Biomedical subjects
Publications and source records attributed to M R MacKenzie.
A patient with IgG kappa multiple myeloma was studied cytogenetically prior to therapy and was found to have a clone of 55,XX cells. After treatment leading to a clinical response, the patient relapsed with a clone of 57,XX cells, which were derivatives of the original neoplastic cell line. This is the first case of demonstrated clonal evolution of myeloma in a patient studied prior to chemotherapy.
A patient is described who presented with a combined preleukaemic, lymphoproliferative and plasma cell disorder. These disorders were not related to cytotoxic therapy. The clonal nature of the lymphoid component was demonstrated by lymphocyte surface marker studies and the clonal nature of the plasma cell component by immunoperoxidase studies. Since the involved lymphoid and plasma cells contained different heavy and light chains, they were felt to originate from two separate B cell clones not related to the clone responsible for the preleukaemic component.
T and B lymphocyte number and lymphocyte response to phytohemagglutinin, pokeweed mitogen, concanavalin A, coccidioidin and streptokinase-streptodornase (SKSD), plus monocyte ingestion of coccidioidin- and IgG-coated chicken erythrocytes were measured in 5 patients with coccidioidal meningitis, 11 with nonmeningeal extrapulmonary cocidioidomycosis and 5 with localized pulmonary infections. These cases were evaluated within six months of the onset of infection. Lymphocytic responses to phytohemagglutinin, pokeweed mitogen, concanavalin A, SKSD and coccidioidin and monocytic ingestion of coccidioidin- and IgG-coated chicken erythrocytes were severely decreased in patients with meningeal and nonmeningeal, extrapulmonary coccidioidomycosis but not in patients with localized pulmonary infections. T and B cell numbers, however, were normal in all groups. Thus, defects in cellular immunity are involved in the pathogenesis of extrapulmonary coccidioidomycosis and measurements of lymphocytic and monocytic function may identify patients prone to extrapulmonary infection.
A stable line of IgG K producing human plasma cells was established from a myelomatous human bone marrow using conditioned media from a rapidly metabolizing lymphoblast line, RPMI 4098. Growth in RPMI 1640 (15% fetal calf serum) at 6% CO2 promoted a 62-hour doubling time with a preferred cell concentration of 1 x 10(6)/mL. Surface marker studies showed: no receptors for sheep erythrocytes, no surface immunoglobulins, variable number of cells bearing complement receptors and 83% bearing Fc receptors. Although transmission electron micrographs demonstrated a poorly developed endoplasmic reticulum, radioimmunoassay showed 23 ng IgG and 28.7 ng Kappa were produced by 1 x 10(6) cells in 72 hours. Further, the cells are lipase, esterase and Epstein-Barr nuclear antigen negative. ASG banding showed a total chromosome number that varied from 46--49. Since the number of human plasma cell lines is limited, it is felt that this line will augment the immunobiological study of human myeloma.
A patient with long-standing chronic lymphocytic leukemia with both humoral and cellular immunodeficiency had lymph node receptor evidence of a B lymphocyte disorder. He was also found to secrete the Epstein--Barr virus and, late in his illness, developed a markedly positive antinuclear antibody. Interrelationship of these findings may be important in the ultimate determination of the etiology and functional mechanisms in lymphocyte malignancies.
Peripheral blood leukocytes (PBL) from myeloma patients were studied for their capacity to lyse plasma cells from myeloma patients, benign monoclonal gammopathy (BMG) patients, and nonneoplastic disease patients. Plasma cells were isolated from bone marrow, labeled with 51Cr, and cultured with PBL isolated from patients with myeloma, BMG, or nonneoplastic disease, as well as normal individuals. PBL from patients with multiple myeloma demonstrated responses to autologous or allogeneic myeloma plasma cells. Optimum conditions for cytotoxic response included a responder-to-stimulator ratio of 1:1 and an effector-to-target ratio of 20:1. PBL from normal individuals or patients with BMG failed to demonstrate this response. However, PBL from BMG patients, but not normal individuals, could be induced to kill myeloma plasma cells (but not nonmyeloma plasma cells) by simultaneous stimulation with allogeneic lymphocytes and myeloma plasma cells.
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The binding of Staph A protein to murine immunoglobulins has previously been thought to be restricted to the IgG2 and IgG3 classes. In this study five IgM proteins were assessed for binding, and of these one showed marked Staph A binding. Pepsin digestion of this IgM molecule produced several different sized fragments, and the binding studies with these fragments indicated that the binding site is in the CH2 domain.
Bone marrow mononuclear cell populations were studied in 35 patients without myeloma, 39 patients with multiple myeloma, and 15 patients with benign monoclonal gammopathy. Bone marrow mononuclear cell receptors, responses to mitogens or allogeneic stimuli, and suppressive effects on in vitro peripheral blood lymphocyte (PBL) function were studied. In bone marrow cell populations from patients with untreated multiple myeloma, the percent of complement receptor-bearing cells and the pokeweed mitogen- and concanavalin A-stimulated responses were significantly greater than were those in bone marrow cell populations from patients without myeloma. Sheep red blood cell receptor-bearing cells were significantly greater in marrow populations from treated multiple myeloma patients compared to those from untreated multiple myeloma patients. Sheep red blood cell receptor-bearing cells from the bone marrow of multiple myeloma patients suppressed responses of the multiple myeloma patients' PBL's to autologous mitomycin C-treated bone marrow plasma cells and to allogeneic stimuli in one-way mixed leukocyte culture. Complement receptor-bearing cells suppressed the response to pokeweed mitogen. The presence of lymphocytes in the marrow compartment that are capable of suppressing the response of myeloma patients' PBL's to plasma cell antigens may be significant in the pathogenesis of multiple myeloma.
Reference values for T and B lymphocytes were determined on lymphocytes from canine thymus, spleen, lymph node, bone marrow, and peripheral blood by use of erythrocyte (E) and erythrocyte-antibody-complement (EAC) rosette assays, plus a direct fluorescent technique for assay of surface immunoglobulins. Numbers of T lymphocytes, indicated by E rosette formation with human erythrocytes, ranged from a low of 1% in the thymus to 13% in the peripheral blood, whereas B-lymphocyte numbers ranged from 3% (thymus) to 41% (bone marrow) and from 6% (thymus) to 36% (bone marrow), as indicated by EAC rosette formation or presence of surface immunoglobulins respectively. Stimulation of peripheral blood lymphocytes with either phytohemagglutinin or concanavalin A increased the total number of E-rosetting cells two to threefold, whereas the number of EAC-rosetting cells decreased by half. Further, the percentage of cells bearing Fc receptors increased after phytohemagglutinin stimulation. These results indicate the E rosette technique can be used to identify and to monitor a population of canine T lymphocytes.
The reduced capacity of patients with multiple myeloma to respond to antigen challenge is well recognized. Response to antigen involves antigen recognition, cell proliferation, and synthesis and secretion of antibody. This study examines this sequence of events in peripheral blood lymphocytes from untreated and treated patients with myeloma, from individuals with benign monoclonal gammopathy, and from normal healthy donors. Antigen-binding capacity was assessed by testing the ability of lymphocytes to bind radio-labeled pneumococcal polysaccharide, tetanus toxoid, or diptheria toxin. The in vitro proliferative response to these antigens as well as to pokeweed mitogen and streptokinase-streptodornase was evaluated. The secretion of immunoglobulin in response to pneumococcal polysaccharide, tetanus toxoid, and pokeweed mitogen by 2-4 x 10(6) lymphocytes in 7-day cultures was determined. The effects of coculture of myeloma peripheral blood lymphocytes and normal peripheral blood lymphocytes on immunoglobulin production and mixed leukocyte reactions were explored. All myeloma patients had normal numbers (3-8/5,000 cells) of antigen-binding cells. However, most showed a diminished antigen-induced blast transformation as measured by uptake of [(125)I]5-iodo-2'-deoxyuridine in culture. Immunoglobulin production in response to specific antigen in myeloma lymphocytes was 30-80% less than in normal lymphocytes. Immunoglobulin synthesis and mixed leukocyte responses by normal peripheral blood lymphocytes could be suppressed by myeloma lymphocytes. Multiple suppressor populations were present. Thus, the immune defect in myeloma is beyond the antigen recognition step and involves both the proliferation of antigen-sensitive cells and immunoglobulin production. Further suppressive effects are imposed on normal cells, implying defects in immunoregulation in this disease.
Seventy-four patients with multiple myeloma, 17 untreated and 57 treated, were studied to characterize their peripheral blood lymphocytes. PBL were studied for E, EAC, and EA rosette-forming cells, SIg, and Fc receptor-bearing cells. The responses to HA, Con A, and PWM were assessed as well as their ability to stimulate or to respond in a MLC. Finally, the capacity of mitogen-stimulated lymphocytes to lyse Chang cells, CRBC, and PHA-stimulated lymphoblasts was examined. These results were compared with a group of normals and patients with benign monoclonal gammopathy. In untreated myeloma patients there was a normal percentage of T cells, but an abnormal distribution of B cells as judged by a decrease in SIg-bearing cells, as well as an increase in EAC rosette-forming cells. Subpopulation analysis showed a marked increase in EAC rosette-forming cells without SIg. PHA, Con A, and PWM, and response in MLC were all normal. However, the ability to stimulate in MLC was significantly depressed. Treated myeloma patients had similar findings, except that the response to PWM was significantly depressed. The capacity of PWM-stimulated cells to lyse target cells was depressed in both groups. The results indicate that, in the peripheral blood of myeloma patients, there are populations of lymphocytes characterized by the presence of the EAC receptor without SIg, which are deficient in the capacity to stimulate an MLC response and the ability to be cytotoxic when stimulated by PWM. The results form a baseline for the study of abnormal lymphoid function in human myeloma.
Patients with Waldenström macroglobulinemia were studied for the presence or absence of the hyperviscosity syndrome, the relative serum viscosity value, and the calculated whole blood viscosity to identify a level at which symptoms occurred. The majority of symptomatic patients had whole blood viscosity values above 8.0 centipoises. There was a direct correlation between whole blood viscosity and relative serum viscosity, r = 0.75. One patient with central nervous system abnormalities was identified as having a high whole blood viscosity but a low serum viscosity. It was concluded that the vast majority of patients with the hyperviscosity syndrome will be identified by measuring the relative serum viscosity. In patients with central nervous system findings and a low serum viscosity, the whole blood viscosity should be determined either by direct measurement or by calculation.
A case of T-cell lymphoma, as defined by immunologic studies of lymph node, peripheral blood, and cultured cells, is presented. Convoluted lymphocytes were noted in the original lymph node biopsy, in cerebral spinal fluid preparations and terminally, in the peripheral blood. The prominent neuologic abnormalities representing both central and peripheral nervous system involvement were atypical. Other features included skin and testicular infiltration, leukemic transformation, and refractoriness to therapy. A somewhat similar clinical picture has been reported in other patients with diffuse, poorly differentiated lymphocytic lymphomas, some of which have proven to have a T-cell origin. T-cell lymphoma may represent a distinct clinical entity that calls for modifications of our traditional therapeutic approaches.
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Individuals with Down's syndrome are thought to have abnormalities of immune function. Studies to quantify the number of peripheral blood T and B lymphocytes and serum immunoglobulins in 12 individuals and 12 sex and age matched control subjects were performed. Hepatitis B antigen and antihyroglobulin antibodies as markers of possible immune dysfunction were determined. The numbers of circulating T and B cells, and the level of serum immunoglobulins in children with Down's syndrome did not differ from nonretarded control children. Circulating hepatitis B antigen and antihyroglobulin antibodies were not present. These studies indicated that quantitative abnormalities of T and B cells are not present in children with Down's syndrome. The data did not exclude the existence of qualitative abnormalities.
Thirty-four patients with macroglobulinemia were studied for the incidence of hyperviscosity syndrome (HVS) and the circumstances in which this complication occurred. The following were evaluated: total serum protein, quantity of IgM paraprotein, and relative serum viscosity. These measurements were coupled with physical-chemical studies of isolated IgM proteins, including molecular weight and evaluation of molecular shape, by determination of intrinsic viscosity, viscosity increment, ratio of frictional coefficient, and coefficient of concentration dependence. It was found that relative serum viscosity values in the symptomatic range (above 6.0) were present in 38 per cent of the patients and were usually associated with IgM values greater than 5.0 gm. per 100 ml. All IgM proteins studied were large, hydrodynamically active molecules. A patient who developed HVS with IgM values below 3.5 gm. per 100 ml. had markedly asymmetrical molecules. The principal factors in the pathogenesis of this syndrome in macroglobulinemia are the concentration and molecular shape of IgM. Additional factors include protein-protein interactions between IgM and serum constituents.
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