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Biomedical subjects

T J Hamblin

Publications and source records attributed to T J Hamblin.

At least 37 records · Page 2Linked to original sources
PubMed1997

Chronic lymphocytic leukaemia: the nature of the leukaemic cell.

Far from being the boring, inactive, inert lymphocyte that haematologists of old perceived it to be, the chronic lymphocytic leukaemia (CLL) cell has set us many complex problems. The cell is apparently stuck in G0 in cell cycle, yet expresses many activation markers. The cells apparently manufacture many cytokines and respond in vitro to even more, yet cells entering even G1 are few. The cell surface marker profile is unique. There is apparently no normal equivalent of the CLL cell. In part, this may be because the cell is malignant; malignant cells often express aberrant markers. Consistent chromosomal abnormalities are emerging but we have no idea how these abnormalities translate into molecular mistakes that dictate the peculiar nature of the cell. CLL cells carry a characteristics set of adhesion molecules, but we cannot read their homing and recycling instructions. The outstanding irregularities of the CLL cell are its CD5 positivity and its sparse surface immunoglobulin. This ought to translate as an anergic B1 cell, perhaps programmed for autoimmunity. If the tumour cell were responsible for the patient's production of immunoglobulin or secretion of autoantibodies, then a pattern might have emerged. Alas, these are the product of the normal B cells. How the CLL cell induces these complications is unknown. Thus, despite the information contained in this review, the CLL cell remains a puzzle.

Animals↗
PubMed1997

Clinician's overview of platelet support.

In a period of 2 years, 48 patients over age 55 were treated for acute myeloblastic leukaemia or myelodysplastic syndrome with greater than 10% blasts. 15 patients were treated with intestine chemotherapy, requiring a mean of 48 units of platelets per course. 33 patients were treated by supportive care alone of whom 19 required a mean of 380 units of platelets each. Long term supportive care is a feasible option in elderly leukaemia. Because of dysplasia some patients bleed at a higher threshold than younger patients. A further hazard is the use of i.v. hydrocortisone to suppress transfusion reactions. Such unintentional use of steroids in patients with dysplastic neutrophils and monocytes may predispose to fungal infections.

Europe↗
PubMed1997

Atypical lymphocyte morphology: an adverse prognostic factor for disease progression in stage A CLL independent of trisomy 12.

We studied 270 patients with Binet stage A chronic lymphocytic leukaemia looking for adverse prognostic factors. In a multivariate analysis the following features were found to be risk factors for disease progression: atypical lymphocyte morphology (defined as either > 10% prolymphocytes or > 15% lymphocytes with cleaved nuclei or lymphoplasmacytoid cells); more than two karyotypic abnormalities; lymphocyte count > 30 x 10(9)/l; lymphocyte doubling time < 1 year; enlargement of one or more lymph node groups. In a univariate analysis the presence of trisomy 12 also correlated with progressive disease, but this was largely a consequence of the association between trisomy 12 and atypical lymphocyte morphology. Atypical lymphocyte morphology is an important prognostic factor in stage A CLL, and one which incurs no additional investigational cost.

Adult↗
PubMed1996

Ig VH gene mutational patterns indicate different tumor cell status in human myeloma and monoclonal gammopathy of undetermined significance.

Plasma cell tumors display a wide spectrum of clinical progression, ranging from aggressive multiple myeloma to a benign form known as monoclonal gammopathy of undetermined significance (MGUS), which requires no treatment. Because both diseases involve mature Ig-secreting plasma cells, the reason for this variation in malignant behavior is unclear. However, assessment of malignant potential is desirable for choice of treatment protocols. Ig variable (VH) gene sequences analysis has previously shown the tumor cell of multiple myeloma to be postfollicular, with mutated homogeneous clonal sequences indicating no continuing exposure to the somatic hypermutation mechanism, and this was confirmed in 7 of 7 patients. Comparison of the VH gene sequences in the monoclonal cells in MGUS yielded a different result, with 3 of 7 patients demonstrating mutated heterogeneous sequences consistent with the tumor cells remaining under the influence of the mutator. In 1 of 3 of these patients, an IgM-positive precursor cell was identified that expressed heterogeneous VH sequences similar to those of the isotype-switched plasma cell. These results indicate that the clonal cells in MGUS differ from those in myeloma and suggest that the difference may reflect malignant potential.

Adult↗
PubMed1996

Response of B-cell lymphoma to a combination of bispecific antibodies and saporin.

Observations are described using a combination of two bispecific F(ab')2 antibodies (BsAb) to deliver the ribosome-inactivating protein, saporin, in the treatment of low-grade, end-stage, B-cell lymphoma. Two BsAb were used, each having one arm directed at saporin and one at the CD22 on target B cells. The BsAb, however, recognized different, non-overlapping epitopes on each molecule, a strategy which permits high-avidity double attachment of saporin to the target. The BsAb and saporin were pre-mixed at a molar ratio of 3:1 24 h before treatment and infused intravenously over a period of 1 h. Five patients have been treated, mostly with weekly doses of between 2 and 4 mg of saporin for a period of up to 6 weeks. Toxicity was minimal. Three complained of weakness and myalgia for 1 to 2 days after treatment, without objective neurological deficit or rise in serum creatine kinase. One patient produced an anti-mouse Fab' and an anti-saporin response. All patients showed a rapid and beneficial response to treatment. When present, circulating tumor cells were cleared (4/4 patients), ascitic and pleural effusions were eliminated (2/2 patients) and one patient with splenomegaly showed a marked reduction in tumor bulk. Malignant lymph nodes showed significant, but partial, shrinkage in all patients and finally marrow responded well with tumor clearance in biopsy material and impressive resolution of pancytopenia in some patients. While these responses were mainly short-lived, with tumor progression once the treatment was stopped, their speed and magnitude, and the relative lack of associated toxicity warrants further study of this treatment to determine maximum tolerated doses and therapeutic utility.

Aged↗
PubMed1996

Tracking of the V4-34 (VH4-21) gene in human tonsil reveals clonal isotype switch events and a highly variable degree of somatic hypermutation.

The V4-34 (VH4-21) gene has been found to encode certain IgM autoantibodies, and is mandatory for pathological IgM anti-erythrocyte antibodies of I/i specificity. The gene is also commonly used by normal IgM-positive B lymphocytes, but its involvement in B cells which have undergone class switching to IgG or IgA is less clear. In order to track V4-34 gene usage and class switching events during a normal immune response, we have probed RNA in a limited area of human tonsil. Results indicate that the V4-34 gene undergoes class switching to IgG or IgA, with the progeny either remaining unmutated or containing large numbers of somatic mutations. Mutational patterns indicate possible 'hot spots', and some mutations appear deleterious. At the level of individual B cells, we have tracked a clonal isotype switch event from IgM to IgA, with each retaining close to germ-line configuration. In addition, we have followed a clonal switch from a mutated IgM to IgG, with no further accumulation of somatic mutations. These data indicate that the V4-34 gene is involved in a maturing immune response, and that the routes to production of IgG or IgA antibodies are various.

Amino Acid Sequence↗
PubMed1995

Treatment of B-cell lymphomas with combination of bispecific antibodies and saporin.

We report the use of a bispecific F(ab')2 antibody to target the ribosome-inactivating protein saporin to the surface antigen CD22 in the treatment of low-grade, end-stage, B-cell lymphoma. Four patients were treated. Toxic effects were minimal (grade I), with mild fever, weakness, and myalgia for 1-2 days after treatment. One patient showed an antibody response to mouse Fab' and saporin. All patients showed rapid and beneficial responses to treatment with improvements in most disease sites and in peripheral blood cytopenia. The responses were short-lived (less than 28 days) but further study of this targeting system is warranted.

Antibodies, Bispecific↗
PubMed1995

Pattern of usage of the VH4-21 gene by B lymphocytes in a patient with EBV infection indicates ongoing mutation and class switching.

Following infection with EBV, patients have selectively raised serum levels of immunoglobulins encoded by the VH4-21 gene. In order to follow the detailed pattern of usage of the VH4-21 gene by blood B lymphocytes of a typical patient during infection, EBV lines were established, and transformed B cells were hybridized and cloned. In addition, to widen the genetic analysis, cDNA preparations from the EBV transformants using the gene were also analysed by polymerase chain reaction, cloning and sequencing. The majority (12/15) of the clonally distinct sequences derived from IgM utilized the VH4-21 gene in germ line configuration; however, 3/15 showed replacement mutations. For one of these, a heterogeneous pattern of mutation within the clone indicated ongoing mutation, and one sequence contained a stop codon. Three distinct clones which had rearranged to C gamma were obtained, and all were extensively mutated, with some evidence for a role for antigen in selection. Following resolution of the infection, no VH4-21-encoded products were detectable by this approach. It appears therefore that infection with EBV leads to selective activation, mutation and class switching of the VH4-21 gene, with the unusual feature that B cells harbouring deleterious mutations in the functional gene are able to survive in the circulation.

Adult↗
PubMed1995

Fludarabine-related autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia.

We have treated 52 patients with chronic lymphocytic leukaemia (CLL) with fludarabine; 12 developed severe autoimmune haemolysis. Only three had a previous history of haemolytic anaemia. Six out of eight patients retreated with fludarabine after control of their haemolysis developed an exacerbation of the haemolytic anaemia. The cause of autoimmune phenomena in CLL is not known, but our findings reinforce the view that they are caused by a disturbance in immunoregulatory T cells. Fludarabine is a known suppressor of T-cell function.

Adult↗