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D Naor

Publications and source records attributed to D Naor.

At least 55 records · Page 3Linked to original sources
PubMed1988

Self-reactive delayed type hypersensitivity induced in mice by syngeneic lymphoblasts. III. Immunological characterization of the small and large antigens of the blast cells.

X-irradiated or normal A mice injected with syngeneic concanavalin A-induced lymphoblasts (syn-Con A blasts) developed inflammatory responses in their footpads 24 to 72 h after the injection of syngeneic lipopolysaccharide-induced lymphoblasts (syn-LPS blasts) into these tissues. This response was designated syngeneic delayed type hypersensitivity (syn-DTH). The Con A blast extracts contain small (apparent MW of 6000-7000) and large (apparent MW of 160,000-175,000) syn-DTH-stimulating antigens, which are found in the total volume (low molecular weight fraction) and the void volume (high molecular weight fraction), respectively, of AcA 44 gel filtrations of this extract. The small and large antigens exhibit different immunological properties. The small antigen of A mouse lymphoblasts induced syn-DTH in X-irradiated (250 rad) mice but not in normal mice, and this immunological activity was elicited with syngeneic but not allogeneic lymphoblasts. The syn-DTH induced with the small antigen was inhibited by Lyt-1+2+, I-Jk+ suppressor T cells or a factor extracted from these cells. In contrast to the small antigen, the large antigen of A mouse lymphoblasts induced syn-DTH in both normal and X-irradiated mice, and this immunological activity was elicited by both syngeneic and allogeneic LPS lymphoblasts. The small and large antigens do not immunologically cross-react, but their immunogenicity is not affected by ultraviolet irradiation, indicating that the immune response against both of them is relatively class II-independent. The possibility that the cellular autoanti-lymphoblast response observed in our studies is in fact a mechanism that down-regulates the lymphoblast activity and thus suppresses the immune response is discussed.

Animals↗
PubMed1988

Experimental autoimmune anemia induced with haptenated syngeneic mouse red blood cells and low dose X-irradiation.

This paper describes an experimental model of autoimmune anemia induced with haptenated syngeneic mouse red blood cells (MRBC). A strain mice immunized with penicillinated MRBC (PEN-MRBC) generated IgM anti-MRBC autoantibody response and a very low level of the corresponding IgG response. The IgG anti-MRBC autoantibody response was augmented when mice were X-irradiated (250 rad) prior to immunization with PEN-MRBC, suggesting that a radiosensitive suppressive mechanism controls the IgG autoantibody response. Both the IgM and the IgG secondary anti-MRBC autoantibody responses emerged in mice that had been injected with PEN-MRBC 2 months before a second PEN-MRBC injection. Low dose X-irradiation (250 rad) of A mice without subsequent immunization induced an early IgG anti-MRBC autoantibody response and late IgM response, suggesting the existence of antierythrocyte autoreactivity in normal animals which is controlled by a radiosensitive suppressor mechanism. The anti-MRBC autoantibody response was not only induced by PEN-MRBC. Multiple injections of A mice with trinitrophenylated MRBC also induced autoantibodies against erythrocytes. The IgG anti-MRBC autoantibody response was associated with anemia, but it is not yet known if the two events are related or independent. Autoantibodies of X-irradiated mice immunized with PEN-MRBC were linearly titrated and partially absorbed with MRBC. Less efficient absorption was achieved with human and sheep red blood cells. Fifty percent of splenocytes from X-irradiated mice injected with PEN-MRBC expressed IL-2 receptor 3 days after the injection, whereas the number of cells expressing this receptor earlier or later was significantly less. The various applications of this autoimmune model are discussed.

Anemia, Hemolytic, Autoimmune↗
PubMed1987

On the immune reaction to autologous human lymphoblasts: evidence for the stimulation by activating factors rather than induction by autoantigens.

This report questions the nature of stimulation in the lymphoblast-induced autologous mixed leukocyte reaction (AMLR). Using immobilized phytohemagglutinin (PHA) and pokeweed mitogen (PWM), we show that the AMLR generated with PHA lymphoblasts (PHA X AMLR) was not significantly different from the AMLR generated with untreated stimulators. The PWM lymphoblasts of 15 out of 33 apparently normal blood donors generated an AMLR (PWM X AMLR) greater than their respective normal AMLR. The positive PWM X AMLR was not related to the expression of HLA-DR or surface IgM, since expression of both was increased by both PHA and PWM, yet only PWM blasts stimulated in the AMLR. Fixation of PWM-stimulated cells prior to the AMLR completely abolished stimulatory capacity, indicating further against new or increased antigen expression. Inactivation by uv irradiation of surface HLA-D on the stimulators had no effect upon the PWM X AMLR, while intact protein synthesis was required in order to stimulate. The ability of cells to stimulate was associated with the release of soluble helper factors capable of stimulating autologous cells independently. These factors were neither contaminating PWM nor secreted IL-1 or IL-2, although IL-1-like activity was released by all cells regardless of their ability to stimulate. The individual variation in the PWM X AMLR response and secretion of helper factors is discussed in relation to B-cell hyperproliferation and altered immunoglobulin production in autoimmune manifestations.

Adult↗
PubMed1986

Anti-interleukin 2 receptor antibody suppresses delayed-type hypersensitivity to foreign and syngeneic antigens.

Delayed-type hypersensitivity (DTH) requires stimulation of antigen-specific helper T cells (Th). Because de novo expression of the interleukin 2 receptor (IL 2R) is a necessary step in T cell activation, we tested the capacity of anti-mouse IL 2R monoclonal antibody (Mab) and anti-Th Mab (anti-L3T4) to block DTH. We examined the effect of these Mab on two distinct DTH systems, i.e., to foreign hapten (trinitrobenzenesulfonic acid) and to this hapten present on syngeneic blasts. Both anti-IL 2R and anti-L3T4 Mab suppress DTH. Therapy is as effective treating with one injection just before challenge with the hapten as giving six daily injections. These data indicate that DTH is dependent on a discrete subset of activated IL 2R-positive T cells, because anti-IL 2R therapy, which targets few cells, is as effective as anti-L3T4 Mab treatment, which targets the entire Th subset.

Animals↗
PubMed1985

Immunological function in osteoporosis.

An imbalance of osteoblastic bone formation and osteoclastic bone resorption is thought to be responsible for the osteoporotic condition. The pathological events leading to this disorder are, in most instances, uncertain. A defect in the ability of osteoporotic patients to respond to foreign histocompatibility antigens in a mixed leukocyte reaction is reported here. The results further show that this defect is due both to a poorly responding lymphocyte population as well as to a suppressor factor in osteoporotic sera. In addition, there is a significant increase in the relative and absolute numbers of T cells in the patients' peripheral blood, while serum IgG, IgA, and IgM remain within the normal range. These findings are discussed in the light of a common immunopathological pathway regulating osteoclastic activity and leading to the osteoporotic condition.

Adult↗
PubMed1985

The effect of cyclosporin on murine autoreactive delayed type hypersensitivity induced with syngeneic lymphoblasts.

The effect of cyclosporin on an immunological autoreactive experimental model was analyzed. The experimental system consisted of X-irradiated A mice injected with syngeneic concanavalin A-induced lymphoblasts and footpad-challenged 7 days later with syngeneic lipopolysaccharide-induced lymphoblasts. 24-72 h after challenge, the footpads of these mice responded with significant swelling, accumulation of 125I-UdR or massive cellular infiltration revealed by histological examination. Since the immunological activity was transferred by Lyt-1+ T cells from the sensitized donors to naive recipients, we designated it 'syngeneic delayed-type hypersensitivity' (syn-DTH). This DTH was induced and elicited mostly by antigens of the syngeneic lymphoblasts and not by contaminants attached to them, indicating the immunological autoreactive nature of this system. Multiple doses of 60 mg/kg cyclosporin, given daily in the time interval between immunization and challenge, or on the last four days before challenge, inhibited the syn-DTH. Multiple injections of cyclosporin Before or close to the induction phase of the syn-DTH was ineffective, whereas single or multiple injections of cyclosporin close to the effector phase (the challenge time) markedly reduced the syn-DTH. Even a single injection of cyclosporin 24 h after the challenge efficiently reduced the 48-h syn-DTH. Adoptive transfer experiments revealed that T cells from X-irradiated mice immunized with concanavalin A-induced lymphoblasts and injected with cyclosporin, failed to efficiently transfer the syn-DTH response to naive recipients. Similarly, the syn-DTH response of naive X-irradiated recipient mice injected with cyclosporin, failed to be reconstituted with primed T cells derived from X-irradiated mice immunized with concanavalin A-induced lymphoblasts. Since the nonspecific footpad swelling response of X-irradiated mice challenged with lymphoblasts alone is resistant to the standard protocol of the cyclosporin treatment, we suggest that cyclosporin inhibits the ability of T cells to produce or release lymphokines at the effector phase of DTH, while phagocytic cells involved in the DTH response are not affected by it. The practical and the theoretical implications of this research are discussed.

Animals↗
PubMed1985

Self reactive delayed type hypersensitivity (DTH) induced in mice by syngeneic lymphoblasts.

Normal and x-irradiated A mice injected with syngeneic concanavalin A (Con A)-induced lymphoblasts revealed after challenge with syngeneic lipopolysaccharide (LPS)-induced lymphoblasts delayed type hypersensitivity (DTH) measured both by footpad swelling and by 125IudR accumulation. Mice injected with allogeneic Con A-induced lymphoblasts and challenged with syngeneic LPS-induced lymphoblasts or vice versa, also generated an appreciable DTH response. In contrast, Con A-induced blast cells of human origin (xenogeneic cells) generated a considerably less effective DTH. The DTH response was more profound and consistent in x-irradiated mice, suggesting that irradiation sensitive cells control this response. The syngeneic DTH response was efficiently transferred to naive recipients with Thy-1+, nylon wool passed cells. The establishment of the DTH activity was associated with the lymphoblasts own (differentiation?) antigens and not with contaminants attached to the cells, such as Con A or fetal calf serum. The results were compared with similar results reported by other groups and the biological significance of all findings was evaluated.

Animals↗
PubMed1985

Effects of low doses of cyclophosphamide and low doses of irradiation on the regulation of induced erythrocyte autoantibodies in mice.

This paper describes some of the characteristics of a suppressor cell which is capable of regulating a rat RBC-induced autoantibody response against mouse RBCs. This cell, which appears to function as an inducer of suppression on transfer to naive recipients, is sensitive to low doses of cyclophosphamide, and its generation is affected by low doses of irradiation. However, the recipients of these cells are insensitive to cyclophosphamide treatment, suppression still being induced in such animals.

Animals↗
PubMed1984

Isolated soluble fractions from the murine B16 melanoma induce primary in vitro syngeneic antitumor responses.

This paper extends our previous studies, which documented our ability to isolate immunogenic entities from nonimmunogenic or weakly immunogenic tumors. B16 melanoma cells failed, in our in vitro experimental system, to induce anti-B16 cytotoxic responses in spleen cells derived from normal syngeneic C57BL/6 mice. The B16 melanoma cellular homogenate was fractionated on an Ultrogel AcA 34 column, and the various fractions were tested for their ability to induce anti-B16 cytotoxic responses under the same conditions as those used for intact B16, the nonimmungenic tumor cells. Certain fractions, some of them with relatively low protein concentrations, induced anti-B16 cytotoxic responses in spleen cells of normal C57BL/6 mice, whereas others, some of them with relatively high protein concentrations, failed to induce such responses. One fraction (Fr.), designated Fr. 5/6, was examined in detail. It was found that in normal syngeneic spleen cells this fraction induced effector cells that efficiently killed (at various E : T ratios) the relevant B16 target cells and RBL5 syngeneic tumor cells, but not the YAC allogeneic tumor cells or C57BL/6 lymphoblasts. Furthermore, an excess of unlabeled B16 cells most efficiently blocked the ability of these anti-B16 effector cells to kill radiolabeled B16 target cells. RBL5 tumor cells, YAC tumor cells, or C57BL/6 lymphoblasts failed to block these effector cells efficiently. A significant fraction of the effector cells induced with Fr. 5/6 was characterized as thymus-derived cells (Thy-1+, Ly-2+3+ cells). It was suggested that another fraction of the cellular population was natural killer cells, which cytolyzed the RBL5 target cells. Various theoretical and practical aspects of these findings are discussed.

Animals↗
PubMed1984

The isolation of immunogenic molecular entities from immunogenic and nonimmunogenic tumor homogenates by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE).

YAC, a Moloney-virus-induced tumor of A-strain mice, is a nonimmunogenic tumor. Mice injected with the inactivated neoplastic cells and challenged with viable tumor cells did not survive longer than mice that received the challenge dose alone. The homogenate of this nonimmunogenic tumor was subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). After electrophoresis, the gel slices containing isolated molecular entities were injected into various groups of mice. The mice were challenged with low doses of viable tumor cells (10-30 cells) and their survival time was recorded. Small but significant numbers of mice injected with apparent 80-90 K SDS-PAGE-isolated molecular entity rejected the tumor or survived longer than the control groups of mice. Spleen cells from mice injected with 80-90 K molecular entity inhibited the YAC tumor cotransferred with them to naive recipients (Winn assay). Spleen cells from mice injected with monoclonal antibody against nonspecific T-cell helper factor and immunized with 80-90 K SDS-PAGE-isolated molecular entity failed to inhibit the tumor growth in naive recipients, indicating that helper T cells are involved in induction of the antitumor resistance. Nylon-wool-passed splenocytes from mice injected with 80-90 K inhibited tumor growth in some of the recipient mice. Spleen cells from these mice treated with anti-Thy-1 and complement also inhibited the tumor growth in some of the recipients, suggesting that the effector cells were both T and non-T cells. C57BL/6 mice immunized with apparent 20 K SDS-PAGE-isolated molecular entity of RBL5 tumor also induced in vivo resistance to the syngeneic viable RBL5 cells, but not to the syngeneic B16 melanoma cells, indicating the specificity of the protective effect. The practical and theoretical implications of these findings are discussed.

Animals↗
PubMed1984

Auto-delayed-type hypersensitivity induced in immunodeficient mice with syngeneic modified self-antigens. II. Suppressor T cells control the autoimmune response.

The control of the autoimmune response to modified self-antigens was explored, using immunodeficient mice injected with syngeneic trinitrophenylated spleen cells (TNP-SC) as an experimental model system. X-irradiated (250 rad) A mice injected with TNP-SC and footpad-challenged 7 to 14 days later with syngeneic lymphoblasts generated a delayed-type hypersensitivity (DTH) response that was expressed by footpad swelling measured 24 h, 48 h and 72 h later. Histopathological examination showed massive inflammatory infiltration in the soft tissues of the limbs with extensive necrosis. This was not observed in X-irradiated mice that received the lymphoblast challenge only. The immunological activity was transferred from the X-irradiated TNP-SC-immunized mice to naive recipients by T cells (Lyt-1+) and not by serum, thus excluding the possibility that the inflammatory reaction is mediated by antibodies. We have previously presented evidence that the differentiation status of the lymphoblasts, and not contaminants from the incubation media, was the determinant factor eliciting the DTH response of immunodeficient mice injected with TNP-SC. Since only syngeneic lymphoblasts were able to elicit the DTH response of immunodeficient mice injected with syngeneic TNP-SC, we suggested that immunological activity was directed against self-antigens, thus expressing an autoimmune reactivity. The ability of immunodeficient mice to generate syngeneic DTH was not restricted to the TNP hapten or to inbred A-strain mice. X-irradiated BALB/c mice injected with syngeneic penicillinated spleen cells and challenged with syngeneic lymphoblasts generated a significant DTH response, in contrast to X-irradiated BALB/c mice exposed to the challenge dose only. X-irradiated A mice injected with syngeneic TNP-SC and simultaneously reconstituted with syngeneic splenocytes failed to generate a DTH response after the lymphoblast challenge, indicating that the syngeneic DTH response is controlled by normal suppressor cells. The suppressor cells were characterized as T cells carrying I-Jk, Lyt-1+, Lyt-2+ and Lyt-3+ antigenic markers. The suppressor cells abrogated the syngeneic DTH response of immunodeficient mice injected with TNP-SC, even when transferred a few days after the induction of immunological activity, but not when transferred 1 h before the lymphoblast challenge, indicating that even the established immunological activity can be restrained. Various immunological aspects of these observations and the significance of the findings in illuminating human autoimmune disorders are considered.

Animals↗
PubMed1984

Auto-delayed-type hypersensitivity induced in immunodeficient mice with modified self-antigens. III. Suppressive T-cell factor controls the autoreactivity against self-antigens.

X-irradiated (250 rad), cyclophosphamide-treated or ATx A mice injected with syngeneic trinitrophenylated spleen cells (TNP-SC) and footpad challenged with syngeneic lymphoblasts generated delayed-type hypersensitivity (DTH) responses 24, 48 and 72 h after challenge. The syngeneic-DTH (syn-DTH) response was mediated by Lyt-1+ cells and suppressed with Lyt-1+2+3+, I-Jk+ cells. The suppressor cells were obtained from spleens or thymuses of normal syngeneic mice. Suppressor factor (SF) was extracted or released from Lyt-1+2+3+, I-Jk+ cells obtained from normal A mice (but not from X-irradiated A mice). The factor blocked the DTH responses of X-irradiated mice injected with syngeneic TNP-SC and challenged with syngeneic lymphoblasts when injected into the mice both at the induction phase and the elicitation phase of the DTH. The factor failed to abrogate allogeneic and xenogeneic DTH. However, allogeneic factor (derived from C57BL/6 mice) abolished the syn-DTH response of mice injected with syngeneic TNP-SC and challenged with syngeneic lymphoblasts. The SF was produced by Lyt-1+2+3+, I-Jk+ T cells or by thymocytes. The combined extracted product of Lyt-1+ and Lyt-2+ cells did not abrogate the syn-DTH response. Normal spleen cells depleted of phagocytes by a magnetic procedure also produced the SF. These findings indicate, therefore, that suppressive factor (or factors; see Discussion in the accompanying paper, Ref. 17) controls the immunological autoreactivity against syngeneic TNP-SC.

Animals↗
PubMed1984

Auto-delayed-type hypersensitivity induced in immunodeficient mice with modified self-antigens. IV. Characterization of the suppressive T-cell factor that controls the autoreactivity against self-antigens.

Suppressor cells obtained from spleens of normal A mice, or factor extracted from these suppressor cells, abolished the syngeneic delayed-type hypersensitivity (syn-DTH) response of X-irradiated A mice injected with trinitrophenylated spleen cells and challenged with syngeneic lymphoblasts. Some of the physical, chemical and biological properties of the suppressive factor (SF) were characterized. The SF was relatively temperature-stable and its activity was destroyed by pronase (but not with RNase or DNase). The activity of the SF was absorbed on concanavalin A and anti-I-Jk Sepharose columns, suggesting that the factor is a glycoprotein-bearing I-Jk product. The approximate molecular weight of the factor is 50,000-60,000. The SF was absorbed on plastic adherent cells (but not on non-adherent cells). Adherent cells that absorbed the SF abrogated the ability of primed T cells to transfer the syn-DTH to naive X-irradiated recipients. In contrast, SF that was presented directly to the primed T cells failed to abolish their ability to transfer DTH. These findings suggest that the adherent cells serve as mediators, transferring the SF from factor-producing cells (Lyt-1+2+3+, I-Jk+ T cells) to target cells (Lyt-1+ primed T cells).

Animals↗
PubMed1984

Intralesional injection of interleukin-2-expanded autologous lymphocytes in melanoma and breast cancer patients: a pilot study.

The clinical effect of intralesional injection of interleukin-2 (IL-2)-cultured autologous lymphocytes was assessed in seven patients with cutaneous, recurrent tumor nodules (12 melanoma and 8 mammary cancer lesions). Each tumor nodule was injected 3-10 times, once weekly, with IL-2-cultured lymphoid cells (CLC), 40-400 million cells at each injection. Lymphoid cells obtained from buffy coats were separated on Ficoll-Paque, cryopreserved in liquid nitrogen, thawed, and cultured for 1-2 weeks in the presence of crude IL-2 (containing phytohemagglutinin) before injection. CLC were tested for sterility, percent E-rosette-forming cells, and cytotoxicity against K562, allogeneic melanoma, and breast cancer cell lines and autologous tumor cells. Enhanced cytotoxicity was expressed by IL-2 CLC, as compared with nonstimulated peripheral blood lymphocytes (PBL). Arrest of tumor growth (compared with untreated lesions) was observed in eight lesions and partial regression in three lesions. Moreover, complete regression was noted in one large melanoma lesion treated with low-dose irradiation prior to intralesional administration of CLC and in three small intracutaneous melanoma lesions treated with CLC only. Histopathological findings of responding lesions showed infiltration with lymphoid cells and macrophages, with the tumor cells sparsely dispersed. No untoward side effects of CLC injections were observed. The present study points to the feasibility of trials of adoptive immunotherapy in cancer patients as indicated by the following: (a) response of lymphoid cells to IL-2 adequate--although reduced--in patients with metastatic disease, including those after chemo- or radiotherapy; (b) possibility of cryopreservation of PBL and repeated culturing in IL-2 after thawing, with cytotoxic activity unimpaired; (c) demonstrably enhanced cytotoxicity in vitro of IL-2 CLC; (d) demonstrable--although limited--clinical response to in situ treatments with IL-2 CLC; (e) good tolerance of treatment with CLC.

Breast Neoplasms↗