Biomedical subjects

N Lahat

Publications and source records attributed to N Lahat.

At least 73 records · Page 4Linked to original sources

PubMed1990

Class II HLA-DR antigens on non-autoimmune human thyroid cells stimulate autologous T cells with high suppressor activity.

Human autoimmune thyroid cells "spontaneously" express MHC-class II antigens. These antigens have been assumed to trigger thyroid-specific helper T cell clones, leading in turn to the expansion of thyroid autoantibody-secreting B cells. Thyroid cells derived from non-autoimmune subjects do not express MHC-class antigens, but these can be readily induced with gamma-interferon. We have addressed the issue of whether it is sufficient for normal thyroid cells to bear class II antigens in order to trigger autologous T cells. We found that non-autoimmune thyrocytes expressing DR antigens fail to stimulate autologous resting T cells. However, proliferative activity and interleukin-2 secretion were observed when fresh T cells were first triggered by autologous non-T cells and then incubated with thyrocytes. More CD8 than CD4 cells proliferated in the T:thyrocyte cultures, but CD4 cells were necessary for the proliferation and interleukin-2 secretion. Addition of antibodies to thyroglobulin or to DR antigens inhibited T cell proliferation and interleukin-2 secretion, thus pointing to T cell recognition of both thyroid-specific and DR antigens. Evaluation of the function of the thyroid stimulated T cells revealed very potent suppressor but negligible helper and cytotoxic activities. It would seem, therefore, that DR-restricted T cell activation by autologous antigen on non-autoimmune thyroid cells does occur, but since it results in enhanced suppression, its nature seems protective, thus leading to maintenance of immunological self-tolerance.

Antigen-Presenting Cells↗

PubMed1989

Decreased natural killer (NK) activity in patients with myeloproliferative disorders.

Natural killer (NK) cell number and activity were measured in 26 patients with myeloproliferative disorders and the results were compared with 16 age-matched control patients. The percent of Leu-11b-positive cells was 11% +/- 3% in the patients, compared with 12% +/- 4% in the control patients. Ten of 26 patients, however, had NK activity lower than all of the control values at three different effector to target cell ratios (E:T) (P less than 0.005). The values of those patients with low unstimulated NK activity remained low despite stimulation with interleukin-2 (IL-2) or alpha-interferon (alpha-IFN), whereas the values of those patients with normal unstimulated activity responded to IL-2 and alpha-IFN like the control patients. Three of the ten patients with low NK activity had a history of malignant neoplasms. None of the 16 patients with normal NK activity had a history of malignant neoplasms (P less than 0.05). We conclude that patients with myeloproliferative disorders frequently have low endogenous NK cell activity in vitro. The dysfunction of the NK system appears to be intrinsic because the relative number of NK cells was similar to control values and the response to stimulation with IL-2 and alpha-IFN was suboptimal. There may be a relationship between low NK activity and the development of malignant disease in such patients.

Bloodletting↗

PubMed1989

The relationship between clinical stage, natural killer activity and related immunological parameters in adenocarcinoma of the prostate.

Several immunological in vitro tests were performed on peripheral blood mononuclear cells of patients with adenocarcinoma of the prostate, stages A, B, C, D. The cytotoxicity of effector natural killer cells towards K-562 targets decreased with increasing disease spread, while their percentage was not significantly changed. The proportion of CD4 (helper/inducer) cells tended to fall with tumor advance, but the proportion of CD8 (suppressor/cytotoxic) cells remained almost constant. Secretion of interleukin-2 from peripheral blood mononuclear cells was diminished with disease progression. Pretreatment of a patient's lymphocytes with cimetidine (antagonist of H-2-bearing suppressor T cells) or indomethacin (inhibitor of prostaglandin synthesis) enhanced natural killer activity. Our data point to the existence of aberrant immune functions in early stages of carcinoma of the prostate and to aggravation of these immune abnormalities in advanced disease.

Adenocarcinoma↗

PubMed1989

Functional immunoregulatory T-cell abnormalities in cystic fibrosis patients.

The role of B cells and regulatory T cells in the reduced in vitro IgG synthesis of cystic fibrosis (CF) patients was studied. Intact proportion, proliferation, and differentiation of B cells and reduced suppressor and helper T-cell function were found. To explore the T-cell defects further, CF sera or supernatant derived from Pseudomonas aeruginosa cultures (PA supernatant) was added to the relevant T helper- and suppressor-cell assays. Both CF sera derived from PA-positive patients and PA supernatant interfered with the appearance of interleukin 2 (IL-2) receptors and with the functional enhancement caused by exogenously added IL-2. PA-negative CF patients, however, also had functional T-cell defects and inhibitory sera, but these sera did not affect IL-2 pathways. Thus different serum factors and intrinsic T-cell defects in CF patients are suggested.

Adolescent↗

PubMed1989

Cimetidine as an immunomodulator in the treatment of herpes zoster.

As there is evidence of a possible immunoregulatory role for H2-histamine receptor antagonists, we carried out a prospective randomized trial to evaluate the in vivo and in vitro effect of cimetidine, an H2-blocker, in the treatment of herpes zoster infection. Cimetidine treatment shortened the median interval until the first decrease in pain, the median interval until the complete resolution of pain and promoted faster complete healing of skin lesions than symptomatic treatment. The immunological trends observed in vitro support an important role for histamine in the induction of immunosuppression, as measured by the response to the mitogen phytohemagglutinin. This effect of histamine was antagonized by cimetidine.

Adjuvants, Immunologic↗

PubMed1989

Increase in the suppressor-inducer T cell subset in multiple myeloma and monoclonal gammopathy of undetermined significance.

The expression of CD4 (helper-inducer), CD8 (suppressor-cytotoxic) and CD4 subpopulations (2H4 and 4B4) were studied in patients with multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS) and in healthy controls. The percentages of CD4+ cells and CD8+ cells among total T cells were not different between the three groups studied. However the percentage of CD4+ cells of the suppressor-inducer type (CD4 + 2H4 +) was 53 +/- 9% in patients with MGUS, and 51 +/- 9% in those with MM, compared to 46 +/- 5 in the controls (P = 0.033 and P = 0.07 respectively). A significant negative correlation between serum polyclonal IgM and the percentage of CD4 + 2H4 + cells was found in patients with MM but not in those with MGUS. No difference was found in the percentage of CD4 + 4B4 + (helper CD4+ cells) between the various groups. These findings suggest that the elevation of the suppressor-inducer subset occurs prior to clinical manifestations of MM, perhaps as an immune response to the malignant clone. The existence of elevated proportions of CD4 suppressor-inducer cells was associated with the hypogammaglobulinaemia observed in patients with MM. Since no hypogammaglobulinaemia was present in those with MGUS, additional factors are needed to explain the influence of the CD4 + 2H4 + cells on the production of immunoglobulins.

Aged↗

PubMed1989

Still's disease associated with adenovirus infection and defect in adenovirus directed natural killing.

Low natural killer (NK) activity towards adenovirus infected fibroblasts was detected in the peripheral blood of a child with Still's disease and was not normalised by the addition of interferon alfa or interleukin 2. NK cytotoxicity directed at K 562 target cells or polio infected fibroblasts was normal. This specific NK deficiency might have contributed to the development of the child's Still's disease.

Adenoviridae Infections↗

PubMed1989

Enhanced induction of thyroid cell MHC class II antigen expression in rats highly responsive to thyroglobulin.

Initial experiments demonstrated that the degree of autoantibody and proliferative T cell responses to syngeneic rat thyroglobulin differed markedly between Buffalo (high responder) and Fisher (low responder) rats after classical immunization schedules. While varying immune responsiveness may be due to qualitative and quantitative T and B cell differences, the role of thyroid cell MHC class II antigens may be pivotal to the onset of autoimmune thyroiditis in such animal models. We, therefore, examined the induction of MHC class II antigens in thyroid monolayers derived from Buffalo and Fisher rats treated with methimazole (0.1% in their water) for 4 weeks to induce mild thyroid hyperplasia. After thyroidectomy, thyroid cell monolayers were prepared and exposed to recombinant rat gamma-interferon (gamma IF; 10-1000 U/ml) for 1-7 days in the presence and absence of TSH (1 mU/ml). Both Buffalo and Fisher thyroid monolayers responded to gamma IF with MHC class II antigen expression when assessed by laser flow cytometry using MRC OX-6 monoclonal anti-RT1.B. In both types of culture, TSH enhanced MHC class II antigen expression in the presence of gamma IF to the same degree. However, there was a consistently earlier and greater degree of MHC class II antigen expression in Buffalo thyroid monolayers compared to Fisher monolayers, a phenomenon not explicable on the basis of fibroblast contamination as assessed by cytokeratin staining. These data demonstrate that end-organ sensitivity to MHC class II antigen expression may be important in the pathogenesis of autoimmune thyroid disease.

Animals↗

PubMed1989

Humoral and cellular immune dysfunction in a patient with Bloom's syndrome and recurrent infections.

Immunological evaluation of a patient with Bloom's syndrome (BS) who suffered from recurrent bacterial and fungal infections, revealed low serum levels of IgG and high levels of IgM accompanied by an elevated proportion of surface membrane IgM positive B-lymphocytes and a decreased proportion of IgG positive B-cells. In vitro IgG secretion was also reduced whereas IgM production was normal. Although proportions of T-cell subsets were normal and proliferative responses to T-cell mitogens were adequate, a defective regulatory T-cell function for the generation of IgG was observed. Natural killer (NK) cell activity against K562 tumor cells was also decreased in this patient. The findings in this patient may suggest a maturation arrest of lymphocytes at an early developmental stage, and this may explain in part the increased susceptibility to infections.

Adolescent↗

PubMed1989

Immature cells identified by the H-1 hematology analyzer predicts thymidine incorporation after mitogenic stimulation.

The incorporation of thymidine by lymphocytes stimulated by phytohemagglutinin (PHA) was correlated with the number of immature cells identified by the Technicon H-1 as blasts. The number of blasts and thymidine incorporation plateaued on day 3. At that time, a high linear correlation between the two variables was found (r = 0.949, p less than 0.01). The H-1 evaluated the samples in 60 seconds as compared to 3 hours of processing required to calculate thymidine incorporation. We conclude that the number of immature cells identified by the Technicon H-1 can predict the degree of thymidine incorporation after stimulation of peripheral blood cells with PHA. The H-1 may replace the more time consuming and dangerous use of radioactive thymidine incorporation in evaluating patients' functional immunologic status.

Blood Cell Count↗

PubMed1988

T-cells of multiple myeloma patients triggered by the autologous mixed lymphocyte reaction suppress polyclonal immunoglobulin synthesis.

To elucidate the possible role of T-cells of patients with multiple myeloma (MM) in the suppression of polyclonal immunoglobulin synthesis. T-cells with and without prior activation by the autologous mixed lymphocyte reaction (AMLR) were added to normal immunoglobulin (Ig)-secreting cultures. The suppression induced by AMLR-activated T-cells from patients with MM was compared to that induced by AMLR-activated T-cells from apparently normal controls. The addition of 10% unstimulated autologous T-cells from patients with MM resulted in minimal suppression of IgG synthesis (87 +/- 19% of baseline values for patients and 115 +/- 21% for controls, no significant difference). The suppression sharply increased when T-cells were preactivated by AMLR and then added in the same concentration to the IgG-secreting cultures (38 + 12% of baseline values for patients compared to 106 + 14% for controls, P less than 0.05). AMLR cultures were performed in the presence of adherent monocytes and after their depletion. The T-cell suppressor effect on normal IgG synthesis was unchanged after monocyte depletion. T-cells preactivated in the AMLR from patients with MM sharply suppress in vitro polyclonal IgG synthesis, and the activation of these suppressor T-cells is not dependent on the presence of monocytes.

Aged↗

PubMed1988

Activation of MHC-restricted rat T cells by cloned syngeneic thyrocytes.

We have previously demonstrated that rat thyrocytes express MHC class II Ag (RT1.B&D) in response to IFN-gamma. To determine whether MHC class II-positive thyrocytes can be recognized by MHC-restricted T cells, we used our clone of rat thyroid cells (1B-6) derived from the Fisher rat thyroid cell line (FRTL-5) and known to express MHC class II Ag in response to recombinant rat IFN-gamma. CD4+ and CD8+ normal syngeneic Fisher rat spleen T cells were selected by flow cytometry and averaged greater than 96% purity. We demonstrated that irradiated MHC class II-positive but not class II-negative 1B-6 thyrocytes stimulated CD4+ T cells in a primary sensitization reaction over 4 days. In contrast, CD8+ T cells had no response in similar experiments. This stimulation of CD4+ T cells was dose dependent for 1B-6 thyrocytes and was abrogated by anti-rat MHC class II mAb (MRC OX-6). Autoreactive (Fisher) and alloreactive (Buffalo) T cell lines and isolated CD4+ T cells derived from these lines, which were developed against Fisher rat spleen cells, similarly recognized MHC class II Ag expressed on 1B-6 cells but had no detectable response to 1B-6 MHC class II-negative thyrocytes or MHC class II-positive human thyroid cells. The CD4+ T cell recognition of 1B-6 cells via MHC class II Ag supports our previous data with autologous human thyroid T cell co-cultures and is indicative of an autospecific role for thyrocytes in the development of autoimmune thyroiditis.

Animals↗

PubMed1988

Immunological profile of chest x-ray-negative, asymptomatic asbestos workers.

Several immunologic parameters, both humoral and cellular, were studied in the serum and peripheral blood lymphocytes derived from chest x-ray-negative, asymptomatic asbestos workers. All humoral and cellular parameters were intact, except the con-A-induced T cell suppressor activity and T cell division in autologous mixed lymphocyte reaction, which were significantly elevated in the asbestos plant workers. The significance of these increased T cell activities in asbestos exposed people is not clear, and further clinical and immunological follow-up is warranted.

Antibodies, Antinuclear↗

PubMed1988

Impaired autologous mixed lymphocyte reaction (AMLR) in patients with ataxia-telangiectasia and their family members.

We used the autologous mixed lymphocyte reaction (AMLR) to test T cell function in four patients with Ataxia-telangiectasia (AT), in 11 first-degree relatives and in 20 controls. There was a marked reduction of AMLR in the patients and in three relatives compared to the age-matched controls. In the AT patients the defect in AMLR was intrinsic to the CD4 subpopulation, since exogenous IL-2 did not improve the response of isolated CD4 cells. In contrast to normal controls, pre-incubation of autologous B cells with Epstein-Barr virus (EBV) did not enhance the reduced AMLR in the AT patients and the three first-degree relatives. We conclude that in both patients with AT and in some of their family members there is an intrinsic defect in CD4 T cells. This defect leads to diminished reactivity to EBV infected autologous B cells, and may explain in part the high incidence of malignancies observed in such families.

Ataxia Telangiectasia↗

PubMed1988

Discordant effect of interferon on natural killer activity and tumor cell sensitivity to lysis in hairy cell leukemia.

We studied the action of alpha-interferon (IFN) and interleukin-2 (IL-2) on natural killer (NK)-rich fractions and autologous tumor cells from two patients with hairy cell leukemia (HCL). The addition of IFN or IL-2 to the NK-rich fractions resulted in a significant increase in NK activity against the autologous tumor cells. This stimulatory effect was blocked if the target hairy cells (HCs) were preincubated with either IFN or IL-2. Pretreatment of the HCs with anti-Tac antibody entirely prevented the blocking effect of IL-2 and partially the blocking effect of IFN. One patient was treated with recombinant alpha c-IFN. After 2 months there was a dramatic reduction in the number of HCs in the peripheral blood coincident with the loss of the protection effect of IFN against NK lysis of the patient's HCs. NK activity against autologous tumor cells correlated poorly with that against the K562 cell line. We conclude that there is a discordant effect of IFN and IL-2 on NK activity and HC sensitivity to lysis. The Tac receptor appears to play a role in this sensitivity. Caution should be exercised in extrapolating the effects of NK activity against K562 cells to those on HC targets.

Antineoplastic Agents↗

PubMed1987

Reduced natural killer activity in patients with Fanconi's anemia and in family members.

Natural killer (NK) activity was measured in the peripheral blood of a family with Fanconi's anemia (FA) and compared to normal controls. One of two children with FA, and 6 of 11 family members had reduced NK activity (less than 30% with an E:T ratio of 25:1) compared to none of 40 controls (p less than 0.001). On retesting 5 of 8 family members and both children with FA had reduced endogenous NK activity compared to 0 of 5 controls (p less than 0.02). The number of NK cells determined by Leu 11b antibody was not reduced in any of the family members. Augmentation with interleukin-2 (IL-2) and alpha interferon (IFN) in those with low endogenous activity was variable. Three demonstrated no response to the 2 immunomodulators, while the 4 others increased to low normal levels. We conclude that some patients with FA and their apparently healthy relatives have reduced NK activity, which appears to be secondary to an intrinsic cell defect.

Anemia, Aplastic↗

PubMed1987

Defective humoral and cellular immune functions associated with veno-occlusive disease of the liver.

We describe veno-occlusive disease of the liver associated with humoral and cellular immune defects in two siblings. Another child, with aplastic anemia, died before the age of 1 year. No consanguinity was found in the family. Both infants had lymphopenia and hypogammaglobulinemia; the surviving infant has defective in vitro immunoglobulin production after stimulation of lymphocytes with pokeweed mitogen, increased proportions of OKT8 positive cells, defective proliferative responses to phytomitogens, and decreased help for immunoglobulin production. A therapeutic trial with cimetidine, an H2 receptor antagonist, has not changed the immunologic status of the surviving child.

Agammaglobulinemia↗

PubMed1987

Thyrotrophin receptor blocking antibodies: incidence, characterization and in-vitro synthesis.

The prevalence and characteristics of TSH receptor blocking activity were examined in patients with different thyroid disorders. Studies were also performed on the in-vitro synthesis and immunoregulation of the blocking antibody. Blocking activity was tested by measuring the inhibition of TSH-stimulated cAMP production of cultured human thyroid cells by patient immunoglobulin (Ig) preparations. The following patients were investigated (number of cases in parentheses): Hashimoto's thyroiditis (33); primary myxoedema (17); euthyroid ophthalmopathy (8); active Graves' disease (19); cold nodule (5); non-toxic goitre (14); toxic adenoma (8); toxic multinodular goitre (9) and 22 normal controls. TSH receptor blocking activity was only detected in primary hypothyroidism with the following characteristics: (i) Such activity was present in only 16% of the patients (both goitrous, i.e. Hashimoto's thyroiditis, and non-goitrous, i.e. primary myxoedema), and in three patients with previously active Graves' hyperthyroidism who had become hypothyroid. (ii) Blocking activity seems to be associated with the Ig fraction of serum as indicated by protein A adsorption. (iii) The block-positive samples did not bind 125I-TSH, which seems to rule out an antibody directed against TSH. (iv) The specificity of the blocking activity seems to be directed towards the TSH-(thyroid stimulating immunoglobulin, TSI) receptor-mediated cAMP response since no inhibition of prostaglandin E1-stimulated cAMP production was found. Moreover, all cases in which an inhibitory effect was demonstrated towards TSH also exhibited blocking of TSI-stimulated cAMP, with a high correlation between the degree of inhibition of the TSH to that of the TSI response (r = 0.89, P less than 0.001, n = 11). The blocking activity may contribute to the pathogenesis of some cases of primary hypothyroid autoimmune thyroiditis, both goitrous and non-goitrous, as well as in the evolution of hyper- to hypothyroidism. By culturing peripheral blood lymphocytes, as well as B/T lymphocyte co-cultures isolated from three patients with blocking activity present in serum, the in-vitro synthesis of the blocking antibody was demonstrated for the first time. Moreover, in-vitro secretion of the antibody by patients B lymphocytes, as well as T cell regulation of autoantibody production, were also shown.

Adult↗