Tehila Umiel

Immunological enhancement of tumor growth by syngeneic thymus-derived lymphocytes.

The role of lymphoid cells in the development of a transplanted syngeneic Lewis lung tumor (3LL) was investigated. It was found that thymocytes or thymus-derived lymphocytes could stimulate 3LL tumor growth in the recipients. This enhancing effect was manifested by a higher number of tumor takes, acceleration of tumor growth, and an increase in metastatic incidence. Lymphocytes from tumor-bearing mice were more effective than lymphocytes from nontumor-bearing controls in the manifestation of this phenomenon. Mice partially deprived of their T cell population by adult thymectomy manifested a striking reduction in tumor development.

Long-term culture of infant leukemia cells: dependence upon stromal cells from the bone marrow and bilineage differentiation

Infant leukemia cells with 46XY,t(11; 17)(q23; p13) karyotype and a hybrid pre B myeloid phenotype (HLA-DR, (Ia), B4 and My7-positive and CALLA and T11-negative) and immunoglobulin heavy chain gene rearrangement were maintained in long-term culture for over 10 months. The in-vitro survival and growth of the leukemia cells were strictly dependent upon the presence of their autologous marrow stromal cells. The latter could be replaced by the 14F1.1 clone of preadipocytes derived from mouse bone marrow. Neither heterologous human marrow or foreskin fibroblasts nor fibroblast or endothelial like cell lines from mouse stroma could mimic the effect of autologous stroma or 14F1.1 adipocytes. The leukemia cells maintained their original phenotype throughout the 10-month culture period with either their autologous stroma or the 14F1.1 adipocytes. They could be induced to differentiate in two distinct directions. Phorbol myristate acetate induced adherence of the leukemia cells and development of macrophage properties. In contrast, conditioned medium from a hybridoma producing B-cell growth factor caused aggregation of the leukemia cells and expression of CALLA antigen and surface IgM. This bipotency of the leukemia cells and their dependence upon marrow stroma are properties in common with stem cells.

Biologic and cytogenetic characteristics of leukemia in infants

Clinical features, leukemic cell characterization, chromosomal findings, and treatment outcome were analyzed in a retrospective study of 30 cases with acute leukemia of infancy, 24 infants with acute lymphoblastic leukemia (ALL), and six cases with acute nonlymphoblastic leukemia (ANLL). Extensive bulky disease with organomegaly, central nervous system (CNS), and skin involvement were prominent features at diagnosis with a higher frequency in ANLL as compared to ALL. Four of six ANLL patients were classified as monocytic or myelomonocytic. In the ALL group nine of 24 (36%) were non‐L1 morphology and six of 17 (33%) were common ALL antigen (CALLA) negative, the majority of them (five of six) were included in the non‐L1 group. Immunophenotyping revealed four cases with early B‐cell (three patients: Ia+B4+, and one patient: Ia+) and two cases with T‐cell. Mixed lineage leukemia was found in five infants. Heavy chain immunoglobulin gene rearrangement was present in six cases tested, two CALLA+, two with Ia+B4+, and two were undifferentiated mixed lineage leukemia. Chromosomal aberrations were detected in ten of 18 patients, mostly in ANLL and CALLA negative ALL. Translocations were detected in six patients, involving 4q21‐23 and 11q23 in three and two cases, respectively. The probability of five‐year DFS was 27% for the whole group. The worst prognosis was observed in infants younger than 6 months of age, in whom the leukemia cell characteristics was compatible with stem cell: ANLL, very early pre‐B, or undifferentiated mixed type. The chromosomal aberrations found in all cases included translocation with the seemingly nonrandom breakpoints at 4q21 and 11q23, and breakpoints that corresponded to known fragile sites. This finding may be suggestive of an underlying genetic predisposition associated with the poor prognosis of leukemia of infancy.

Characterization of embryonic liver suppressor cells by peanut agglutinin

Abstract Liver cells of 19-day-old mouse embryos were separated by peanut agglutinin (PNA) into two fractions. The fraction agglutinated with the PNA was found to be enriched for cells capable of suppressing the MLC reaction and the response to the mitogens Con A, PHA, and LPS. The fraction not agglutinated by PNA was significantly less suppressive. The response to DxS was not suppressed by any of these fractions. On the other hand, the response to LPS and DxS, but not to Con A or PHA, was expressed by the nonagglutinated fraction. It is thus inferred that the suppressor cells in the embryonic liver are separable from the potentially reactive cells.

Immunosuppression by embryonic liver cells.

Liver cells from embryonic and newborn mice were found to interfere with mixed lymphocyte culture (MLC) reactions measuring either cytotoxicity by 51Cr release from target cells or 3H-thymidine incorporation. In both experimental systems a suppression was noted when the stimulator cells were syngeneic or unrelated to the liver donor. In addition, 18-day embryonic and neonatal liver cells were found to interfere with production of antibodies to α-dinitrophenyl-poly-L-lysine (α-DNP-PLL) in vitro. These findings conform with the hypothesis that embryonic cells can actively suppress immune reactions and thereby prevent a possible response to self.

Leukemia of early infancy. Early B-cell lineage associated with t(4:11).

A case of infantile acute leukemia associated with translocation t(4:11)(q21:q23) is reported. This leukemia has a very poor prognosis, and this patient survived for only 9 months. The blast cell morphology was L1/L2 according to the FAB classification and showed a lymphoid appearance on transmission electron microscopy. The histochemical stains showed a pattern of periodic acid‐Schiff positivity and variable alpha‐naphtyl acetate staining. The cells were TdT‐positive and surface‐marker phenotyping was positive for Ia‐like and B4 antigens but negative for CALLA, T‐cell markers, myelocyte and monocyte markers. The leukemic cells represent a frozen state of a very early precursor, corresponding to the earliest recognizable stage of the B‐cell lineage. This observation may contribute to the controversion regarding the cell origin of this unique leukemia associated with t(4:11), lymphatic versus null cell, early myeloid, or mixed, and points to the possibility of a very early B‐cell lineage leukemia.

Inhibition or acceleration of tumor growth by subpopulations of thymus cells separable by a peanut lectin.

Abstract The effect of different lymphocytes subpopulations on tumor growth in mice was investigated using an in vivo adoptive neutralization test (Winn test). Thymocytes from non-tumor-bearing mice accelerated the growth of the tumors tested [Lewis lung carcinoma (3LL), thymoma 40-127-299 and fibrosarcoma P-14] when injected into syngeneic or F 1 mice in a mixture with the tumor cells. The thymocytes were separated with the aid of peanut agglutinin into immunologically mature and immature subpopulations (Reisner Y., Linker-Israeli and Sharon N., Cell. Immunol . 25 , 129, 1976). The immature thymocytes accelerated tumor growth to an extent similar to that of the unfractionated cells, whereas the mature subpopulation exhibited pronounced inhibitory activity. Our findings demonstrate that the murine thymus contains two thymocyte subpopulations with opposite activities on tumor growth and that the mature thymocytes have an inhibitory effect on tumor growth similar to that of spleen cells.

T cell progenitors in the mouse fetal liver

Fourteen-day mouse fetal liver was found to contain cells capable of giving rise to T as well as B cell functions. The experimental system consisted of congenic C3H/DiSn and (C3H/DiSn X C3H.SW)F1 lethally irradiated (900 R) mice reconstituted with C3H/DiSn fetal liver or bone marrow cells. Assays included thyroid allograft rejection as well as in vitro measurement of reactivity to phytohemagglutinin (PHA) and concanavalin A (Con A) and in a mixed lymphocyte culture (MLC) system in spleen, lymph node, and thymus cells. The fetal liver chimeras were found to become as capable as the bone marrow chimeras in responding in these various assays. The T cell responses lagged behind the responses to the B cell mitogens dextran sulfate (DXS) and lipopolysaccharide (LPS) (30 days after reconstitution, as compared with 14 days for DXS and 21 for LPS). The reacting cells were of the donor genotype, as revealed after treatment with C3H/DiSn (H-2k) anti-C3H.SW (H-2b) congenic sera. T cell responses were not manifest in thymectomized (TX) chimeras. Hence, the liver seems to contain cells capable of developing into T cell lineages in a thymus-dependent process.

Immune reactivity during ageing III. Removal of peanut-agglutinin binding cells from ageing mouse spleen cells leads to increased reactivity to mitogens

Spleen cells from ageing (24--30-month-old) mice, manifesting low response to concanavalin A (Con A) and phytohemagglutinin (PHA), were separated by peanut agglutinin (PNA) into agglutinable (PNA+) and unagglutinable (PNA-) fractions. The PNA+ cells were found to suppress the response of young (2--3-month-old) mouse spleen cells to the mitogens Con A and PHA. On the other hand, PNA- cells of the ageing mice expressed a response to these mitogens, at levels higher than those of the unseparated cells. Re-mixing of the PNA- and PNA+ cells of the ageing mouse spleens at various proportions indicated that the PNA- cells are indeed suppressible by the PNA+ cells. Anti Thy-1.2 treatment to the PNA+ fraction suggested that this suppression was not exerted by T cells. It thus appears that at least part of the reduced lymphoid cell function in ageing is related to an effect of suppressor cells, interfering with the expression of available reactive cells.

Ontogeny of suppressor cells. II. Suppression of graft- -versus-host and mixed leukocyte culture responses by embryonic cells.

SUMMARY Ontogenic development of suppressor cells was studied in mouse embryos. It was found that liver cells of embryos at various stages of gestation were capable of interfering with the mixed leukocyte culture (MLC) reaction. The MLC reaction was also inhibited by embryonic spleen and thymus cells. However, the latter were inhibitory only when originating in 16− and 17-day-old embryos. Embryonic liver cells were also found to interfere with the graft-versus-host (GVH) response induced in neonatal (BALB/c × C57BL)F, or (C3H × C57BL)F1 mice by adult parental-type C57BL spleen cells. The effect was expressed in the mortality rates but was less pronounced in the splenomegaly reaction measured in vivo or in an in vitro test system. Suppression of the GVH mortality response was manifested predominantly when the liver cells were syngeneic with the effector cells. In contrast, the MLC reaction was inhibited by liver cells syngeneic or allogeneic with the effector cells. The possible developmental patterns of these cells are discussed.