Suppressor Cell Deficiency Research Articles

A subset of patients with recurrent spontaneous abortion is deficient in transforming growth factor beta-2-producing "suppressor cells" in uterine tissue near the placental attachment site.

To determine if patients with unexplained recurrent miscarriage have a deficiency of decidual immunosuppressor cells that produce transforming growth factor beta type 2, as has been found in mice with abortion due to rejection and/or trophoblast failure. Decidual biopsy specimens were taken as near to the placental attachment site as possible under ultrasound guidance from first trimester legal termination (control) patients with recurrent miscarriage and non-viable pregnancy, and from patients with sporadic missed abortion. The tissue was tested for TGF beta-2+ suppressor cells by in situ hybridization, immunohistochemistry, and analysis of supernatants. TGF beta-2-related suppressor molecules similar but not identical to those identified in pregnant mice were released by decidual lymphoid cells. Fifty percent of 14 recurrent miscarriage patients showed a lack of suppressor cells and 59% were subnormal in comparison to 20 controls and 5 sporadic miscarriage patients, where 80-85% of the patients had detectable suppressor cells. Suppressor cell deficiency is compatible with a role for rejection and/or trophoblast failure in some patients with recurrent miscarriage. Presence of suppressor cells in most patients with missed abortion (4/5) is compatible with an alternative cause of fetal death, similar to findings reported in genetic fetal death mice.

Multifocal idiopathic pyogranulomatous bone disease in a dog

ABSTRACTDisseminated, multifocal idiopathic pyogranulomatous bone disease in a five‐year‐old neutered female crossbred cattle dog is described. The dog was presented for neck pain and reluctance to exercise. Radiography demonstrated polyostotic bone disease, the predominant change consisting of a mottled pattern of osteosclerosis interspersed with punctate foci of osteolysis. Numerous bones of the axial and appendicular skeleton were affected including cervical vertebrae, ribs, scapulae and humeri. Biopsy revealed sterile pyogranulomatous osteomyelitis. This was confirmed at necropsy which showed that lesions were restricted to bone. Idiopathic granulomatous or pyogranulomatous conditions have been described in the dog in relation to skin but not bone. In people, idiopathic granulomatous bone disease is one of a group of conditions collectively called histiocytosis X, which are thought to be immunoregulatory disorders related to Tlymphocyte suppressor cell deficiency and Langerhans' cell proliferation.

Recurrent Hereditary Polyserositis or Familial Mediterranean Fever: An Overview

The etiology and pathogenesis of recurrent hereditary polyserositis (RHP) remain undetermined. There is a good evidence for a genetic basis (transmission being by a recessive Mendelian mode of inheritance), but not all cases have a family history and an infective (or other environmental) components has not been excluded. The marked variation in presentation and complications (in particular the prevalence of amyloid deposition) in different series suggests that this might not be a homogeneous entity. Vascular involvement is a basic prerequisite for the periodic attacks, and evidence for transient immunological abnormalities is incontrovertible. There are no reliable diagnostic techniques. Colchicine is of value in treatment, but its mode of action is unclear. More macro- and microepidemiological studies are required and will be of paramount importance. Clinical observations and molecular genetic studies should address the possibility that two or more immunological or metabolic defects might be interwoven; why for example do only some affected groups develop AA amyloidosis? Simple, non-invasive diagnostic tests are required for the uncomplicated disease and also for the presence of amyloid deposition. Preventive strategies might eventually involve genetic engineering techniques, but in the immediate future, education of doctors and other health care workers - to raise the "index of awareness" of RHP, in order that colchicine treatment can be commenced early in the disease - forms an important strategy. Colchicine therapy is not without complications and an alternative chemotherapeutic agent should be sought.

Histopathologic alterations in the decidua in human spontaneous abortion: loss of cells with large cytoplasmic granules.

The histopathology of decidua obtained from the placental bed was evaluated by phloxine-tartrazine staining, which allows clear definition of cells with cytoplasmic granules. Mononuclear cells with large granules were seen in biopsy specimens taken from women at 8-31 weeks of normal pregnancy. In contrast, cells with large granules were missing in sections taken from the decidua of five women who were aborting or were destined to abort. Since the presence of suppressor cell activity in murine decidua correlates with the success of pregnancy and since this suppression is associated with small lymphocytes with cytoplasmic granules, the observations made using human placental bed biopsy material suggest that a possible suppressor cell deficiency might occur in the early stages of spontaneous abortion in human females.

Active suppression of host-vs-graft reaction in pregnant mice. VII. Spontaneous abortion of allogeneic CBA/J x DBA/2 fetuses in the uterus of CBA/J mice correlates with deficient non-T suppressor cell activity.

The mammalian fetus has been viewed as an unusually successful type of "allograft" and "unexplained" spontaneous abortion as a possible example of maternal rejection. Previous studies have shown the presence of small lymphocytic suppressor cells in the murine decidua which block the generation and reactivation of anti-paternal cytotoxic T lymphocytes (CTL) and lymphokine-activated killer cells (LAK) by elaborating a factor that inhibits the response to interleukin 2 (IL 2). A deficiency of these suppressor cells was associated with implants of xenogeneic Mus caroli embryos in the Mus musculus uterus which are infiltrated by maternal lymphoid cells and aborted. We have also shown a deficiency of such suppressor cells in the lymph nodes draining the uterus of CBA/J females in the process of aborting their semi-allogeneic CBA X DBA/2 F1 progeny. CBA/J females possess significantly lower levels of decidua-associated non-T suppressor cells on day 8.5 to 10.5 of allopregnancy than do mothers that will produce large litters of live babies. The F1 embryos are infiltrated by maternal lymphocytes prior to abortion, and the infiltration and abortion rate appears to be augmented by pre-immunization with paternal DBA/2 spleen cells. Susceptibility to spontaneous abortion is dependent upon maternal age and strain of male mate, and the high abortion rate of CBA/J mated to DBA/2 males can be reduced by immunization with BALB/c spleen cells. The CBA/J x DBA/2J mating combination provides a model of spontaneous abortion in which immunologic factors play an important role and demonstrates that the association between deficiency of decidua-associated suppressor cells and xenopregnancy failure also holds true for the failure of allopregnancies resulting from natural within-species mating.

T cell subsets in idiopathic glomerulonephritis.

Determination of T lymphocyte subsets using monoclonal antibodies revealed a deficiency of suppressor cells and an elevated helper:suppressor T cell ratio in 7 patients with untreated idiopathic immune complex glomerulonephritis and nephrotic syndrome. Possible pathogenetic mechanisms of immunoregulatory cell imbalance and their implications specifically in reference to idiopathic glomerulonephritis are discussed.

Lymphocyte Subpopulations in Allergic Granulomatosis and Angiitis (Churg-Strauss Syndrome)

We report a case of allergic granulomatosis and angiitis (Churg-Strauss syndrome) in which immunologic parameters, including lymphocyte subpopulations, were determined in the acute phase of the disease and during remission. Hyperimmunoglobulinemia E and immune complexes were present. A low proportion of suppressor/cytotoxic (T8+) lymphocytes and a high helper/suppressor ratio were seen throughout the course of the disease, although immunoglobulin levels and circulating immune complex levels decreased with therapy. We hypothesize that the deficiency of suppressor cells may play a role in the pathogenesis of this syndrome.

Lymphocyte Subpopulations in Patients with Allergic Rhinitis

The lymphocyte subpopulations were classified using monoclonal antibodies specific for B lymphocytes (B1 antibodies), T lymphocytes (T11 and OKT3 antibodies), helper/inducer T cells (T4 antibodies) and suppressor/cytotoxic T cells (T8 antibodies). Three groups of subjects were studied: 20 normal controls, 29 patients with allergic rhinitis and a subgroup of nine patients who had received immunotherapy. The proportion of B lymphocytes, total T cells and T4 positive (helper/inducer) cells were not significantly different between the groups, but allergic patients were found to have a decreased proportion of suppressor T8 positive (suppressor/cytotoxic) cells and hence a high helper/suppressor cell ratio. These abnormal parameters were found to be normal in the group of allergic patients who had received immunotherapy. These results imply that a suppressor cell deficiency may be an underlying mechanism of allergic disease, and that immunotherapy could correct the suppressor cell deficiency.

Deficiency of suppressor T-cells in insulin-dependent diabetes mellitus: An analysis with monoclonal antibodies

Peripheral blood from 25 patients with insulin-dependent diabetes mellitus was examined for any alteration in the proportions and or functions of immunoregulatory T-cell subsets, defined with monoclonal antibodies. Ten of 25 (40%) patients demonstrated deficiency of OKT8 + (suppressor/cytotoxic) T-cells. Eight of these 10 patients had abnormally high ratios of OKT4 +/OKT8 + T-cells. Nine of 10 patients with abnormally low proportion of OKT8 + T-cells had deficient concanavalin A-induced suppressor cell activity against the proliferative response of autologous or allogeneic lymphocytes to phytohemagglutinin. No correlation was observed between the deficiency of suppressor T-cells and the control of diabetes. Therefore, it is likely that the deficiency of suppressor cells is related to insulin-dependent diabetes mellitus itself and not to the metabolic changes that are associated with diabetes mellitus. This study demonstrates both quantitative and qualitative deficiency of suppressor T-cells in at least some patients with insulin-dependent diabetes, that might play an important role in the pathogenesis and autoimmune manifestations of a proportion of patients with insulin-dependent diabetes mellitus.

Alterations in T gamma cells in patients with chronic idiopathic thrombocytopenic purpura.

The number and percentage of T cells bearing Fc gamma receptors (T gamma) was quantitated in peripheral blood of patients with the autoimmune disease chronic ITP. In over half the patients, low initial percentages were obtained, the great majority of which returned to within the normal range after incubation under capping conditions. The phenomenon could be reproduced by pretreating normal T cells with immune complex containing sera or aggregated HGG. Furthermore, a reversible reduction in T gamma cells was observed in control patients with nonimmune thrombocytopenia and in pregnancy. In each case an association was observed between the reduced T gamma cell levels and the presence of circulating immune complexes, which suggested that the results could be explained by masking of Fc gamma receptors with preformed IgG-containing complexes. By contrast, patients with other autoimmune diseases such as scleroderma and rheumatoid arthritis had high or normal numbers of T gamma cells, respectively. Taken together, the findings do not support the existence of a gross deficiency of suppressor cells in patients with autoimmune disease and emphasize the need for caution in selection of markers for identification of T cell subsets.

Hyperproduction of IgE and T-cell dysfunction in Hodgkin's disease.

Serum IgE levels were evaluated in 119 untreated and 112 treated patients with Hodgkin's disease (HD). 38 of the nonatopic untreated patients showed significantly increased (> 300 IU/ml) IgE concentrations. No relationship could be found between increased IgE levels and depressed lymphocyte response to phytohemagglutinin (PHA) or the imbalance of TM and TG lymphocyte subsets. On the other hand, the mean level of suppressor activity elicitable from cells of untreated HD patients by concanavalin A preincubation did not differ significantly from that of healthy control subjects. In contrast, in treated patients, where there was a significant reduction in the number of circulating T lymphocytes, a further depression of the lymphocyte response to PHA, a more marked disproportion of TM and TG cell subsets and a noticeable fall in IgE concentration was found. These data suggest that increased IgE concentrations seen in untreated patients with HD are unrelated to the T-cell defects. They also suggest that hyperproduction of IgE is probably not invariably a consequence of a suppressor cell deficiency.

Lymphocyte Stimulation with Phorbol Myristate Acetate in Atopic and Non-Atopic Individuals

Phorbol myristate acetate (PMA) was found to be a potent stimulator of DNA synthesis in human whole blood cell cultures. Stimulation with pokeweed mitogen was strongly enhanced by addition of PMA-activated cells. PMA responsiveness varied with age, being low or absent in newborns and very pronounced in adults. In atopic children, PMA responsiveness was normal or increased. The ratio of phytohemagglutinin to PMA responsiveness was significantly reduced in cultures from such children. This finding would be compatible with the hypothesis of a relative suppressor cell deficiency in atopic disease. The results of tests designed to detect suppressor and helper cell activity, added further support to this hypothesis.

Selective Loss of Suppressor Cell Function in New Zealand Mice Induced by NTA

Abstract New Zealand mice develop a naturally occurring thymocytotoxic antibody (NTA) which increases in titer with age. This antibody causes a loss of recirculating peripheral T cells and interferes with T cell functions. To study the potential pathogenic role of NTA in murine autoimmune disease, NZB/W mice were injected daily with NTA-containing serum starting at 3 to 5 days of age. Littermate controls received normal mouse serum (NMS). After 4.5 weeks of treatment, spleen cells from female NZB/W mice treated with NTA had a significant increase in capacity to induce graft-vs-host disease in newborn Swiss mice, suggesting a deficiency of suppressor cells. Con A-activated spleen cells from NMS-treated animals suppressed IgM synthesis in vitro; however, Con A-activated spleen cells from NTA-treated mice were not suppressive. The NTA-induced loss of suppressor cell function was prevented by prior absorption of the NTA with thymocytes. Cells from control (NMS-treated) and NTA-treated litter-mates responded similarly to mitogens (Con A, PHA, PWM, LPS) and allogeneic lymphocytes in vitro. Although the number of nucleated spleen cells and splenic B cells was not changed by NTA treatment, a moderate reduction of T cells was seen (37% to 26% Thy 1.2 positive cells). Nevertheless, NTA treatment did not alter either skin allograft injection or the antibody response to immunization with the T-dependent antigen SRBC. These studies suggest that NTA causes a selective loss of suppressor cells in NZB/W mice, supporting the hypothesis that NTA may play a pathogenic role in murine autoimmunity.

DOUBLE BLIND CROSSOVER TRIAL OF LEVAMISOLE IN RECURRENT APHTHOUS ULCERATION

A double blind crossover trial of levamisole has been carried out in 47 patients with recurrent oral ulceration. Significant decreases in the number of ulcers and ulcer days were found after 2 months of intermittent administration of levamisole. About 64% of patients responded to the drug by a decrease in the number of ulcers of more than 50%, for two or more months. The remaining 36% of patients failed to respond to levamisole and 23% of these had an increased number of ulcers. The side-effects recorded in patients taking levamisole were comparable with those in patients on placebo, except for a flu-like syndrome in 1 patient and urticaria in another, necessitating withdrawal of the drug. The mechanism of action of levamisole in recurrent oral ulceration is not known, but it is suggested that levamisole may correct a deficiency of suppressor cells, or potentiate the cellular responses to crossreacting microbial agents.