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Biomedical subjects

T J Hamblin

Publications and source records attributed to T J Hamblin.

At least 19 recordsLinked to original sources
PubMed1992

Euthanasia.

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Ethics, Medical↗
PubMed1992

VH restriction among human cold agglutinins. The VH4-21 gene segment is required to encode anti-I and anti-i specificities.

We previously reported that human autoantibodies with cold agglutinin activity contained a single human VH gene segment (VH4-21) which was also responsible for the cross-idiotypic specificity characteristic of the cold agglutinin response. To confirm and extend this observation we have analyzed at the nucleotide level the H and L chains of six new cold agglutinin molecules derived from different patients. We found that regardless of whether the antibody recognizes the i or the I red cell Ag, restriction at the VH gene segment level is absolute. We also found that even in the absence of somatic mutation the VH4-21 gene segment can encode both anti-i and anti-I specificities. Finally, although the VH4-21 gene segment is essential for cold agglutinin activity, the other genetic elements that contribute to the V region of the antibody molecules can be extremely diverse. The structural information provided in this report sharply restricts the requirement for encoding pathogenic cold agglutinin activity to one of the components of the H chain V region, specifically the VH gene segment. The implications of this apparently absolute requirement for a single VH gene segment, unprecedented in the human autoimmune response, are discussed.

Aged↗
PubMed1992

Intensive chemotherapy in myelodysplastic syndromes.

Patients with myelodysplastic syndrome (MDS) who have more than 10% blasts in their bone marrow have a very short survival. Treatment has not improved for these patients for the past 10 years and supportive care alone is still the gold standard. Intensive chemotherapy for poor prognosis MDS has been little tried, but complete remission rates are higher in such studies than in patients with acute myeloid leukaemia (AML) supervening on the MDS. Although these groups may not be comparable, and neither group is representative of the majority of patients with the MDS who are generally older, a case can be made for a randomised prospective study comparing intensive chemotherapy and supportive care alone in poor prognosis MDS. For patients with the myelodysplastic syndrome intensive chemotherapy may carry special risks. The involvement of the whole marrow in the neoplastic clone, and the likelihood of anthracycline resistance are two such hazards which may need to be circumvented.

Age Factors↗
PubMed1991

Nucleotide sequence analysis of the V regions of two IgM cold agglutinins. Evidence that the VH4-21 gene segment is responsible for the major cross-reactive idiotype.

Cold agglutinins are human autoantibodies, usually of the IgM class, which agglutinate RBC at low temperature. The major subset recognizes the I/i carbohydrate Ag, and many of these antibodies bear cross-reacting idiotypic determinants. An anti-idiotypic mAb that is specific for one of the idiotopes largely confined to cold agglutinins has been used to identify and monitor tumor cells that secrete these molecules in two patients. The tumor cells were immortalized with EBV and the idiotope-positive lines used to investigate the utilization of the VH and VL genes by these antibodies. Nucleotide sequence analysis of the two cold agglutinins (FS-1 and FS-2) revealed the utilization of a single common gene segment, VH4-21. Serologic analysis documented that only human antibodies utilizing the VH4-21 gene segment were reactive in the idiotope assay, other VHIV antibodies as well as a panel of antibodies derived from other VH families being negative. The DH, JH, VK, and JK gene segments of FS-1 and FS-2 were structurally distinct. These data suggest that the structural basis for the cross-reactive idiotope as well as cold agglutinin activity is the VH4-21 gene segment. A nucleotide change in H chain CDR1 of both cold agglutinins results in the substitution of an aspartic acid residue for glycine at position 31, suggesting that this amino acid might be critical to recognition of the red cell Ag.

Aged↗
PubMed1991

Preliminary studies for an immunotherapeutic approach to the treatment of human myeloma using chimeric anti-CD38 antibody.

Multiple myeloma is a disease in which conventional chemotherapy has only limited value, but which may be ideal for treatment with passive antibody against a suitable cell surface antigen on the neoplastic plasma cell. The CD38 antigen is known to be present on the majority of neoplastic plasma cells, and this was confirmed by detailed examination of bone marrow aspirates from three patients. Strong expression of CD38 was confined to cells which, by the criteria of light-scattering profiles and possession of cytoplasmic Ig, were plasma cells. The vast majority of neoplastic plasma cells appeared to be involved. Using a cell line as a model, it was found that the CD38 antigen acts as a target for a chimeric antibody prepared from the antibody OKT10. The chimeric antibody consists of the Fab portion of the mouse monoclonal antibody linked by a stable thioether bond to an Fc molecule derived from human IgG1, thereby forming mouse Fab-human Fc. In contrast to the parent antibody, the chimeric molecule mediates antibody-dependent cellular cytotoxicity (ADCC) very efficiently with human blood mononuclear effector cells, and is effective at low concentration. Also, even though the CD38 antigen is present on natural killer cells, there appears to be little deleterious action of the antibody on effector cell function. The antibody also failed to affect the growth of progenitor cells of the granulocyte/macrophage or erythroid lineages present in normal bone marrows, despite the suspicion that these cells express the antigen. Other advantages of the CD38 molecule are that it is not found in the serum of patients with myeloma, and it does not appear to modulate in vitro. Fourteen patients with florid myeloma and on various chemotherapeutic regimes had an undiminished capacity to mediate ADCC with the chimeric antibody, when compared with normal individuals. The maintenance of ADCC activity, coupled with the known suppression of the antibody response in these patients, augers well for treatment with chimeric antibody.

ADP-ribosyl Cyclase↗
PubMed1991

Idiotypic vaccination against B-cell lymphoma leads to dormant tumour.

Idiotypic immunoglobulin, which can be considered to bear tumour-associated antigens in the context of B-cell lymphoma, has been obtained from the splenic A31 tumour, purified, and used to immunise syngeneic mice. On subsequent exposure to a lethal challenge of lymphoma cells, the mice showed no overt tumour development over an observation period of 6 months, whereas mice immunised with an unrelated idiotypic immunoglobulin succumbed to lymphoma after about 20 days. Anti-idiotypic immunity persisted in protected mice, since a second exposure to a lethal tumour dose 4 months after the first challenge also failed to induce lymphoma. Anti-idiotypic antibody appeared to have a major role in protection when analysed by passive transfer experiments, with no contribution from transferred cells. Protected mice were investigated for the presence of lymphoma cells 4-8 months following exposure to tumour, but the spleens, which were of normal weight and appearance, contained few or no tumour cells by phenotypic analysis. However, passage of cells dispersed from these spleens led, in 60% of cases, to tumour development in unimmunised recipients. The emergent tumours were indistinguishable from the original A31 lymphoma, with no evidence for variants, indicating that the cells were unable to grow in the immune mice, but that this dormant state could be disrupted by transfer.

Animals↗
PubMed1991

Red cell aplasia in myelodysplastic syndrome.

Six cases of red cell aplasia occurring in patients with myelodysplastic syndromes (MDS) showed a diversity of clinical course and prognosis. In some patients red cell aplasia may have represented an evolution of MDS while in others autoimmune destruction of erythoblasts may have been the mechanism. A proliferative phase is seen in many of these patients, the clinical importance of which is uncertain.

Aged↗
PubMed1990

Endothelins.

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Cell Communication↗
PubMed1990

Interleukin 2.

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Acute Kidney Injury↗
PubMed1990

Isolation and EBV-transformation of a minor population of normal human tonsillar B cells bearing a cold agglutinin-associated idiotope.

Human autoantibodies which bind to red blood cells and cause agglutination in the cold, collectively comprise the cold agglutinins: a subset of these antibodies with specificity for the Ii carbohydrate antigen on the red cell surface bears cross-reacting idiotypic determinants. A monoclonal antibody has been raised which specifically inhibits the cold agglutination reaction, and has been used to probe normal lymphoid cell populations for the presence of B cells expressing the same idiotope. Although such cells comprise only 1-2% of the lymphoid cells in the tonsil, it has been possible to isolate them in good yield and purity using the antibody and magnetic beads. Released cells were infected with the Epstein-Barr (EB) virus and an idiotope-bearing line established. The IgM secreted by the line was found to agglutinate red cells in the cold indicating that cold agglutinin-producing cells were among this idiotope-positive population. The immunophenotype of the line, and the agglutinating power of the secreted IgM, have been compared with a similarly immortalized idiotope-bearing line established from neoplastic B cells of a patient with frank cold agglutination disease.

Agglutinins↗
PubMed1990

Prognostic factors in stage AO B-cell chronic lymphocytic leukaemia.

85 patients presenting to a single centre with stage AO B-cell chronic lymphocytic leukaemia (B-CLL) have been studied. The duration of follow-up has ranged from a minimum of 1 year to a maximum of 18 years with a mean of 6 years. 14 patients have had progressive disease and 23 patients have died, of whom nine had CLL-related deaths. We assessed the prognostic significance of the following parameters: age at presentation, sex, haemoglobin concentration, initial lymphocyte count, surface membrane phenotype, serum immunoglobulin levels at presentation and karyotype. None of these factors were predictive of survival, but there was a correlation between initial lymphocyte count, surface immunoglobulin MD lambda phenotype, and complex karyotypic abnormalities and disease progression. Two patients with a complex karyotype have been followed for more than 5 years without evidence of progression.

Adult↗
PubMed1990

Correlation of chromosome abnormalities with laboratory features and clinical course in B-cell chronic lymphocytic leukaemia.

141 patients with B-cell chronic lymphocytic leukaemia (B-CLL) have been studied for a minimum of 12 months and a maximum of 25 years. 30 of 133 patients (32.5%) had greater than 10% FMC7 positive peripheral blood lymphocytes and 19 of 131 patients (14.5%) had a serum or urinary paraprotein. At presentation 88 patients were stage A0, 18 A1, 18 A2, 11 B and six C. 44 (31%) had progressive disease and 42 (30%) died during the study period. 63 patients had a normal karyotype, 75 a clonal abnormality and in three no metaphases were obtained. The finding of a complex karyotypic abnormality was significantly associated with lambda surface phenotype (P less than 0.01), the presence of greater than 10% FMC7 positive cells (P less than 0.025), and the presence of a paraprotein (P = 0.025). Patients whose leukaemic cells had a complex karyotype and those with structural abnormalities of chromosomes 14 and 6 required treatment earlier than those with a normal karyotype.

Aged↗