Ruth Lomnitzer

Defective monocyte function in patients with systemic lupus erythematosus

Peripheral blood adherent cells from patients with systemic lupus erythematosus (SLE) were shown to have markedly reduced phagocytic activity as compared to normal adherent cells or those from non-SLE patients receiving corticosteroid therapy. Both resting and phagocytosing monocytes showed decreased hexose monophosphate shunt and glycolytic activity. Mononuclear cells from SLE patients showed grossly impaired proliferative activity after NaIO4 activation. Furthermore, addition of SLE adherent cells to normal adherent cell-depleted lymphocytes decreased [3H]thymidine incorporation of the latter cells following NaIO4 treatment. Addition of normal adherent cells to SLE lymphocytes corrected the previous defect, indicating that an adherent abnormality is responsible for the defect in SLE mononuclear cell proliferation to NaIO4 activation.

A double-blind study comparing monomethoxy polyethylene glycol-modified honeybee venom and unmodified honeybee venom for immunotherapy. I. Clinical results.

Thirty-five patients were allocated at random to immunotherapy (IT) in a double-blind way with either monomethoxy polyethylene glycol (mPEG)-modified honeybee venom (HBV) or HBV. The two groups were well matched regarding age, sex, skin sensitivity, HBV-specific serum IgE and IgG antibodies, and history of reactions after a field sting; mPEG-HBV-treated patients received doses that increased more steeply than doses of the HBV-treated patients. The maintenance dose of the former group (200 micrograms) was greater than that of the latter group (100 micrograms). During IT, both groups had the same frequency of local swellings after injections. Four patients receiving mPEG-HBV developed one mild systemic reaction (SR) during dose increase, whereas 10 patients receiving HBV demonstrated one or more of these reactions, compelling two patients to stop therapy. Following challenge with a honeybee sting after about 14 weeks of IT, six patients with SR were observed, four in the mPEG-HBV-treated group and two in the HBV-treated group. In the HBV-treated group, three patients were not challenged, one because of an insufficient IgG increase and two other patients because they dropped out of IT before reaching maintenance dose because of repeated SRs. Since the mPEG-HBV is extremely well tolerated during IT and the success rate is not significantly lower than with unmodified HBV, we suggest it as an attractive alternative to HBV for the treatment of HBV hypersensitivity. Increase of the maintenance dose may result in an even better clinical efficacy.

Lack of suppressor cell activity in systemic lupus erythematosus

Suppressor cell activity was assessed in 15 patients with active systemic lupus erythematosus (SLE) using two techniques: (a) induction of suppressor cells using concanavalin A and (b) quantitation of T cells which formed rosettes with IgG-coated ox red cells. Con A-induced suppressor cell function was found to be depressed in two-thirds of the patients tested and in some cases it was completely absent. We were unable to identify that group of patients with normal suppressor function as compared to those who had depressed function. The number of circulating Tγ cells, however, was significantly reduced in all SLE patients as compared to both normal controls and 5 non-SLE patients receiving similar doses of corticosteroids. It is suggested that the presence of B-cell hyperfunction in SLE could be secondary to depressed suppressor cell activity.

Production of leukocyte inhibitory factor (LIF) in Hodgkin's disease: Spontaneous production of an inhibitor of normal lymphocyte transformation

Skin reactivity and phytohemagglutinin (PHA)-induced lymphokine production (leukocyte inhibitory factor, LIF) were assessed in 30 patients with untreated Hodgkins disease and found to be markedly depressed. These two parameters of cell-mediated immunity showed a 78.5% positive correlation. In addition increased LIF-like activity was found in supernatants of unstimulated mononuclear cells in 40% of Hodgkins disease patients but rarely in other malignancies. A close association was found between spontaneous release of a LIF-like substance and depressed PHA-induced LIF production. Furthermore lymphocytes from 10 of 12 Hodgkins disease patients studied demonstrated spontaneous uptake of [3H]thymidine. The supernatants produced by some unstimulated Hodgkins disease mononuclear cells were able to suppress the lympho-proliferative response of normal cells to PHA. It is postulated that cellular unresponsiveness observed in Hodgkins disease is partly explained by the production of an inhibitory factor (or factors), possibly by suppressor T cells.

Low specific IgE, IgG and lymphocyte reactivity in a group of patients developing anaphylaxis following a honey-bee sting

Ten patients who developed severe generalized reactions following a honey‐bee sting were investigated for the presence of specific IgE and IgG antibodies, and for lymphocyte reactivity following in‐vitro honey‐bee venom (HBV) stimulation. Five of the patients (high responders) showed high HBV‐specific IgE and IgG levels, whereas the other five patients (low responders) showed low HBV‐specific IgE and IgG levels. Mononuclear cells from the high responder group incorporated significant amounts of 3H‐thymidine when activated with pure bee venom, whereas insignificant lymphocyte proliferation was observed in the low‐responder group. It is concluded that, amongst HBV‐sensitive patients, a group of low responders exists in whom the mechanism of anaphylaxis cannot be explained.

The effect of hydrocortisone (HC) on sodium periodate and phytohemagglutinin-induced [3H]thymidine incorporation and lymphokine production by human lymphocytes

Hydrocortisone (HC) in pharmacologically attainable concentrations was shown to inhibit mitogen-induced lymphocyte blastogenesis. When adherent and nonadherent cells were treated separately with hydrocortisone and then reconstituted, treatment of either cell population resulted in a diminished mitogen-activated response. HC-treated adherent cells produced less interleukin 1 (IL-1) than control cells, and interleukin 2 (IL-2) production by HC-treated lymphocytes was also reduced. This latter finding could not be reversed by adding IL-1-containing adherent cell supernatants to the culture systems. Leukocyte inhibiting factor (LIF) production by sodium periodate-activated mononuclear cells was also reduced after HC treatment, but could be corrected by adding IL-1-containing adherent cell supernatants to the cultures. PHA-induced LIF production, which is less dependent upon adherent cells and their products, was not affected by HC treatment. It is concluded that HC exerts its suppressive effect by independently inhibiting IL-1 production by adherent cells and IL-2 production by lymphocytes.

Suppression of leukocyte inhibitory factor (LIF) production and [3H]thymidine incorporation by concanavalin A-activated mononuclear cells

Abstract The capacity of human mononuclear (MN) cells pretreated with concanavalin A (Con A) to suppress the activity of fresh phytohemagglutinin (PHA)-pulsed mononuclear cells was assessed. Con A-pretreated MN cells suppressed leukocyte inhibitory factor (LIF) activity in supernatants of PHA-pulsed cell cultures and [3H]thymidine incorporation by these cells. Suppression was obtained in both allogeneic and autologous systems with mitomycin-treated, irradiated, or untreated Con A-induced cells. Lymphocytes from two patients that, following treatment with Con A, did not suppress mitogen-induced proliferative response of normal cells also did not suppress LIF production.

Lack of responsiveness of beekeeper mononuclear cells to in vitro stimulation with pure bee venom

Lymphocyte proliferation activity after in vitro bee venom (BV) stimulation was examined in a group of patients allergic to bee stings and in a group of beekeepers. Although the allergic patients responded strongly to increasing doses of BV, the beekeepers demonstrated no proliferative activity and an inability to produce interleukin-2 after BV stimulation. Removal of adherent cells or various populations of suppressor cells, including T gamma cells and OKT8 positive cells, did not influence the cellular unresponsiveness of cells of beekeepers after BV stimulation. Furthermore, cells of beekeepers, when they were trypsinized or when they were preincubated for 72 hours, did not proliferate after BV challenge. It is concluded that the lack of proliferation of lymphocytes of beekeepers and the inability to produce interleukin-2 is not due to a suppressor mechanism or to the presence of anti-idiotype antibodies coating the surface of lymphocytes of beekeepers. The mechanism behind the failure of cells of beekeepers to proliferate remains unclear.

Modulation of the sodium periodate (NaIO4) response in systemic lupus erythematosus (SLE): Effect of Interleukin-1 (IL-1), Interleukin-2 (IL-2), phorbol myristate acetate (PMA), and indomethacin

The proliferative activity of peripheral blood mononuclear cells (PBMN) from patients with systemic lupus erythematosus (SLE) activated by sodium periodate (NaIO4) is greatly diminished. The effect of the cytokines Interleukin-1 (IL-1) and Interleukin-2 (IL-2) on the NaIO4 reaction was investigated. Addition of IL-1 resulted in partial restoration of the reaction of SLE PBMN to NaIO4, and a similar effect was demonstrated in the presence of phorbol myristate acetate (PMA). Addition of IL-2 to NaIO4 activated SLE PBMN, however, caused a marked improvement in their proliferative activity. The presence of indomethacin resulted in only a slight increase in [3H]thymidine incorporation by the NaIO4-treated SLE cells. The results suggest that the defect in the response of SLE PBMN cells to NaIO4 is due to inadequate availability of IL-1 and IL-2. Excessive production of prostaglandin in SLE might also contribute to the defective response to NaIO4 but does not appear to play a major role.

Mononuclear cell function in Mycobacterium tuberculosis infected guinea pigs

In this study mononuclear cell function was studied in the lymph glands, spleen, and peripheral blood of Mycobacterium tuberculosis infected guinea pigs. Adherent cells from draining lymph nodes and spleens of infected animals spontaneously produced a factor which inhibited normal lymphocyte proliferative responses. As it has previously been shown that this factor activates a population of suppressor T cells, resident lymphocytes in the lymph nodes and spleen were examined and were shown to inhibit normal lymphocyte functions. It is suggested that adherent cells ingesting M. tuberculosis spontaneously release a suppressor cell activating factor (SCAF) which locally activates lymphocytes to become suppressor cells. Even at a time of overwhelming infection, peripheral blood adherent cells could not be shown to release SCAF and peripheral blood suppressor cells could not be identified. Although peripheral blood lymphocyte proliferative responses to PHA were normal in infected animals, their ability to produce the lymphokine macrophage inhibition factor was considerably reduced after the second week of infection. This dissociation between lymphocyte proliferation and lymphokine production is similar to that previously described in humans overwhelming tuberculosis.