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Biomedical subjects

J Milleck

Publications and source records attributed to J Milleck.

11 recordsLinked to original sources
PubMed1992

Biological activity of mutants of human tumour necrosis factor-alpha.

Point mutations in different regions of the tumour necrosis factor-alpha (TNF-alpha) molecule influence anti-tumour cytotoxic/cytostatic activities as well as haemorrhagic tumour necrosis, tumour regression and lethal toxicity in mice. Mutations in the C-terminal region in positions 150 and 155 markedly decrease cytotoxicity for murine L929 fibroblasts and human MCF7 mammary carcinoma cells. Competitive binding experiments with 125I-labelled TNF-alpha revealed that the loss of cytotoxicity is caused by a loss of target cell binding. In contrast to the reduced activity against L929 and MCF7 cells, neither binding to nor cytostatic activity against the human myeloid leukaemia cell lines HL60 and U937 are affected. This target cell type-dependent behaviour is probably due to the fact that L929 and MCF7 cells express different types of TNF receptor compared with myeloid leukaemia cells. While a mutation in position 127 decreases the overall activity of TNF-alpha, a deletion of four N-terminal amino acids does not reduce biological activity. In vivo the TNF mutants differed in their anti-tumour effects and lethal toxicity, but a segregation of anti-tumour activity and toxicity was not observed.

Amino Acid Sequence↗
PubMed1979

Human leukaemia-associated antigens expressed by acute myelocytic leukaemia cells and their detection by heterologous antisera.

Antisera against human acute myelocytic leukaemias were tested in complement-dependent in-vitro cytotocity tests against leukaemia cells and normal cells as targets. After absorption with erythrocytes and spleen cells from allogeneous donors the antisera reacted with leukaemia cells, but not with leukocytes from bone marrow and the peripheral blood of children in remission, lymphocytes from healthy donors, enriched B-lymphocytes, enriched T-lymphocytes, PHA-induced blasts and cord blood lymphocytes. Extensive cross reactions were obtained in the tests against leukaemia cells. The antisera reacted not only with AML cells, but also with ALL, CLL, and CML cells. It was possible to remove the cross-reactivity with ALL cells through absorption with ALL cells or with fetal tissue, and to remove the cross reactivity with CLL cells through absorption with CLL. A complete absorption of the anti-AML sera was possible with AML and CML cells. After absorption with fetal tissue and CLL cells the antisera showed exclusively specificity for myelocytic leukaemias. Thus, AML cells contain three leukaemia-associated membrane antigen components: an antigen of fetal origin, a "CLL-specific" antigen, and an antigen that occurs on myelocytic leukaemias.

Adult↗
PubMed1979

Human leukaemia-associated antigens expressed by acute lymphocytic leukaemias and their detection with heterologous antisera to T, B-, and non-T-non-B subtype AL blasts.

Antisera from rabbits and goats against subtypes of acute lymphocytic leukaemia (ALL with T-cell markers, ALL with B-cell markers, Non-T-non-B ALL) were tested for their specificity in complement-dependent in-vitro cytotoxicity testing. After absorption of the fivefold diluted antisera with erythrocytes and spleen cells of allogenous donors they reacted with ALL cells, but not with leukaemias of other types (AML, CLL, CML), lymphocytes of healthy donors, enriched B-lymphocytes, enriched T-lymphocytes, PHA-stimulated lymphocytes, cord lymphocytes and bone marrow lymphocytes of patients in remission. In the reactions of the antisera against ALL cells the subtype of ALL is of major importance: Six rabbit antisera and one goat antiserum against T-subtype ALL reacted in all 19 tests with the leukaemia cells of 5 patients with T-cell ALL and in all 9 tests with thymocytes of 3 donors, but only in 14 out of 41 tests with the leukaemia cells of 14 Non-T-non-B ALL patients. One antiserum against a B-subtype ALL lysed B-cell ALL (1/1), but not T-cell ALL (0/3), Non-T-non-B-cell ALL (1/5) and thymocytes (0/2). Four antisera against Non-T-non-B-subtype ALL reacted in 22 out of 46 tests with the Non-T-non-B cells of 17 ALL patients, but did not react with the leukaemia cells of 4 children with T-cell ALL (0/16), one child with B-cell ALL (0/1) thymocytes of 2 donors (0/4). The reactions of the anti-ALL sera with fetal liver cells, complete absorbability of the antileukaemic activity of the antisera with fetal tissue and the reactions of an anti-fetal serum with ALL cells point to the existence of fetal antigen components as leukaemia-associated antigens.

Adolescent↗
PubMed1978

[Foetal antigens on leukaemia cells (author's transl)].

An antiserum against human foetal liver cells reacted in in-vitro-cytotoxic test with the leukaemia cells of 6 out of 10 children with acute lymphocytic leukaemias (ALL) and with the lymphoma cells of 1 out 2 children with lymphosarcoma (LS). No cytotoxic reactions were obtained against leukaemia cells of 5 children with acute myelogenic leukaemia (AML), leukaemia cells of 7 adults with chronic lymphocytic leukaemia (CLL), bone marrow cells of 9 children in clinical remission and lymphocytes of normal donors. The cytotoxic activity of the anti-foetalserum was removed by absorption with foetal liver but not with adult liver. The results suggest that foetal antigens may occur on ALL-cells and LS-cells.

Adult↗
PubMed1978

[Complement activity in leukemic patients].

The in vitro test of heterologous anti-leukaemic sera against human leukaemic cells resulted in the serum of leukaemic patients being able to produce a lysis of leukaemic cells in the leukaemic phase as well as in remission when specific heterologous antibodies were present.

Antibody Specificity↗
PubMed1978

Specificities of heterologous antisera against human leukaemia cells. 1. Reactions against leukaemia cells.

Rabbit or goat antisera directed to ALL, CLL, AML and CML cells were investigated in cytotoxicity tests with different leukaemia and normal cells as targets. After absorptions with erythrocytes and spleen cells from allogeneic donors the antisera killed only leukaemia cells. There was no reaction with remission leukocytes or blood leukocytes from normal donors. Anti-ALL-Sera reacted in 35 out of 49 tests with ALL cells from 13 patients. Apparently the ALL antisera which were directed to the T cell subtype of ALL preferentially affected ALL cells of this subtype. Cross reactions with cells from CLL, AML and CML were not found. Anti-CLL-sera reacted in 10 out of 12 tests with CLL cells from 4 donors, and in 4 out of 20 tests with ALL cells from 7 donors and also with the cells of a CML patient. AML cells from two patients were not killed. Antisera against AML and CML showed extensive cross reactions with cells of myelocytic and lymphocytic leukaemias. Absorption tests demonstrated the presence of two antibody specificities in AML antisera, one of which being directed to a common antigen of AML and ALL cells and another against an antigen of myelocytic leukaemia cells.

Antibodies, Neoplasm↗
PubMed1978

Specificities of heterologous antisera against human leukaemia cells. 2. Reactions against fetal liver cells and absorption studies with fetal tissue.

Rabbit or goat antisera directed to ALL and AML cells were investigated in cytotoxicity tests with fetal liver cells as targets. After absorption with erythrocytes and spleen cells from allogenic donors the antisera killed fetal liver cells. There was no reaction with remission leukocytes or blood leukocytes from normal donors. Treatment with fetal tissue removed the activity of the AML and ALL antisera against ALL cells but not of the AML antisera against AML cells. This indicates the existence of at least two antigens on the surface of AML cells, one antigen is common with ALL cells and of fetal origin and another one seems to be characteristic of AML cells and not of fetal origin. Because treatment with fetal tissue removed all activity of the ALL antisera it can be assumed that leukaemia-associated antigens on ALL cells are of fetal origin.

Antibody Specificity↗
PubMed1975

[On the mode of action of heterologous antileukemic sera. Growth of syngeneically transplanted leukemia cells on serum treated neonatally thymectomized mice (author's transl)].

A heterologous antiserum against a Nitrosomethylurea--induced mouse leukemia prevented the outgrowth of syngeneically transplanted leukemia cells in neonatally thymectomized mice. After subcutaneous challenge with 50 000 leukemia-ascites cells thymectomized CBA mice at the age of 8 weeks were given 5 intraperitoneal injections each of 0,1 ml of the heterologous serum. While the antileukemic serum protected 9 out of 11 mice all of the 11 mice treated with normal rabbit serum developed a tumor. The absence of the thymus was confirmed by macroscopic control and by the absence of antibodies against the injected rabbit serum. With regard to previous findings showing a cooperation of heterologous antibodies with host cells as responsible for the antileukemic effect this result indicates that the effector cells are thymus-independent.

Animals↗
PubMedDate not supplied

Differences in the biological activity of TNF alpha and TNF beta correlate with their different abilities for binding to the target cells.

TNF alpha and TNF beta were compared regarding their binding to different types of target cells, cytotoxic/cytostatic activity against murine and human tumor cell lines as well as human capillary endothelial cells, their ability to induce differentiation in myeloid leukemia cell lines, and induction of hemorrhagic tumor necrosis and tumor regression as well as lethal toxicity in tumor-bearing mice. The results show considerable quantitative differences in the biological activity between TNF alpha and TNF beta depending on the type of target cell which has been used. TNF beta was 3 fold more cytotoxic than TNF alpha against murine L929 fibroblasts and 3-5 times more active concerning the induction of hemorrhagic tumor necrosis, complete tumor regression and more toxic in tumor-bearing mice. In contrast to this, TNF beta was markedly less cytotoxic against human capillary endothelial cells and the human mammary carcinoma cell line MCF7 and much less cytostatic against the human myeloid leukemia cell lines HL60 and U937. The lesser antiproliferative effect of TNF beta correlated with a lower ability for induction of differentiation in these cell lines. Competitive radioligand binding assays showed that TNF beta was about 4 fold more effective than TNF alpha in competing with 125I-labeled TNF alpha for the binding to murine L929 fibroblasts. But it was 15-20 times less effective in binding to the human MCF7 cells and the human myeloid leukemia cell lines HL60 and U937. This revealed that, at least for these targets, the differences in the biological activity between TNF alpha and TNF beta are due to different abilities for binding to the target cells. Possible mechanisms for these different binding abilities are discussed.

Animals↗