achieved in eight of 15 patients (53.3%) treated with nIFN alpha and nine of 17 (52.9%) treated with nIFN alpha plus PDN, as compared with three of 18 patients (16.7%) who received PDN only (P < .05) and one of 15 (6.7%) untreated controls (P < .01). Partial response occurred in two of 15 (13.3%) patients treated with nIFN alpha, three of 17 (17.6%) who received nIFN alpha plus PDN, one of 18 (5.5%) who received PDN only, and one of 15 (6.7%) controls. A complete response in six patients (66.7%) was achieved within 3 months in the group that received nIFN alpha plus PDN, as compared with two patients (25%) of those who received nIFN alpha alone (P < .02). In anti-HCV-positive patients, the clinical response occurred in step with reduced or undetectable levels of HCV RNA and transaminase normalization. Quantification of circulating HCV RNA represented a good predictive response marker. The probability of relapse within 3 months after treatment was 100% (three of three patients) and 75% (six of eight patients), respectively, in patients who received PDN alone or nIFN alpha alone as compared with none of those who received nIFN alpha plus PDN (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)     

世界胃肠病学组织(WGO-OMGE)临床指南——发展中国家幽门螺杆菌感染

我非常高兴向大家推荐这份发展中国家幽门螺杆菌（H．priori）临床指南。该指南的编译是由数位在该领域具有丰富临床经验的世界知名专家共同完成的。     

Identification of Bakb, a new platelet-specific antigen associated with posttransfusion purpura

Baka is a platelet alloantigen whose putative allele, Bakb, has not been identified previously. By using a serum, "Har," obtained from a patient with posttransfusion purpura, we describe the platelet alloantigen Bakb. The Har serum reacted with an NP-40-extractable platelet membrane protein of 142 kd with mobility similar to platelet glycoprotein IIb alpha. We found that the antigen recognized by the Har serum is inherited in an autosomal dominant mode with an apparent gene frequency of .39. Chi-square analysis of observed and expected phenotype frequencies indicated that serum Har recognizes Bakb, the anticipated allele of Baka. Our findings provide new evidence for polymorphism of glycoprotein IIb and for the association of posttransfusion purpura with alloimmunization to determinants on this glycoprotein.     

Tranexamic acid, an inhibitor of plasminogen activation, reduces urinary collagen cross-link excretion in both experimental and rheumatoid arthritis

The plasminogen activation system is one of the enzyme systems held responsible for bone and cartilage degradation in rheumatoid arthritis (RA). In this study, we evaluated the effect of tranexamic acid (TEA), an inhibitor of plasminogen activation, on urinary collagen cross-link excretion and radiological joint damage in rat adjuvant arthritis (AA) and on urinary collagen cross-link excretion in patients with RA. In the animal study, adjuvant arthritis was induced in male Lewis rats. From day 7 onward, high-dose TEA (500 mg/kg body weight, once daily) or placebo was administered orally. Study groups consisted of TEA-treated normal rats (C + TEA), placebo-treated normal rats (C + plac), AA rats treated with TEA (AA + TEA) or with placebo (AA + plac). To monitor joint destruction, urinary collagen cross-link excretion (pyridinoline, HP; deoxypyridinoline, LP) was measured by high-performance liquid chromatography at days 14 and 21. Radiological evaluation of joints was performed at day 21. In the patient study, TEA was administered to nine patients with RA as adjuvant medication (approximately 20 mg/kg body weight, three times daily) for 12 weeks. Urinary HP and LP excretion levels were measured before and during TEA treatment, and 4 weeks after the cessation of TEA treatment. In AA + TEA rats, a significant reduction of HP and a tendency towards a reduction of LP excretion were found compared with AA + plac rats (P < 0.05), at day 14, whereas the HP/LP ratio did not change. No difference was observed in HP, LP excretion, HP/LP ratio and radiological damage score between the TEA- and placebo-treated AA rats at day 21. In RA patients, a significant reduction of HP and LP excretion was found during the TEA treatment period (P < 0.05). After the cessation of TEA treatment, HP and LP excretion increased towards baseline levels. No effect on disease activity was observed. The plasmin antagonist TEA reduced the excretion of collagen pyridinoline cross-links in both experimental and rheumatoid arthritis. As such, this study not only supports the involvement of the plasminogen activation system in the destructive phase of arthritis, but also suggests a beneficial effect of therapeutic strategies directed against inhibition of matrix proteolysis.      

Monoclonal antibody T101 in T cell malignancies: a clinical, pharmacokinetic, and immunologic correlation

Eight patients with cutaneous T cell lymphomas (CTCL) and five with various other T cell malignancies were treated with mouse monoclonal antibody (MoAb) T101. Doses of 1 to 500 mg were administered weekly over a two-hour period and resulted in one complete remission (convoluted T cell lymphoma) and one partial remission (CTCL). Remission duration was 6 weeks and 3 months, respectively. Frequent toxicities were pruritus, hives, flushing, and shortness of breath. Supraventricular arrhythmias and blood pressure instability were also observed. Complete targeting of peripheral blood T cells was achieved with 1 mg of MoAb in the nonleukemic patients (WBC less than 10,000/microL), and free, bioavailable antibody was present at the next (10-mg) dose level. Even higher doses resulted in substantial antibody excess that persisted for as long as 6 weeks. Serum concentrations of MoAb decreased with increasing number of peripheral blood T cells, and 25 to 35 mg of T101 were required for induction of antibody excess in leukemic patients. Excess antibody induced antigenic modulation, which was of consequence only if MoAb excess persisted to the next treatment. In the original treatment, the rapidly administered MoAb was able to target and remove peripheral blood T cells before the development of antigenic modulation. Antimouse antibodies developed in three patients. Their presence rendered further therapy ineffective and was associated with an anaphylactic reaction in one patient. Development of these antibodies could not be predicted by lymphoproliferative assays. In these assays, however, the T101 protein strongly stimulated the mononuclear cells of the patient who reached the only complete remission of this trial. Immunologic stimulation by the MoAb thus might have played a role in this patient's antitumor response. In summary, therapy with MoAb T101 was specific but only modestly efficacious. Rapid infusion of nonmodulating doses of antibody provided excellent targeting and removal of peripheral blood T cells and might be a valid approach in future trials with immunoconjugated T101.     

Highly sensitive polymerase chain reaction methods show the frequent survival of residual recipient multipotent progenitors after non-T-cell- depleted bone marrow transplantation

Twenty-four male patients grafted for various pathologies with the marrow of a female donor and presenting a complete donor-type hematopoiesis when analyzed by polymerase chain reaction (PCR) amplification of minisatellite sequences 33.6.3 and MS51 (0.1% to 1% sensitivity) were studied by the highly sensitive technique of PCR amplification of the Y-chromosome-specific DYZ1 sequence (0.01% sensitivity). Residual recipient male cells were detected in all peripheral blood samples collected within 1 year posttransplantation. These residual cells were present in both the lymphocyte and polymorphonuclear cell fractions when such a separation was performed by Ficoll gradient centrifugation and, for samples of 13 of 15 patients, at comparable levels in both fractions. In 3 samples collected from 3 patients 4 months or more posttransplantation, residual recipient cells were detected in the polymorphonuclear cell fraction but were present at a lower level or were undetectable in the lymphocyte fraction. These cells are of hematopoietic origin because they were detected at equivalent levels in whole blood and in B and T lymphocytes sorted with antibody-coated magnetic beads. They were not detected in samples collected more than 15 months posttransplantation for 6 of 7 patients. The persistence of residual recipient cells within 1 year posttransplantation is not restricted to male patients receiving a transplant from a female donor because they were also detected in 2 female patients using an allele-specific amplification method for the thyroid peroxydase gene that also has a high sensitivity (0.01%). Our results indicate that at least residual recipient myeloid progenitors and possibly totipotent hematopoietic stem cells may survive intensive pretransplant conditioning regimen and support a transient residual hematopoiesis of the host posttransplantation.     

A test for Fanconi's anemia

A simple and reliable cytogenetic test for Fanconi's anemia (FA) that is based on the hypersensitivity of FA cells to mitomycin C (MC) is described. Equal volumes of whole blood from a patient in whom the diagnosis of FA is suspected and from a normal person of the opposite sex are co-cultured in phytohemagglutinin-containing medium in the presence and absence of MC. After five days' co-cultivation, 100 quinacrine-stained metaphases from both the MC-containing and the MC- free cultures are examined for the presence of a Y chromosome using fluorescence microscopy. In all bona fide FA patients in whom testing was successful, hypersensitivity to MC was readily demonstrated by the striking deficiency of FA metaphases (0.9% to 14.9%) in the MC- containing co-cultures. In contrast, none of the three patients with Diamond-Blackfan anemia and none of the five with undiagnosed conditions reminiscent of FA exhibited hypersensitivity to MC; cells from them, from parents of FA patients, and from several normal laboratory personnel constituted approximately half of the metaphases (40.4% to 71.2%) of MC-containing co-cultures, as would be expected in the absence of hypersensitivity to MC.