Yukinobu Ichikawa

Induction of autorosette-forming cells from human peripheral lymphocytes by several T-cell mitogens.

Abstract It is known that both spontaneous and Con A-induced autologous erythrocyte rosette-forming cells (ARFC) in human peripheral blood lymphocytes (PBL) are thymus-derived lymphocytes (T cells). A characteristic role for the ARFC in immune responses has been suggested. We studied mitogen-induced ARFC in human PBL, and the following results were obtained: (i) ARFC were inducible by T-cell mitogens such as phytohemagglutinin-P (PHA) and allogeneic non-T cells in addition to concanavalin A (Con A); (ii) the elimination studies of the T cells or their subsets by using monoclonal antibodies (OKT3, OKT4, or OKT8) confirmed that the ARFC are T cells; in addition, PHA recruited the ARFC from the OKT4-reactive T-cell subset, whereas Con A recruited the ARFC from the T-cell subsets reactive to either OKT4 or OKT8; (iii) Con A-induced ARFC are highly activated T cells, since lymphocyte proliferative responses were significantly higher in the ARFC-enriched fraction than those in the ARFC-depleted fraction; suppressor T-cell activity, however, was not significantly different between these two fractions; and (iv) several metabolic inhibitors including radiation, mitomycin C (MMC), and puromycin were employed before or during Con A stimulation, and only the puromycin could inhibit the induction of ARFC. Thymosin (fraction 5) had no effect on the induction of ARFC by Con A stimulation, although ARFC previously induced by Con A were sensitive to thymosin (fraction 5). These results suggest that the receptor to autologous erythrocytes may be enhanced or reexpressed by protein synthesis on those T cells which are highly sensitive to mitogen stimulation. The process is parallel to that of cell proliferation, although DNA synthesis is not essential for the induction of ARFC.

Reactivity of mitogen-lnduced autorosette-forming cells to interleukin 2 (T-cell growth factor)

The reactivity of mitogen-induced autologous rosette-forming cells (ARFC) to interleukin 2 (IL-2; T-cell growth factor) was studied in the present report. Both ARFC-enriched T cells and ARFC-depleted T cells, which were separated from concanavalin A (Con A)-activated T cells, were reactive to this factor. The IL-2 activity was absorbed by both ARFC-enriched and ARFC-depleted T cells, although ARFC-enriched T cells could absorb more IL-2 activity. Furthermore, ARFC were further inducible by IL-2 from non-ARFC. These results suggest the expression of the receptors for IL-2 on both ARFC and non-ARFC following mitogen stimulation. They further support the possibility that mitogen-induced ARFC, rather than being recruited only from such a minor T-cell subset as the spontaneous ARFC, are more likely the result of most T cells being responsive to mitogenic stimulation and expressing the receptors for autologous erythrocytes by the effects of IL-2 and mitogen.

Further characterization of mitogen-induced autorosette-forming cells: Correlation with T-cell subsets and with lymphocyte proliferative responses to mitogens

Spontaneous autologous rosette-forming cells (ARFC), which form rosettes with autologous erythrocytes, have been of interest as a subset of thymus-derived lymphocytes (T cells). An association of these cells with concanavalin A (Con A)-induced ARFC has been suggested. Furthermore, the Con A-induced ARFC have been shown to be a suppressor T-cell subset in the Con A-generated suppressor system. We have previously reported the induction of ARFC from T cells by several T-cell mitogens such as phytohemagglutinin-P (PHA) and allogeneic non-T cells other than Con A. In the present report, we further characterized the mitogen-induced ARFC and have extended the study to patients with systemic lupus erythematosus (SLE). We have found that ARFC are also inducible from peripheral blood T cells by pokeweed mitogen (PWM). Studies of T-cell surface markers on the ARFC using OKT monoclonal antibodies confirmed the induction of ARFC from both OKT4- and OKT8-reactive T cells by either Con A, PHA, or PWM stimulation. However, OKT4-reactive T cells were the major cellular source of the ARFC induced by all of the mitogens. In studies of SLE patients, proportions of both Con A- and PWM-induced ARFC were found to be significantly low in PBL of SLE patients treated with moderate or large doses of prednisone, with or without concomitant immunosuppressants, but not in SLE patients without such treatment. Proportional analysis of the T cells and their subsets suggested association of these alterations in the mitogen-induced ARFC with the OKT4-reactive T cells, since a significant decrease in the OKT4-reactive T-cell subset was demonstrated in the PBL of these patients. Proportions of PHA-induced ARFC, however, were not significantly different between SLE patients and healthy adults. Moreover, positive correlations of the mitogen-induced ARFC with lymphocyte proliferative responses to each mitogen were established in both SLE patients and healthy adults. These results further support our previous observation that suggest the receptors for autologous erythrocytes are enhanced or reexpressed on those T cells which are highly activated by mitogens.

Intravenous immune globulin therapy. Treatment of a patient with severe immunodeficiency, chronic malabsorption, and fulminant septicemia

Biweekly 200 mg/kg infusions of immune globulin (Gamimune) were given to a 46-year-old woman with severe common variable immunodeficiency, bronchiectasis, and chronic diarrhea with malabsorption. Failure to achieve therapeutically effective serum IgG concentrations in the face of fulminant sepsis was accompanied by a shortened serum IgG half-life of 10.6 days. Currently recommended doses of 200 mg/kg may prove inadequate in very ill patients with sepsis and malabsorption.

Evaluation of immune-enhancing effects of ibuprofen in an immunodeficiency model

Abstract: Three children and one adult with chronic mucocutaneous candidosis with documented deficient cellular immunity to Candida antigen were evaluated as a model to study the specific cellular immune‐enhancing potential of the prostaglandin synthetase inhibitor ibuprofen. Oral ibuprofen failed to have any consistent effect during sequential 4‐week on and off cycles on the following parameters: delayed hypersensitivity skin testing; lymphocyte transformation to Candida antigen; T‐cell subsets as determined by monoclonal antibody techniques; production of human immune interferon in response to staphylococcal enterotoxin A (SEA). Two patients showed a trend toward enhanced lymphocyte transformation to PHA while taking ibuprofen. In two patients who were studied 8–10 weeks after discontinuation of oral ketoconazole therapy, clinical recurrence of CMC was not prevented by oral ibuproten therapy.