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Biomedical subjects

L G Lum

Publications and source records attributed to L G Lum.

At least 37 records · Page 2Linked to original sources
PubMed1993

Busulfan-based regimens and allogeneic bone marrow transplantation in patients with myelodysplastic syndromes.

Preparative regimens containing busulfan (BU) followed by allogeneic bone marrow transplantation (BMT) were used in 27 consecutive patients with myelodysplastic syndromes (MDS). The median age was 33 years (range, 4 to 54). Ten were female and 17 male. Sixteen patients had primary MDS, 11 other patients had antecedent hematologic diseases or developed MDS after cytotoxic and/or radiation therapy. Six patients had leukemic transformation and received antileukemic therapy before BMT. Pre-BMT cytogenetic studies showed complex chromosomal abnormalities in 13 patients, a simple abnormality in 5 patients, and normal chromosome in 8 patients. Three BU-based preparative regimens were used: 1 patient received BU 4 mg/kg orally (PO) daily for 4 days and cyclophosphamide (CY) 50 mg/kg intravenously (IV) daily for 4 days (BUCY-4); 24 patients received BU 4 mg/kg PO daily for 4 days, cytosine arabinoside (ara-C) 2 g/m2 IV every 12 hours for 4 doses, and CY 60 mg/kg IV daily for 2 days (BAC); and 2 patients with preceding Fanconi anemia received BU 2 mg/kg PO daily for 4 days followed by total lymphoid irradiation of 5 Gy. Seventeen of 27 patients are alive with no evidence of disease. Ten patients have died: 2 from hepatic veno-occlusive disease, 3 from sepsis, 1 from a cerebral bleed, 1 from a massive gastrointestinal (GI) bleed associated with acute graft-versus-host disease, 1 from hemolytic uremic syndrome with adult respiratory distress syndrome, 1 from bronchiolitis obliterans, and the only patient who did not engraft died from acute myeloid leukemia. Regimen-related toxicities (RRT) include GI tract (diarrhea, 14; stomatitis, 11), liver (9), cardiac (1), and skin (5). Patients who received a genotypically matched marrow graft had a significantly better disease-free survival (DFS) than patients who received a nongenotypic marrow graft (P = .02). The Kaplan-Meier analysis projects an overall DFS of 56% +/- 13% and 78% +/- 10% for patients who received a genotypically matched marrow graft. With the exception of a child who did not engraft, there was no relapse of MDS or leukemia. Excellent DFS, acceptable RRT, and the ease of administration are advantages of this regimen.

Adolescent↗
PubMed1993

Specific humoral immunity in the elderly: in vivo and in vitro response to vaccination.

Vaccinations are often unsuccessful in preventing infection among elderly populations because of generally poor humoral immune responses. We have used tetanus toxoid (TT) antigen to stimulate in vitro anti-tetanus toxoid antibody (anti-TT) synthesis and have found that lymphocytes from many healthy elderly individuals have a reduced production of anti-TT in vitro compared to young adults. This is associated with decreased numbers of B cells secreting anti-TT IgG and a decrease in the mean amount of anti-TT IgG produced per TT-specific B cell. In the present study we report that immunization results in a significant increase in serum titers in young adults for up to one year, whereas levels in old adults fall to baseline by 6 months. The number of B cells that secrete anti-TT IgG increases after immunizations in both young and old subjects, although the number in old subjects is significantly lower than in young subjects at all times except 6 months after. The mean amount of anti-TT produced per B cell (B-cell potency) is significantly lower for the old adults both before and at 6 and 12 months after booster. Immunization does not significantly change the mean amount of anti-TT produced per B cell for either age group. The decreased response to immunization with aging is associated with decreased numbers of specific Ab-secreting B cells and usually decreased potency of those B cells.

Adolescent↗
PubMed1993

Coactivation with anti-CD28 monoclonal antibody enhances anti-CD3 monoclonal antibody-induced proliferation and IL-2 synthesis in T cells from autologous bone marrow transplant recipients.

Recent studies show that costimulation of T cells with anti-CD28 Mab (anti-CD28) enhances anti-CD3 Mab (anti-CD3)-induced proliferative responses and cytokine production. This study determines if coactivation with anti-CD3 and anti-CD28 corrects defects in proliferation and IL-2 secretion in peripheral blood lymphocytes (PBL) from bone marrow transplant (BMT) recipients. PBL or T cells from 5 of 16 autologous and 5 of 22 allogeneic recipients increased their anti-CD3-induced proliferation responses by > 50% after coactivation. In short-term (< 180 days after BMT) autologous recipients, the group mean response increased after anti-CD3 activation from 62,900 to 97,800 cpm after coactivation. In long-term (> 180 day after BMT) autologous recipients, the group mean response after anti-CD3 activation increased from 62,600 to 78,400 cpm after coactivation. The long-term autologous recipient group had costimulated responses from PBL that were significantly higher than the paired anti-CD3-induced responses (p < 0.01); in contrast, such differences were not seen in allogeneic recipient groups. After anti-CD3 stimulation, the mean response of 88,000 cpm for PBL from short-term allogeneic recipients and the mean response of 83,600 cpm for PBL from long-term allogeneic recipients were higher than those in PBL from autologous recipients were higher than those in PBL from autologous recipient groups. The amount of IL-2 secreted by T cells from three autologous and three allogeneic recipients was enhanced 0.9-25-fold by coactivation. Coactivation of PBL from selected recipients increased proliferation into the normal range and increased IL-2 secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Preclinical studies for adoptive immunotherapy in bone marrow transplantation. Generation of anti-CD3 activated cytotoxic T cells from normal donors and autologous bone marrow transplant candidates.

In order to obtain T cells for adoptive immunotherapy after autologous bone marrow transplantation (ABMT) for patients with resistant hematological malignancies, a culture system was developed for growing T cells and inducing non-MHC-restricted cytotoxicity using anti-CD3 monoclonal antibody (OKT3) activation. In this investigation, we show that (1) peripheral blood lymphocytes or bone marrow mononuclear cells (BMMNC) from normal donors and cancer patients can be activated with OKT3 and grown in interleukin-2; (2) normal BMMNC activated with OKT3/IL-2 exhibited non-MHC-restricted cytotoxicity and surface markers comparable to that exhibited by normal PBL activated with OKT3/IL-2; (3) both proliferation and cytotoxic functions were IL-2-dependent; (4) PBL activated with OKT3/IL-2 after cryogenic storage grew and killed comparable to PBL activated with OKT3/IL-2 prior to cryopreservation; (5) OKT3/IL-2-activated PBL and BMMNC obtained from 5 patients with non-Hodgkin's lymphomas (NHL) and 1 patient with acute myelogenous leukemia (AML) increased cell numbers 41-75-fold in 2 weeks of culture; 5 of 6 patients with NHL or AML had PBL and BMMNC that exhibited cytotoxic activity; and (6) contaminating leukemic cells did not overgrow in OKT3/IL-2-activated cultures and could no longer be detected on cytospin specimens after 3 weeks of culture. These data show that T cells in PBL or BMMNC from ABMT candidates can be activated with OKT3/IL-2 for adoptive immunotherapy in combination with ABMT.

Antibodies↗
PubMed1992

Immunodeficiency and the role of suppressor cells after human bone marrow transplantation.

Although not totally analogous to a fetus or newborn, the donor-derived immune system attempts to recapitulate immune ontogeny over a 1- to 2-year period. Early after BMT, primitive functions such as cytotoxicity are present in an immunologic environment dominated by suppressive signals. The suppressive signals are so intense that helper cells are inhibited in their ability to function. Teleologically, the suppressive signals may be required for the development of specific tolerance. Full immune reconstitution is accompanied by the development of specific suppressor activity and specific immune functions. Cognitive T cell-T cell and T cell-B cell interactions are dependent upon the finely tuned and orchestrated synthesis of lymphokines, as well as the expression of specific receptors for the lymphokines on target cells. Future studies will elucidate the mechanisms involved in such interactions in lymphocytes from BMT recipients. Understanding the mechanisms involved will permit the development of therapeutic strategies to manipulate immune responses after BMT.

Bone Marrow Transplantation↗
PubMed1992

Allogeneic bone marrow transplantation in high-risk myeloid disorders using busulfan, cytosine arabinoside and cyclophosphamide (BAC).

Twenty-one patients (median age = 34, range = 10-49; F:M = 7:14) received a preparative regimen consisting of busulfan 4 mg/kg/day x 4, cytosine arabinoside 2 g/m2/12 h x 4 and cyclophosphamide 60 mg/kg/day x 2 ('BAC' regimen) for allogeneic bone marrow transplantation. Out of 12 patients with acute myeloid leukemia (AML), two were in first remission, six were in second remission and four had resistant, relapsed disease or prolonged marrow aplasia after induction chemotherapy. Five of the 12 patients with AML had secondary AML. Four patients had transfusion-dependent myelodysplastic syndrome. Three patients with chronic myeloid leukemia were in the accelerated phase and two were in the blastic phase. Organ toxicities related to the preparative regimen were graded. Liver toxicity occurred in 11 patients, two of these were fatal veno-occlusive disease (VOD) (10%). Nineteen of the 21 patients had grade 2 or less diarrhea, and 13 also had mucositis. One patient developed grade 3 cardiac toxicity, and one other patient had grade 1 skin toxicity. Four patients had gross hematuria related to treatment (19%). No renal, pulmonary or CNS toxicities were encountered. Ten patients have died, two from regimen-related hepatic VOD. Of the remaining eight deaths, four were from respiratory failure in four patients (one case each of Pneumocystis pneumonia, CMV pneumonia, bronchiolitis obliterans associated with chronic graft-versus-host disease, and interstitial pneumonitis complicated pulmonary emboli), and one patient each from GI bleeding, cardiac arrhythmia, sepsis and CNS bleeding. Thus far, only one patient transplanted for secondary AML in second remission relapsed at day 230.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

The immunoregulatory effects of merocyanine 540 on in vitro human T- and B-lymphocyte functions.

Merocyanine 540 (MC 540) is a photoactive dye used to purge bone marrow of tumor cells in autologous bone marrow transplantation. The effects of MC 540 on the lymphoid components in the marrow are unknown. This study evaluates the treatment of lymphocytes by MC 540 (15 micrograms/mL) and light (70 W/m2) on: (1) phytohemagglutinin and Con A-induced proliferation; (2) allogeneic mixed lymphocyte cultures (MLC); (3) the regulation of Ig synthesis by T cells; and (4) the ability of B cells to produce polyclonal Igs as measured by an enzyme-linked immunosorbent assay-plaque assay. The results show that MC 540 and light treatment reduced Con A-stimulated T-cell proliferation greater than 50% after 30 minutes and greater than 80% after 60 minutes of MC 540-sensitized photoirradiation. Ninety minutes of MC 540 and light exposure (designated treatment) inhibited MLC greater than 90%. In polyclonal Ig synthesis, T-cell helper activity could be abrogated by 90 minutes of treatment in cocultures containing untreated B cells. Purified B cells treated for 90 minutes cocultured with normal T cells did not produce Ig. Treatment of B cells completely inhibited Epstein-Barr virus-stimulated Ig synthesis. These data show that T- and B-cell immunity is suppressed by the MC 540-sensitized photoirradiation. Treatment of bone marrow with MC 540 and light may have profound effects on immune reconstitution in autologous marrow graft recipients. More provocative is the fact that the same immunomodulatory effects may be applicable to partially mismatched marrow transplant situations as a means of reducing graft-versus-host reactions.

B-Lymphocytes↗
PubMed1990

Decreased specific antibody synthesis in old adults: decreased potency of antigen-specific B cells with aging.

The rise in rates of infection in adults over the age of 60 is accompanied by a decreased ability of older adults to make specific immune responses after immunization with a variety of specific antigens (Ag). This investigation delineates age-related changes in Ag-specific humoral immunity, comparing adults over age 60 to young adults aged 18-40, using tetanus toxoid (TT) as an immunologic probe. A culture system which does not require TT booster immunizations of study subjects was used to induce in vitro specific antibody responses. The amount of anti-TT antibody (Ab) produced in serum and in culture was measured by a TT-specific enzyme-linked immunosorbent assay (ELISA). The numbers of anti-TT Ab-secreting B cells were measured by a TT-specific ELISA-plaque assay. The TT-specific responses of old subjects were significantly less than that seen for young control subjects in the following measures: (1) serum anti-TT Ab titers (mean +/- S.E. log 2 titer = 3.3 +/- 1.1 vs. 9.5 +/- 1.4, P less than 0.01); (2) anti-TT Ab produced by peripheral blood lymphocytes (PBL) in cultures stimulated with TT (6 +/- 2.1 ng/ml vs. 22 +/- 8.4 ng/ml, P less than 0.01); (3) numbers of anti-TT Ab secreting B cells per million cells cultured (6.7 +/- 3.4 vs. 26.6 +/- 7.6, P less than 0.001) and (4) mean ng Ab secreted per anti-TT Ab-secreting B cell (0.6 +/- 0.4 ng vs. 12.7 +/- 7.8 ng, P less than 0.01). This study shows that both decreased numbers of Ag-specific immune B cells and decreased potency on a per cell basis contribute to the impaired immune responses to immunizations in older adults.

Adolescent↗
PubMed1990

IgG anti-tetanus toxoid antibody synthesis by human bone marrow. I. Two distinct populations of marrow B cells and functional differences between marrow and peripheral blood B cells.

This investigation uses a system for inducing and detecting anti-tetanus toxoid antibody (anti-TT) synthesis to study specific antibody (Ab) synthesis by bone marrow mononuclear cells (MC). We measured the amounts of anti-TT secreted and the number of B cells secreting antibody (Ab). The ELISA plaque detects single B cells secreting specific Ab. The results show that (1) spontaneous anti-TT secretion by MC is higher than spontaneous anti-TT secretion by peripheral blood lymphocytes (PBL) using an ELISA plaque (P less than 0.01); (2) spontaneous anti-TT production by MC correlated with the serum anti-TT titers as measured by an ELISA (r = 0.75, P = 0.005); (3) two types of marrow B cells were identified--one that spontaneously secretes anti-TT and another that produces anti-TT after TT-stimulation; (4) the frequency of anti-TT-secreting B cells is higher in MC than in PBL; (5) the amount of Ab secreted per marrow B cell is not different from that secreted by a peripheral B cell; and (6) marrow B cells could be induced to produce anti-TT in vitro up to 10 months without added cytokines. These results show that bone marrow is a major repository for differentiated B cells that spontaneously produce Abs to maintain circulating Abs titers and for memory B cells that can be induced to produce specific Ab.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1990

Failure of T cell receptor-anti-CD3 monoclonal antibody interaction in T cells from marrow recipients to induce increases in intracellular ionized calcium.

There are multiple immune defects in T cells from recipients after bone marrow transplantation (BMT). This study examines recipient T cells for increases in intracellular ionized calcium concentration [( Ca2+]i) after binding the T cell receptor-CD3 complex with anti-CD3 MAb. PBL from 10 of 23 short-term recipients (less than 1 yr after BMT) responded poorly (less than 35% of control) to anti-CD3 stimulation and PBL from 9 of 23 had blunted calcium flux responses (35-70% of control). Purified CD2+, CD56- cells from seven additional short-term recipients including three autologous marrow recipients were closely examined, and a sizable proportion of CD3+ cells from six of seven recipients did not increase [Ca2+]i after anti-CD3 stimulation. The decreased magnitude of the responses was due to decreased numbers of responding cells and not to a decrease in mean CD3 fluorescent intensity or in calcium flux responses on a single cell basis. Five of seven long-term recipients (greater than 1 yr after BMT) had PBL that responded normally and two of seven had PBL with blunted calcium flux responses. The data show that the signal transduction response mediated by the CD3-antigen receptor as measured by calcium flux is defective early after autologus or allogeneic BMT.

Adolescent↗
PubMed1990

Immune recovery after bone marrow transplantation.

The donor-derived immune system that forms after bone marrow transplantation (BMT) takes as long as 2 years to develop in healthy BMT recipients. Soon after BMT, GVHD and its treatment increase the susceptibility of the recipient to overwhelming infections, and they retard the development of the immune system. The new system develops from a primitive state characterized by cytotoxic and suppressive functions and progresses to a mature state characterized by the development of specialized lymphocyte functions such as lymphokine production, proliferation, and expression of growth factor receptors. These specialized functions develop in healthy long-term recipients, whereas the same functions may be absent or impaired in those who develop chronic GVHD.

Acute Disease↗
PubMed1990

Autoimmune thyroiditis after bone marrow transplantation.

We describe the transfer of autoimmune thyroiditis by bone marrow transplantation. The male recipient developed compensated hypothyroidism 3 years after transplantation, and progressed to thyroid failure 1 year later. The female sibling had compensated hypothyroidism when screened 4 years after marrow donation. The donor, the recipient, and an older male sibling were HLA DR4, 5; the father was presumed homozygous for DR4 and the mother for DR5. Only the donor and recipient had abnormal thyroid function and positive antithyroid antimicrosomal antibodies. The most probable mechanism for the organ specific autoimmune dysfunction is the transfer of abnormal B and T cell clones from the donor. Radiation damage to the thyroid prior to transplantation, the mild graft-versus-host disease immediately following transplantation, and the general immune dysregulation seen in the first several years after marrow engraftment may have contributed to an acceleration of the autoimmune destruction of the recipient's thyroid.

Asthma↗
PubMed1989

Lipoxygenase inhibitors enhance the proliferation of human B cells.

The addition of drugs which inhibit the lipoxygenase pathways of arachidonic acid metabolism to 5 day cultures of mitogen-stimulated human B cells enhanced the proliferative response more than 10-fold. Several chemically dissimilar lipoxygenase inhibitors increased proliferation in this system, whereas the specific cyclooxygenase inhibitor indomethacin had no effect. A lipoxygenase inhibitor could be added as late as 48 to 72 h after the initiation of culture and still cause a significant increase in B cell proliferation. These drugs increased the proliferation of both peripheral blood B cells and tonsillar B cells activated by Staphylococcus aureus Cowan I or anti-Ig M antibodies, in combination with a crude T cell supernate, a commercial B cell growth factor preparation, or recombinant lymphotoxin. A similar effect was observed in tonsillar B cells purified by counterflow centrifugal elutriation to remove esterase positive accessory cells, suggesting this is a direct effect on the B cell. Lipoxygenase blockade also caused a greater than twofold increase in polyclonal Ig production. The enhanced proliferation caused by lipoxygenase blockade could not be reversed by adding back exogenous leukotrienes or hydroxyeicosatetraenoic acids to the cultures. Furthermore, B cells prelabeled with [3H]arachidonic acid did not produce radiolabeled lipoxygenase metabolites of arachidonic acid under the same culture conditions in which the addition of lipoxygenase inhibitors had a profound effect on proliferation. Thus, lipoxygenase inhibitors markedly stimulate B cell proliferation under a variety of experimental conditions, although the mechanism responsible for this action has not yet been elucidated.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1989

Modulation of lymphocyte proliferation and immunoglobulin production by transferrin-gallium.

Gallium resembles iron with respect to transferrin (Tf) binding and cellular uptake via Tf receptors. We have previously shown that transferrin-gallium (Tf-Ga) complexes interfere with the cellular incorporation of iron and inhibit the proliferation of HL60 cells. Since mitogen-stimulated peripheral blood lymphocytes express Tf receptors, we examined the effect of Tf-Ga on lymphocyte proliferation and on immunoglobulin synthesis by B-lymphocytes. Tf-Ga inhibited phytohemagglutinin, pokeweed mitogen, and tetanus toxoid-stimulated lymphocyte proliferation by greater than 50%, an effect which appeared to be cytostatic rather than cytotoxic. In cocultures of T-lymphocytes or CD4+ T-lymphocytes and B-lymphocytes, Tf-Ga also inhibited pokeweed mitogen-stimulated immunoglobulin production by 84 to 100%. Tf-Ga inhibited both T-independent Epstein Barr virus-stimulated B-lymphocyte proliferation and immunoglobulin production; however, these effects appeared to be independent of each other, since immunoglobulin production was inhibited by 75% by a concentration of Tf-Ga which did not uniformly inhibit proliferation. Tf-Ga is capable of targeting Tf receptor-bearing T- and B-lymphocytes and interfering with their proliferation and function. Such effects may be of relevance to patients being treated with this metal. The potential immunosuppressive activity of gallium warrants further investigation.

Gallium↗
PubMed1989

Immunoregulatory effects of alpha-endorphin, beta-endorphin, methionine-enkephalin, and adrenocorticotropic hormone on anti-tetanus toxoid antibody synthesis by human lymphocytes.

This study assesses the effects of adrenocorticotropic hormone (ACTH), alpha-endorphin (alpha-endo), beta-endorphin (beta-endo), and methionine-enkephalin (met-enk) on tetanus toxoid-stimulated in vitro specific antibody (anti-TT) synthesis. ACTH and TT-costimulated cultures enhanced antibody (Ab) synthesis over control TT-stimulated cultures at 10(-9) and 10(-11) M and suppressed Ab synthesis at 10(-13) and 10(-17) M. The alpha-endo and TT-costimulated cultures enhanced Ab synthesis over control cultures at all concentrations tested (10(-7) to 10(-15) M). Cultures costimulated with beta-endo and TT enhanced Ab synthesis over control cultures at 10(-11) M and suppressed Ab synthesis at doses above and below 10(-11) M. The met-enk and TT-costimulated cultures produced more Ab than controls at 10(-9) M; and the met-enk and TT-costimulated cultures produced less Ab than controls at other concentrations as low as 10(-17) M and as high as 10(-7) M. The results of this study provide one reason as to why the interactions between the neuroendocrine and immune systems remain unclear.

Adrenocorticotropic Hormone↗
PubMed1988

Transfer of allergen-specific IgE-mediated hypersensitivity with allogeneic bone marrow transplantation.

We investigated whether allergen-specific IgE-mediated hypersensitivity is transferred by bone marrow transplantation. Twelve patients, 14 to 47 years of age, undergoing allogeneic bone marrow transplantation for the treatment of hematologic cancer were selected, along with their donors, by a screening questionnaire for a history of atopy in the donor. We evaluated these donor-recipient pairs before transplantation and at several points afterward for immediate skin-test reactivity to 17 allergens. For allergens for which pretransplantation skin tests had been positive in the donors and negative in the recipients, 20 of 46 post-transplantation skin tests were positive in 8 of the 11 recipients who survived for more than one year after transplantation. For allergens for which both donors and recipients had had negative skin tests before transplantation, only 6 of 256 tests (2.3 percent) were positive in the recipients after transplantation. Long-term transfer of donor-derived mite-specific IgE was demonstrated by radioallergosorbent testing in two recipients. Seven recipients either acquired or had an exacerbation of allergic rhinitis, and two recipients without a history of asthma had asthma one year after transplantation. We conclude that allergen-specific IgE-mediated hypersensitivity is adoptively transferred by bone marrow transplantation from donor to recipient by B cells with allergen-specific memory.

Adolescent↗