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D G Nathan

Publications and source records attributed to D G Nathan.

At least 127 records · Page 7Linked to original sources
PubMed1983

Evidence for genetic restriction in the suppression of erythropoiesis by a unique subset of T lymphocytes in man.

The suppression of erythropoiesis by lymphocytes from patients with a T cell lymphoproliferative syndrome and pure erythrocyte aplasia has been previously demonstrated. To study the nature of the suppressor cell and possible genetic restriction of this suppression, we investigated a patient with severe anemia, splenomegaly, lymphocytosis, and erythroid aplasia. A 3-mo course of low-dose daily oral cyclophosphamide achieved a complete remission for over 12 mo. The surface phenotype of his lymphocytes was analyzed by means of antibodies to lineage, differentiation, and activation-specific surface antigens. The cells expressed mature T cell antigens T3, T8, and T11, while lacking T1. Immature T cell, B cell, and the monocyte-specific antigen Mo2 were absent, while Mo1, a monocyte-associated antigen not normally expressed on T cells, was present. T10 and Ia expressed as activation antigens were also present. The cells, cryopreserved at diagnosis, were thawed and co-cultured in plasma clot with patient remission marrow samples at T cell/bone marrow ratios of 1:1 and 2:1. There was nearly 90% suppression of erythroid colony-forming unit expression and 60% suppression of erythroid burst-forming unit expression at 2:1 T cell to bone marrow ratios and somewhat less suppression at 1:1. Granulocyte/macrophage progenitor expression was unaffected. Erythroid progenitor differentiation in the marrows of two HLA identical siblings was similarly suppressed. The cells were co-cultured with the marrows of nine nonrelated donors to investigate the potential genetic restriction of this suppression. Colony suppression equal to that observed in the marrow of the patient and his siblings was found in studies of two partially HLA identical individuals. No suppression was detected in marrow co-cultures of two entirely HLA dissimilar individuals. These results show that suppression of erythropoiesis by a unique subset of T8, Mo1, Ia-positive lymphocytes isolated from a patient with lymphocytosis and erythrocyte aplasia is genetically restricted.

Adult↗
PubMed1983

Evidence for a clonal model for hemoglobin switching.

The ontogenic switch from fetal to adult hemoglobin could be due to gradual replacement of fetal by adult erythroid progenitor cells, each with unique potential hemoglobin expression programs. We have studied globin synthesis in single colonies derived from the BFU-E of human newborn infants and rhesus monkey fetuses, both at the time of the switch. In the 140-day rhesus fetal colonies, beta synthesis ranged from 8% to 44% of (beta + gamma) in 47 colonies. When fetal colonies were arbitrarily defined as those with below 26% beta, and adult colonies those with above 26% beta, we predicted that there would be 12 adult colonies; 14 were observed. The rhesus fetal results were compatible with the presence of two or more classes of progenitors within the population seen at the time of the switch. In the human newborn study, the number of colonies increased fourfold from day 14 to day 21 in culture. beta synthesis also increased. These increases occurred even in cultures from which red, well-hemoglobinized colonies were completely removed as they appeared. New cohorts of late-appearing colonies were derived from immature progenitors. The early colonies showed correlation of G gamma and beta synthesis, but the late colonies did not show this correlation. We had found the latter pattern previously in adult, fetal-like colonies. Thus fetal progenitors in man have high levels of Hb F and G gamma, with correlation of these parameters at the level of single-progenitor-derived colonies; these fetal progenitors are found in fetuses and newborns. Adult, fetal-like progenitors have lower levels of Hb F and G gamma, without any correlation between the levels of each. The adult progenitors appear in newborn infants as the switch occurs, and they are the only class found in adults. Our observations in the simian and human studies support a clonal model for hemoglobin switching.

Animals↗
PubMed1983

Elimination of leukemic cells from human bone marrow using monoclonal antibody and complement.

Human leukemic cells which bear the common acute lymphoblastic leukemia antigen can be lysed with a murine monoclonal antibody (J-5) in the presence of rabbit complement. Conditions have been defined for eliminating 51Cr-labeled common acute lymphoblastic leukemia antigen-positive NALM-1 cells or cryopreserved leukemic lymphoblasts from a 100-fold excess of human bone marrow. Optimal lysis is obtained with treatment for a total of 90 min. Three treatments for 30 min are more effective than two treatments for 45 min or one treatment for 90 min. Separation of marrow on a Ficoll:diatrizoate gradient does not permit more effective elimination of leukemic cells. Tumor cell lysis is inhibited by high concentrations of common acute lymphoblastic leukemia antigen-positive cells (2 X 10(7)/ml) and by high concentrations of bone marrow (10(8)/ml). Under optimal conditions, greater than 99% of 51Cr-labeled leukemic lymphoblasts can be eliminated from a 100-fold excess of human marrow. Selective removal of leukemic cells from human bone marrow in vitro should facilitate trials of autologous marrow transplantation.

Antibodies, Monoclonal↗
PubMed1983

Influence of intensive asparaginase in the treatment of childhood non-T-cell acute lymphoblastic leukemia.

Between June 1977 and December 1979, 72 evaluable patients with childhood non-T-cell acute lymphoblastic leukemia were induced into complete remission using vincristine, prednisone, and doxorubicin. All received asparaginase consolidation and central nervous system prophylaxis with cranial irradiation and intrathecal methotrexate. All patients then received prolonged intensification with vincristine, prednisone, and doxorubicin, and half of them were randomized to receive weekly high-dose asparaginase. Continuation therapy was with vincristine, prednisone, methotrexate, and 6-mercaptopurine. After a median follow-up of 57 months, there were four remission deaths and 25 relapses. Central nervous system relapse was the first event in 4% of patients. There were fewer treatment failures in the asparaginase-treated group [2-sided, p = 0.04 (0.07 controlling for standard and high-risk groups)]. Asparaginase toxicity occurred in six patients (8%) and was self-limited, but it precluded further use of the drug in those patients. The major toxicity of this treatment program was drug-induced cardiomyopathy which occurred in 10 patients (14%) and was fatal in three of them. In summary, we conclude that the intensive use of high-dose asparaginase has an important role in the treatment of children with acute lymphoblastic leukemia. The morbidity of multiple doses of doxorubicin outweighed its antileukemic advantage in standard-risk patients.

Adolescent↗
PubMed1982

Autologous bone-marrow transplantation in CALLA-positive acute lymphoblastic leukemia after in-vitro treatment with J5 monoclonal antibody and complement.

A monoclonal antibody (J5) specific for the common acute-lymphoblastic-leukaemia antigen (CALLA) was used for in-vitro pre-treatment of bone-marrow before autologous transplantation in four patients with CALLA-positive acute lymphoblastic leukaemia (ALL) in relapse, who did not have HLA-compatible donors. After remission induction and intensification, bone-marrow cells were harvested, treated with J5 antibody and rabbit complement, and cryopreserved in liquid nitrogen. Patients received ablative chemotherapy and total-body irradiation before reinfusion of autologous J5-treated bone marrow. The transplantation protocol was well tolerated, and engraftment of normal myeloid cells occurred in all for patients. Two patients have continued in unmaintained remission with complete haematopoietic reconstitution for more than 1 year after autologous transplantation.

Antibodies, Monoclonal↗
PubMed1982

Synthesis of hemoglobin F in adult simian erythroid progenitor-derived colonies.

The simian hematopoietic system is known to respond to anemic stress with the production of erythrocytes containing large amounts of fetal hemoglobin. To determine the regulatory mechanism responsible for hemoglobin F (HbF) production in stress erythropoiesis, adult simian bone marrow cells were cultured in plasma clots in the presence or absence of erythropoietin and burst-promoting activities, and the HbF content of progenitor-derived colonies was determined by radioimmunoligand assay. Three classes of erythroid progenitors were detected: BFU-E, CFU-E, and a very mature cohort of dense highly erythropoietin-responsive cells (HERC). These classes varied in inverse proportion to their maturity with respect to their potential for HbF accumulation in the colonies to which they give rise. Both erythropoietin and burst-promoting activity stimulated HbF production, particularly in colonies derived from immature progenitors. For example, under conditions of high erythropoietin stimulation, BFU-E colonies contained 13.7-37.7% HbF, CFU-E colonies contained 2.8-13.5% HbF, and HERC colonies 0-1% HbF. These results suggest that under nonstress conditions simian erythrocytes are derived almost entirely from HERC progenitors and proerythroblasts in which gamma chain synthesis is suppressed. During stress erythropoiesis, augmented HbF accumulation could be explained by the rapid entrance into the marrow of proerythroblasts directly derived from immature progenitors. Gamma chain production in these proerythroblasts is additionally regulated by the changes in environmental erythropoietin and burst-promoting activities.

Animals↗
PubMed1981

Monoclonal antibody assessments of T cell interactions in erythropoietin studies.

The contemporary application of clonal assay techniques has greatly expanded our knowledge of the regulation of hematopoiesis. Our efforts have been directed toward the investigation of non-erythropoietin-mediated regulation of human erythropoiesis in the form of cell-to-cell interaction between mature T cells and erythroid progenitors. Our data indicate that three such progenitors, the early marrow erythrocyte precursor BFU-E, the more mature marrow erythrocyte precursor, CFU-E and the peripheral blood BFU-E, each exhibit totally different requirements for their colony expression in culture, with respect to the absence of erythropoietin and the presence of mature T cells or their products. The capacity of erythroid progenitors to withstand incubation in the absence of erythropoietin appears to be a characteristic of immature rather than mature erythroid progenitors. Furthermore, use of OKT3 antibody depletion techniques shows that peripheral blood-derived BFU-E appear to depend upon mature lymphocytes or T cell-conditioned medium for erythropoietin-stimulated differentiation while bone marrow BFU-E and CFU-E have no requirement for mature T cells to produce erythropoietin-dependent maturation. Our results, plus a vast array of data provided by other investigators in the field, are integrated into a proposed framework for further investigation of T cell induction of erythropoietin-dependent erythroid differentiation aimed at more specifically identifying the inducer cell subset(s) in that system.

Animals↗