Inhibit T-cell Function Research Articles

Immunological changes after hyposensitization in house-dust-sensitive asthmatic children: a review.

Patients with allergic diseases are characterized by the presence of elevated total serum IgE and specific IgE antibodies against a variety of environmental allergens. To explore the causes for augmented IgE antibody production and the working mechanisms of hyposensitization (HS), a series of studies has been conducted on house-dust-sensitive, newly diagnosed, and hyposensitized asthmatic children and normals. The specific IgE and IgG antibodies were measured by radioallergosorbent test; the lymphoproliferative capability was measured by 3H-thymidine incorporation; the allergen-specific suppressor activity was determined by the extent of house-dust-activated, interleukin-2 (IL-2)-expanded lymphocytes to suppress the allergen-induced proliferation of autologous mononuclear cells (MNC); and IL-2 was produced by stimulating MNC with allergen or phytohemagglutinin (PHA) and quantitated by its capability to support the proliferation of mouse IL-2-dependent cytotoxic T-cell line. The results showed: 1) HS was effective in 90% of patients in terms of decreased attacks and medication taken; 2) the patients were defective in suppressor T-cell function for IgE production; 3) HS was able to restore the regulatory T-cell function and increase the production of IgG-blocking antibody; and 4) IL-2 production may be used as an indicator for initiation and discontinuation of HS. Therefore, hyposensitization is an effective and specific treatment for allergic bronchial asthma and can partially correct an immunoregulatory aberration in atopic individuals.

Human suppressor T cells: Induction, differentiation, and regulatory functions

T-cell-mediated suppression of human immune responses involves a complex interaction between distinct lymphocyte subsets with suppressor-inducer and suppressor-effector functions. Recent studies with subset-specific monoclonal antibodies have defined a characteristic phenotype of suppressor-inducer cells (CD4 + Leu8 + 2H4 + 4B4 −) that can be distinguished from that of helper cells for antibody synthesis (CD4 + Leu8 − 2H4 − 4B4 +). Similarly, suppressor-effector cells (CD8 + CD11 + Tp44 − can typically be defined as a subset separable from cytotoxic T cells (CD8 + CD11 − Tp44 +). Both antigen-specific and nonspecific interactions are important in suppressor T-cell activation and function. Soluble signals required for differentiation of CD8 + suppressor cells include an indomethacin-sensitive monocyte product and interferon gamma. In contrast, proliferation of the CD8 + suppressor cell subset depends on stimulations first by a product of CD4 + Leu8 + cells, T suppressor cell growth factor, and second by interleukin 2. Although the molecular basis of antigen-specific interactions between CD4 + and CD8 + cells in suppressor cell generation has not been defined, it may involve both conventional, presumably MHC-restricted, interactions between antigen and antigen receptors, as well as anti-idiotypic interactions of suppressor-effectors with determinants on suppressor-inducer receptors. Progress in elucidating requirements for activation, growth, and differentiation of suppressor cells should facilitate long-term culture of such cells and lead to clearer understanding of mechanism of suppressor-cell mediated immunoregulation.

Suppressor cell function and anti-DNA antibody ldiotypes in the serum of SLE patients and their first-degree relatives

Sixteen-six ( 16 6 ) is a major cross-reactive idiotype of monoclonal anti-DNA antibodies, which was derived from the fusion of lymphocytes of a patient with systemic lupus erythematosus (SLE). Antibodies with the 16 6 idiotype ( 16 6 Id) are increased in the sera of patients with SLE and deposited in their gomeruli and skin. Since stimulated lymphocytes from healthy persons have the capacity to produce 16 6 Id, the mechanisms controlling its expression in health and their possible failure in SLE are of considerable interest. A defect in suppressor cell function was found in a high proportion of patients with SLE and in some of their first-degree relatives. Suppressor cell function in 15 SLE patients and in 53 relatives was compared with the level of 16 6 Id as well as with immunoglobulin levels and anti-DNA antibodies. Ten of 15 SLE patients and 26 of 53 first-degree relatives had increased serum 16 6 levels, which was found in only 1 of 35 healthy controls and household members. Of the 10 SLE patients with increased 16 6 , six had a suppressor cell defect ( P < 0.1). Among the 26 first-degree relatives with elevated 16 6 Id levels, 12 had associated suppressor defect and in only two cases was a suppressor cell defect unaccompanied by increased 16 6 ( P < 0.005). For the group of 18 patients and relatives howing concomitant suppressor cell defect and increased 16 6 , a correlation was found between the severity of the suppressor cell defect and the level of 16 6 Id in the serum. The increased 16 6 in the relatives was not associated with hypergammaglobulinemia or with measurable anti-DNA activity in the serum. We conclude that the suppressor cell defect in relatives of SLE patients is often associated with increased expression of antibodies with the 16 6 idiotype. However, additional mechanisms are involved in the regulation of 16 6 Id and the development of clinical SLE, since increased 16 6 was commonly found in the presence of a normal suppressor T-cell function.

Humoral and cellular immunoresponsiveness of stanchioned cattle infested with Psoroptes ovis

Bovine scabies in a clinical problem during the cool autumn and cold winter months. In south Texas it is necessary to stanchion animals in order to elicit patent infestation during summer months. Environmental factors and grooming have been purported to account for summer resistance to infestation. However, stanchioned animals exhibit varied levels of susceptibility to infestation, suggesting that the noted variability may be influenced by the host immune response. In this study, animals were infested with Psoroptes ovis while in stanchions. The development of anti- P. ovis antibody activity was measured by the enzyme-linked immunosorbent assay and cellular immune function was monitored with mitogens and P. ovis antigens. A correlation was noted between the development of anti- P. ovis antibody activity and the increase in mite numbers and dermatitis. Coincident with the developing infestation was a suppression of T-cell function that appeared to be stress-related as a result of stanchioning. A working hypothesis is presented that attempts to correlate the developing humoral response and the depressed T-cell response with both an increasing dermatitis and mite population.

Restoration of suppressor T-cell functions in children with AIDS following intravenous gamma globulin treatment.

Suppressor T-cell function was analyzed in seven children with acquired autoimmunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). Four of the patients had markedly increased serum IgG levels. All patients had elevated percentages and absolute numbers of peripheral blood T8 cells. In vitro concanavalin A generation of suppressor cells for T-cell mitogenic responses and suppression of pokeweed mitogen-driven immunoglobulin secretion were diminished in all patients. After intravenous treatment with gamma globulin, four patients regained in vitro suppression of pokeweed mitogen-driven gamma globulin secretion. Treatment with intravenous gamma globulin also modified in vitro suppressor T-cell functions in children with AIDS or ARC.

Helper Cells (Leu-3a+) Carry the Specificity of Nickel Sensitivity Reaction In Vitro in Humans

Suppressor and helper T-cell functions were studied in nickel (6.25 micrograms/ml)-induced 7-day blast transformation reaction in vitro. This was done in cocultures of 5 pairs of HLA-identical siblings; one of the siblings was nickel-sensitive and the other healthy. Suppressor and helper cells were isolated by panning, using monoclonal antibodies Leu-2a and Leu-3a. Helper cells from the nickel-sensitive siblings were obligatory for the blast transformation reaction to occur. Helper cells from the healthy sibling were not able to elicit blast transformation. Suppressor cells from nickel-sensitive and healthy subjects did not functionally differ from each other in their ability to support nickel-induced blast transformation, but the presence of suppressor cells was essential for the blast transformation reaction to occur. Proportional amounts of suppressor, helper, and Ia-antigen (Leu-10 positive)-bearing cells and monocytes (Leu-3M positive) were determined by avidin-biotin-peroxidase complex immunoperoxidase method before culturing the cells and on the seventh day of nickel-induced blast transformation culture. This was done in 6 pairs of unrelated nickel-sensitive and healthy subjects. Amounts of neither suppressor cells nor monocytes increased during the culture. Helper cells increased in both groups (p less than 0.0025). Ia-antigen bearing cells increased only in the cultures of nickel-sensitive subjects (p less than 0.0025). In conclusion, helper T cells seem to carry the specificity of nickel-induced blast transformation reaction, but suppressor T cells are also needed. Unresponsiveness to nickel is not due to specific suppressor T cells.

Use of anti-idiotypic antibodies to identify a receptor for the T-cell I-J determinant.

In order to identify the molecule(s) interacting with the I-J determinant on suppressor T cells, we have generated two anti-idiotypic sera: one to monoclonal anti-I-Jd antibody and one to monoclonal anti-I-Jk antibody. These antisera specifically block suppressor T-cell function in a genetically restricted manner and have no effect on helper T-cell activation. Both recognize a marker on primary monocytes and B cells but not on T cells. A myeloma cell line bearing this marker has been identified. Therefore, these antisera may recognize a molecule on cells interacting with suppressor T cells that is involved in mediating suppressor T-cell activity. The relationship between the T-cell I-J determinant and the molecule identified by the anti-idiotype may be similar to the relationship between the receptor on helper T cells and Ia molecules.

Circulating activated B cells in primary biliary cirrhosis.

Since patients with primary biliary cirrhosis (PBC) have evidence of abnormal function of the humoral immune system, we determined if B cells from patients with this disease show evidence of activation and can be stimulated by polyclonal activators. Using a reverse hemolytic plaque assay, it was found that patients with PBC had a significant increase in the number of circulating immunoglobulin-secreting cells, compared to normal controls and patients with chronic type B hepatitis virus (HBV) infection. However, the total number of activated cells was less than 1% of the total circulating B-cell population. Furthermore, we were unable to detect an increase in the expression of transferrin receptors, a membrane receptor associated with B-cell activation, in the majority of B cells in patients with PBC. In other studies, immunoglobulin production by lymphocytes from patients with PBC, when stimulated with the polyclonal activators pokeweed mitogen and Epstein-Barr virus (EBV), was reduced. This hyporesponsiveness was not due to a decrease in the number of B cells, as determined by staining with the monoclonal antibody anti-Leu 12. Furthermore, the decreased response to B cells to polyclonal activation in PBC patients was not due increased suppressor T-cell function, since EBV-simulated cultures of lymphocytes from patients with PBC demonstrated diminished suppression of immunoglobulin-secreting cells after 14 days of culture compared to controls. These findings suggest that the humoral abnormalities in PBC are due to the activation of a small subpopulation of B cells rather than to generalized B-cell hyperactivity.

Immunoregulatory Function of Lamina Propria T Cells in Crohn's Disease

The pathogenesis of Crohn's disease may involve altered function of immunoregulatory T cells in the intestine. To investigate this hypothesis, lamina propria lymphocytes were isolated from intestinal specimens resected from patients with active Crohn's disease and control subjects (colon carcinoma and diverticular disease) using an enzymatic technique. The T-cell phenotypes and function of these lymphocytes were compared with that of peripheral blood lymphocytes. The proportion of Leu-2-positive (suppressor/cytotoxic) cells was similar in peripheral blood and isolated lamina propria lymphocytes, both in Crohn's disease and control patients. Although the proportion of Leu-3-positive (helper/inducer) lymphocytes was lower in lamina propria lymphocytes than peripheral blood lymphocytes, there was no difference comparing Crohn's disease and control patients. Helper T-cell function, as determined by measuring the ability of T cells to increase immunoglobulin synthesis by pokeweed mitogen-stimulated normal peripheral blood B cells, was similar in peripheral blood lymphocytes and lamina propria lymphocytes, and comparing Crohn's disease with control patients. Suppressor T-cell function, as determined by measuring the ability of T cells to inhibit immunoglobulin production by cultures containing pokeweed mitogen-stimulated normal peripheral blood T and B cells, was also similar comparing peripheral blood lymphocytes and lamina propria lymphocytes, and comparing Crohn's disease with control patients: neither peripheral blood lymphocytes nor lamina propria lymphocytes significantly suppressed immunoglobulin synthesis. OKT8 (suppressor/cytotoxic)-enriched lamina propria lymphocytes mediated only marginal suppression, whereas concanavalin A-activated intestinal T cells did mediate significant suppression, in both Crohn's disease and control patients. Thus, patients with active Crohn's disease have no alteration of immunoregulatory T-cell function for polyclonal mitogen-induced immunoglobulin synthesis at the gut mucosal level, despite the presence of an inflammatory process in the intestine.

A case of T-cell chronic lymphocytic leukemia with an unusual phenotype and central nervous system involvement

A case of T-cell chronic lymphocytic leukemia is reported. The leukemic cells had the morphologic features of medium-sized, mature-looking lymphocytes, and had an affinity for the central nervous system. Cytochemically, they were positive for alpha-naphthyl acetate esterase and acid phosphatase. They formed E-rosettes (E+) and reacted with OKT11 but not with OKT3/Leu-4, OKT4/Leu-3, OKT8/Leu-2, or OKM1, and did not possess IgG-Fc receptors (Fc gamma R). Functionally, they did not respond to phytohemagglutinin or concanavalin A, were not natural killer cells or antibody-dependent as well as alloantigen-reactive killer cells. Furthermore, they did not possess a helper or suppressor T-cell function for immunoglobulin synthesis. Results of immunologic studies suggest that the leukemic cells were derived from a normal counterpart of a lymphocyte subset present as a minor component of the peripheral blood, namely an E+, OKT3-, OKM1-, Fc gamma R- subset, the function of which is not yet identified.

T-cell sensitization to autologous thyroid cells and normal non-specific suppressor T-cell function in Graves' disease.

We have employed a syngeneic system utilizing thyroid cell monolayers initiated following thyroid surgery co-cultured with autologous T cells to demonstrate T cell autosensitization in patients with Graves' disease. Antigen-induced blastogenesis was monitored using 24 h [3H]thymidine uptake. Control experiments with 5 d cultured normal human thyroid cells from tissue around benign adenomata showed no evidence of syngeneic T cell autosensitization. Human thyroid cells alone were unable to incorporate [3H]thymidine in the presence of bTSH. In three of four experiments with Graves' thyroid cells there was significant induction of autologous T cell blastogenesis with a mean stimulation index of 220%. In parallel experiments we explored the non-specific helper and suppressor T cell function of these and similar patients with Graves' disease. In normal controls (n = 6) increasing numbers of T cells added to a constant number of B cells (consisting of a T cell depleted peripheral mononuclear cell preparation) showed a marked helper effect measured as increasing IgG secretion. As the ratio of T:B cells increased above 4:1 there was a suppression of IgG secretion. One of two hyperthyroid Graves' patients was observed to have deficient T cell function as demonstrated by lack of IgG suppression. The remaining five patients (all but one of whom were euthyroid at the time of testing) had results similar to the controls indicating normal suppressor T cell function in this disease. Such data showed that patients with Graves' disease possessed circulating T cells which exhibited autosensitization to syngeneic thyroid cell surface antigens, a phenomenon not demonstrable in control individuals. Furthermore, this specific T cell autosensitization did not interfere with non-specific T cell function as judged by its influence on IgG secretion.

Effect of dexamethasone on de novo IgE synthesis by human blood lymphocytes

The effect of dexamethasone (DM) on de novo in vitro total IgE synthesis by blood mononuclear cells (MNC) was studied in atopic patients with eczema and in nonatopic control subjects. Unfractionated blood MNC were cultured at 1 × 10 6 cells per milliliter for 7 days in RPMI 1640 with 10% fetal calf serum with or without decreasing concentrations of DM (10 −7 to 10 −11). Net IgE synthesis was calculated by subtracting preformed (+ cycloheximide at day 0) from total IgE in 7-day supernatants. Supernatant IgE was measured by use of a modified PRIST assay. A significant increase in net IgE synthesis occurred in the presence of DM in 11 of 11 atopic patients with eczema (mean percent increase = 68%; p < 0.05) and five of five atopic patients without eczema (mean percent increase = 53%; p 0.05) but not in seven of seven nonatopic controls. This increase in de novo IgE synthesis could not be explained by a significant change in cell viability. In five of five experiments, a mean increase of 78% was still noted when DM was added to atopic blood MNCs depleted of T cells by sheep red blood cell rosetting. The addition of 10 −9M of DM to eczema B + T cell recombinations enriched for suppressor cells (depleted of Leu 3a + helper T cells) resulted in a loss of suppressor-T cell activity and maximal augmentation of IgE synthesis. Enhancement of IgE synthesis was also noted when DM was added to ecema B + T cell recombinations enriched for helper T cells (depleted of suppressor Leu 2a + T cells). Furthermore, B cell cultures that were severely depleted of both T cells and monocytes synthesized higher amounts of IgE in the presence of DM. We conclude that the augmentation of spontaneous in vitro IgE synthesis by DM involves not only an ablation of suppressor-T cell function but may also- be due to a direct action on B cells.

Immunoregulation in severe generalized periodontitis

Severe generalized periodontitis (SGP) is an inflammatory disease which leads to extensive alveolar bone loss in young adults. Peripheral blood lymphocytes from SGP patients have been previously reported to exhibit an in vitro hyperproliferative response when exposed to B cell mitogens derived from Staphylococcus aureus and Actinomyces viscosus. Therefore hyperresponsiveness to B-cell mitogens could be an important pathogenic factor in the susceptibility to and progression of SGP. We have tested whether the hyperproliferative response of lymphocytes from SGP patients was due to (i) a functional deficiency of suppressor T cells, or (ii) to numerical alterations of lymphocytes. Supernatant fluids from concanavalin A-stimulated T cells from 14 SGP patients and 14 normal subjects were compared for their ability to suppress the IgM synthesis of B-cell mitogen-stimulated mouse splenocytes. No significant differences were noted in suppressor T-cell function between control subjects and SGP patients. However, SGP patients had significantly higher lymphocyte counts than control subjects, and there was a positive correlation between high lymphocyte counts and high mitogen-stimulated proliferation. SGP patients also had higher lymphocyte:monocyte ratios than control subjects, suggesting that a defect in macrophage-mediated suppression might be involved in the hyperproliferation phenomenon. Our data do not support the hypothesis that a suppressor T-cell defect is the cause of mitogen-induced hyperproliferative responsiveness of peripheral blood lymphocytes from SGP patients. Rather, hyperproliferation may be due to an expansion of the lymphocyte pool which responds to mitogens, or/and a regulatory disturbance which arises because of altered lymphocyte:macrophage ratios.

Atypical Lymphoplasmacytic and Immunoblastic Proliferation in Lymph Nodes of Patients with Autoimmune Disease (Autoimmune-Disease-Associated Lymphadenopathy)

This study is based on an analysis of the morphologic, clinical, and laboratory findings in 26 patients whose pretherapy lymph node biopsies showed some, but not all, of the diagnostic features of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). Partial or complete effacement of nodal architecture by a diffuse lymphoplasmacytic and immunoblastic proliferation was a constant histologic finding. In contrast to the findings in AILD, lymphocytic depletion and pronounced arborizing vascular proliferation were often lacking. Clinically, many of the patients had fever, sweats, weight loss, skin rashes, generalized lymphadenopathy, hepatosplenomegaly, and, in some cases, pulmonary infiltrates. Of the 26 patients, 23 had clinical and/or laboratory evidence of autoimmune disease or immune complex disease. In 12 patients (Group I--idiopathic), various autoantibodies or immune complexes were demonstrable, but these patients did not manifest a well-defined immunologic disease or syndrome. In 11 patients (Group II--secondary), the lymphadenopathy occurred secondary to a well-defined, clinically recognized immunologic disease. Three patients (Group III) had neither a well-defined autoimmune disease nor demonstrable autoantibodies, but two of them had a history of exposure to antibiotics. We suggest that patients whose lymph nodes have the morphologic features described here frequently have an autoimmune disorder, and that the pathogenesis of this clinicopathologic picture is probably related to a deficiency in suppressor T-cell function which results in an unopposed proliferation of B cells with autoantibody formation and polyclonal gammopathy. Our observations should stimulate clinicians to consider the possibility of an autoimmune pathogenesis for a lymphadenopathy in which a florid lymphoplasmacytic and immunoblastic proliferation similar to that observed in AILD is demonstrated, even though the sections may not meet all the histologic criteria reported for the diagnosis of AILD. Clinical and laboratory investigations necessary to confirm the presence of autoimmunity are indicated in these cases. Moreover, since there is evidence of genetic factors predisposing to autoimmune disease (17, 43), it would be important to investigate close relatives of patients whose lymph nodes showed the histologic changes described in this paper in prospective studies which include suppressor T-cell function, autoantibodies, HLA type of blood lymphocytes and chromosomal analysis. The median survival of the 23 patients with stigmata of autoimmune disease or immune complex disease was 36 months.(ABSTRACT TRUNCATED AT 400 WORDS)

SUPPRESSIN, A PEPTIDE THAT INDUCES SUPPRESSOR T-CELLS: IDENTIFICATION, CHARACTERIZATION AND CLINICAL RESULTS

We report at this time the identification and characterization of suppressin, a novel peptide that induces suppressor T-cells. Following calf thymus homogenization the peptide is isolated by ultrafiltration, (NH4)2SO4 precipitation, and ion exchange and hydrophobic chromatography. The isolated peptide has a MW of approximately 2000, consists of 16-18 residues and is distinct from other previously described thymic hormones. Incubation of human thymocytes in suppressin causes expression of (OK)T8 antigen and histamine H2 receptors, lymphocyte phenotypes associated with suppressor T-cells. Functionally, the induced suppressor cells can suppress, in vitro, autologous lymphocyte response to PHA as well as both specific and non-specific antibody production. When administered in vivo, suppressin causes significant suppression of delayed type hypersensitivity (DTH) response to both modified self-antigen and allo-antigen, improves the clinical course of experimental allergic encephalitis and adjuvant induced arthritis, and produces decreased antibody production in NZB/W mice. When suppressin was administered in a clinical trial to patients with suppressor T-cell deficiency, 11/13 demonstrated significant increase in suppressor T-cell number and function. This newly identified hormone will be useful in the understanding of thymic function and T-cell differentiation and offers the potential for therapeutic benefit in the treatment of autoimmune/hyperimmune diseases characterized by suppressor T-cell deficiency.

Inhibition of antigen-induced T-cell clone proliferation by antigen-specific antibodies.

Attempts to inhibit the recognition of soluble antigens by T lymphocytes using antibodies specific for the antigen in question have been uniformally unsuccessful, in contrast to the observed specific inhibition of antibody generation by B cells. One exception is the unique situation whereby anti-hapten antisera inhibit the T-cell proliferative responses observed when hapten-specific T lymphocytes or clones are cultured with hapten-derivatized cells or proteins. The inability to inhibit T-cell functions by antigen-specific antibodies has been interpreted in several ways: (1) T cells possess a different repertoire from B cells; (2) the antibodies tested recognize epitopes present on the native antigen, whereas T cells recognize non-native (processed) structures; (3) the antigenic determinant(s) recognized by T cells on the surface of antigen presenting cells are either not accessible to antibodies, or are present in low amounts. The development of antigen-specific T-cell clones and monoclonal antibodies both specific for the same antigenic determinants now allows this question to be investigated definitively. Here, we report for the first time the specific inhibition of antigen-induced T-cell clone proliferation by a monoclonal antibody directed against the relevant soluble protein antigen.

Cyclosporine nephrotoxicity.

Editorials1 December 1983Cyclosporine NephrotoxicityWILLIAM M. BENNETT, M.D., JOSEPH P. PULLIAM, M.D.WILLIAM M. BENNETT, M.D.Search for more papers by this author, JOSEPH P. PULLIAM, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-99-6-851 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptCyclosporine is a potent new immunosuppressive agent that selectively inhibits T-cell function, allowing survival of allografts without myelosuppression. Its use should minimize the many adverse effects of long-term steroid therapy. Although the long-term effects of cyclosporine on renal allograft longevity are not well documented, enthusiastic reports in the medical literature and lay press have led to an unprecedented anticipation by prospective allograft recipients, particularly patients with chronic renal failure receiving long-term dialysis. However, these reports have not sufficiently emphasized the nephrotoxicity that frequently accompanies cyclosporine therapy.Cyclosporine is a lipophilic molecule with a molecular weight of 1202 daltons. When the...

Functional differences of anti-T-cell antibody in patients with systemic lupus erythematosus and ulcerative colitis.

The loss of suppressor T-cell function results in an abundant production of autoantibodies in systemic lupus erythematosus (SLE). As a cause of this suppressor T-cell defect, anti-T-cell antibody seems to be of prime importance. On the other hand, anti-T-cell antibodies can be detected in various other autoimmune diseases, but their functional characteristics have not been determined. In the present study, the functional characteristics of anti-T-cell antibody from a selected subgroup of patients with ulcerative colitis (UC) were compared with those from patients with SLE. Anti-T-cell antibody from the patients with SLE reacted with a T8 subset, resulting in a suppressor defect, whereas anti-T-cell antibody from the UC patients reacted primarily with a T4 subset. Functionally, SLE- T cells failed to proliferate in response to concanavalin A, whereas UC- T cells from UC patients failed to proliferate in response to phytohaemagglutinin. In the Ig synthesis system, both SLE- and UC- T cells increased Ig production of B cells. Since UC+ T cells did not contribute to the generation of Con-A-inducible suppressor activity, we believe that serum from the selected subgroup of patients with UC reacted with the inducer T-cell subset.

Immunoregulatory factors controlling terminal differentiation of malignant B-lymphocytes.

B-lymphocytes of patients with chronic lymphocytic leukemia differentiate in vitro towards plasma cells upon activation with Pokeweed mitogen (PWM) and Cowan. The level of response is much lower than that of normal cells and so is the helper T-cell function. However, concanavalin A-activated suppressor T-cell function of Ig synthesis is normal. Malignant B-cells have a normal capacity to stimulate Ig synthesis in the mixed lymphocyte cultures, but they respond poorly to an allogeneic stimulus. Thymosin (TFX) causes a marked enhancement of PWM-driven differentiation of malignant B-cells.

Immunomodulatory effect of procainamide in man. Inhibition of human suppressor T-cell activity in vitro.

Procainamide (PA) induces the production of a number of autoantibodies in a high proportion of treated individuals and in some a syndrome closely resembling systemic lupus erythematosus. The mechanism underlying this action of PA is unclear. To examine the possibility that PA might induce autoantibody formation by altering normal immunoregulatory mechanisms, the action of this drug on an in vitro model of antibody formation in man was examined. PA was found to augment the generation of immunoglobulin-secreting cells (ISC) from human peripheral blood mononuclear cells (PBM) in response to pokeweed mitogen but had no effect on pokeweed mitogen-induced tritiated thymidine incorporation. When purified populations of B and T cells were used, PA enhanced the generation of ISC in B-cell cultures supported by untreated T cells but not by T cells treated with mitomycin C. These results indicate that PA augmented B-cell responses by inhibiting suppressor T-cell activity and not by augmenting helper T-cell or B-cell function. N-Acetyl-procainamide had no effect on the generation of ISC in this system. The effect of PA on concanavalin A (Con A)-induced suppressor cell activity was also examined to determine whether PA altered the generation or expression of suppressor T-cell function. PBM were cultured with 30 microgram/ml of Con A for 48 h to generate suppressor cells. When these were co-cultured with fresh PBM, the number of ISC generated was decreased by 58.1 +/- 3.4% (mean +/- SEM, n = 6). Cells that had been similarly incubated without Con A were not inhibitory. The addition of PA to the Con A-stimulated cultures inhibited the generation of suppressor cells as indicated by the fact that the response of fresh cells co-cultured with the Con A-stimulated cells was diminished by only 27.2 +/- 4.3%. In this system too, N-acetyl-procaimamide had no effect. By contrast, adding PA only to the co-culture of Con A-stimulated cells with fresh PBM had a less marked effect on suppressor cell function. These results indicate that the major action of PA is to inhibit the generation of suppressor T-cell activity. Such an effect may explain the capacity of this agent to induce autoantibody formation in treated individuals.