T Nagaoki

Maturation of B-cell differentiation ability and T-cell regulatory function in infancy and childhood.

The immunologic ontogeny of the child is a biological growth process. The development of antibody response requires the generation of antigen-responsive B lymphocytes and, for response to most antigens, the functional maturation of T lymphocytes and macrophages. There are many imbalances of T cells and their interactions with other cells in the immune system in early human ontogeny. Pokeweed mitogen (PWM) has been the most studied human B cell mitogen and its use has yielded valuable information in human B cell ontogeny. However, PWM is a T cell-dependent B cell mitogen and. cord blood T lymphocytes, unlike adult T cells, are triggered by PWM to become activated suppressor T cells that prevent nonspecifically the differentiation of B cells into immunoglobulin (Ig)-producing cells (Oldstone et al. 1977, Hayward & Lawton 1977). Such neonatal suppressor activity is seen in other situations where cellular interactions take place, as demonstrated by the inhibitory effect of T cells from newborn babies, exerted on the proliferative response of normal lymphocytes and adult B cell differentiation (Olding & Oldstone 1976, Hayward & Lydyard 1978).

Some evidence for the in vivo functional activation of suppressor T cells in asymptomatic patients with hemophilia A receiving factor VIII concentrates

Of 14 asymptomatic hemophilia A patients receiving factor VIII concentrates, 11 severe hemophilia patients had an inverted T-helper/suppressor ratio but 3 moderate patients had a normal ratio. Most hemophilia patients showed poor lymphocyte proliferative responses to mitogens and diminished in vitro immunoglobulin-producing ability of lymphocytes. One important finding was that most patients were found to have increased numbers of Ia-like antigen-positive suppressor T cells, suggesting that circulation activated suppressor T cells. In addition, OKT8+ suppressor T cells from severe hemophilia patients showed strong suppressor activity on B-cell differentiation in a Nocardia delipidated cell mitogen-driven system, whereas those from normal age-matched controls showed no suppressor function. These results suggested that suppressor T cells in hemophilia patients treated with factors might be already activated in vivo by undetermined mechanisms, implying the presence of a peculiar immunoregulatory status in this disease.

Transient increase of IgG Fc receptor-bearing T lymphocytes following positive PPD skin testing.

In tuberculin‐sensitive individuals, IgG Fc receptor (FcR)‐hearing lymphocytes in the peripheral blood increased transiently following PPD‐tuberculin skin test. This rise in circulating FcR‐bearing cells appeared to peak about 36–48 h after the intradermal inoculation of PPD and seemed to occur largely in the T cell population. Skin test‐negative individuals showed no significant changes in their circulating FcR‐bearing cells following PPD inoculation. Peripheral blood lymphocytes from PPD‐sensitive individuals were fractionated into non‐T cell and T cell‐enriched populations by E rosette sedimentation technique. FcR‐bearing cells in the T cell‐enriched population were eliminated by EA rosette sedimentation: i. e. FcR‐negative T cells. Then, equal numbers (1 × 105 cells each) of non‐T cells and unfractionated or FcR‐negative T cells were recombined in culture. Prior to PPD inoculation, there was no significant difference between these two cell mixtures in the in vitro cellular response to PPD or mitogens. When these cell populations were obtained. 16–48 h after PPD inoculation, however, the combination of non‐T tells and FcR‐negative T cells responded to PPD much better than the combination of non‐T cells and unfractionated T cells, whereas the mitogen‐induced cellular proliferation of these two cell mixtures did not differ from each other.

Induction of Suppressor Activity on B‐Cell Differentiation in Human T‐Cell Subset without Fc(IgG) Receptors by Levamisole Administration

A single oral dose of 150 mg levamisole was administered to five healthy adults. Circulating Fc(IgG) receptor‐bearing T cells (Tγ cells) increased for 5 days after levamisole intake, but total E rosette‐forming cells showed no significant alterations. The generation of immunoglobulin‐producing cells in the peripheral blood lymphocytes (PBL), which was induced in the in vitro pokeweed mitogen (PWM)‐stimulated cultures, was significantly suppressed for 5 days after levamisole administration. Suppressor T‐cell activity on B‐cell differentiation, which was induced by levamisole intake, was evaluated by co‐culturing with allogeneic untreated adult PBL in the PWM system in six other volunteers. A seemingly dose‐dependent suppression on B‐cell differentiation was exerted by T cells isolated on day 3 of levamisole treatment, but not by T cells which were isolated before or on day 14 of the experiment. When T cells were fractionated into two subsets with regard to the presence or absence of Fc(IgG) receptors, suppressor T‐cell activity appeared to be generated by levamisole largely in T cells lacking Fc(IgG) receptors, but not in Tγ cells.

Induction of E‐Rosette‐Promoting Factor in Human Plasma by Levamisole: An Assessment in a Patient with Partial DiGeorge Syndrome

A male infant with partial DiGeorge syndrome responded to weekly administration of levamisole (2.5 mg/kg of body weight) with an increase of circulating E‐rosette‐forming T cells. Thymic hormone activity in plasma appeared to be elevated to a near‐normal level of 11.6 ng thymopoietin equivalent/ml after levamisole administration. The in vitro incubation studies indicated that levamisole by itself had no E‐rosette‐promoting ability, but a dialysable and relatively heat‐stable plasma factor induced by levamisole both in the patient and in heallhy individuals had E‐rosette‐promoting activity for the patients lymphocytes. Such a plasma factor, however, could not be induced in all four thymectomized myasthenic subjects examined, suggesting a thymus‐dependent nature of the plasma factor. These results suggest that levamisole might mediate an increased secretion of humoral factor(s) with E‐rosette‐promoting activity, even from such a rudimentary thymus as in the partial DiGeorge syndrome.

Blocking effect of human T lymphocyte extracts on E-rosette inhibition by sheep red cell fragments

Abstract Rosette formation, particularly active rosette formation, of human peripheral blood lymphocytes with sheep red blood cells (SRBC) was inhibited by the pretreatment of lymphocytes with sonicated SRBC fragments. However, when SRBC fragments were pretreated with a freeze-thawed extract of unfractionated peripheral blood lymphocytes, the inhibitory activity of SRBC fragments on E-rosette formation was abolished. Based on the different rosetting abilities, peripheral lymphocytes were separated into the populations enriched with active rosette-forming cells, late rosette-forming cells, and non-rosette-forming cells by rosette formation with SRBC followed by gradient centrifugation. A soluble extract of each population was prepared by extensive freeze-thawing in phosphate-buffered saline and the activity of each extract was assayed with the blocking effect on E rosette inhibition by SRBC fragments. This blocking activity was identified in the extract from the population enriched with active rosette-forming cells as well as in the extract from unfractionated peripheral blood lymphocytes, but not in the extracts from the other cell populations. These results suggest that the active rosette-forming cells of human lymphocytes have a unique receptor activity for SRBC fragments, presumably for intact SRBC, and the active materials in this cell population, although dissociated from the cells. retain their ability to bind competitively to SRBC fragments.