T-suppressor Ratio Research Articles

Effect of cerebrocrast on the lymphocyte blast transformation activity in normal and streptozotocin‐induced diabetic rats

Both IDDM and NIDDM are characterized by deviations in peripheral T and B lymphocyte count, Thelper:Tsuppressor ratio, as well as by impaired Tsuppressor function. These abnormalities may promote insulin antibody and other antibody production, contributing to overt diabetes mellitus development in early stage of the disease. In the present study we explored the effects of cerebrocrast (1,4-dihydropyridine derivative) administration on Con A- and IL-2-stimulated tissue lymphocyte blast transformation activity and on the thymus and lymph node mass in normal and streptozotocin (STZ)-induced diabetic rats. It was established that cerebrocrast, administered four times at the doses of 0·05 and 0·5 mg kg−1, has long-term (up to 14 days) effects on the immune system and protects against the toxic effect of STZ in STZ-induced diabetic rats, preventing thymus and lymph node mass loss. We conclude that cerebrocrast administration leads to the increase in number and activity of Thelper and Tsuppressor lymphocytes. Glycolysis and DNA synthesis in these cells is augmented under the influence of cerebrocrast administration. We propose that the increase in lymphocyte suppressive activity caused by cerebrocrast administration may prevent the development of IDDM and NIDDM in patients with pre-diabetes, but in patients with early and overt diabetes mellitus the drug administration may prevent the overexpression of insulin antibodies and other antibodies. The effect of cerebrocrast on the de novo production of insulin and IL-2 receptors may be beneficial for IDDM and NIDDM patients. Copyright © 1999 John Wiley & Sons, Ltd.

Effect of cerebrocrast on the lymphocyte blast transformation activity in normal and streptozotocin-induced diabetic rats.

Both IDDM and NIDDM are characterized by deviations in peripheral T and B lymphocyte count, Thelper: Tsuppressor ratio, as well as by impaired Tsuppressor function. These abnormalities may promote insulin antibody and other antibody production, contributing to overt diabetes mellitus development in early stage of the disease. In the present study we explored the effects of cerebrocrast(1, 4-dihydropyridine derivative) administration on Con A- and IL-2-stimulated tissue lymphocyte blast transformation activity and on the thymus and lymph node mass in normal and streptozotocin (STZ)-induced diabetic rats. It was established that cerebrocrast, administered four times at the doses of 0.05 and 0.5 mg kg-1, has long-term (up to 14 days) effects on the immune system and protects against the toxic effect of STZ in STZ-induced diabetic rats, preventing thymus and lymph node mass loss. We conclude that cerebrocrast administration leads to the increase in number and activity of Thelper and Tsuppressor lymphocytes. Glycolysis and DNA synthesis in these cells is augmented under the influence of cerebrocrast administration. We propose that the increase in lymphocyte suppressive activity caused by cerebrocrast administration may prevent the development of IDDM and NIDDM in patients with pre-diabetes, but in patients with early and overt diabetes mellitus the drug administration may prevent the overexpression of insulin antibodies and other antibodies. The effect of cerebrocrast on the de novo production of insulin and IL-2 receptors may be beneficial for IDDM and NIDDM patients.

Immunological effects of occupational exposure to metallic mercury in the population of T-cells and NK-cells.

This paper presents a study of the counts of lymphocytes, (CD3+)T-cells, (CD4+)T-helper and (CD8+)T-suppressor and (CD16+)NK-cells in the peripheral blood of 101 males with a history of occupational exposure to metallic mercury vapours (Hg0) and in 36 males without this exposure. These workers were divided depending on the duration of exposure: 37 males with a short-term history of exposure to Hg0 (up to 10 years) and 64 males with a history of long-term exposure (10 to 37 years). For the determination of T-cell populations monoclonal antibodies were used in indirect immunofluorescence tests. The time weighted average of mercury concentrations in air was 0.028 mg m-3. Mercury concentration in the urine of the exposed subjects ranged from 20-260 micrograms dm-3, and in blood it was from 4 to 72 micrograms dm-3. Stimulation of the T-cell line was noted as evidenced by increased numbers of (CD3+)T-cells, (CD4+)T-helper and (CD8+)T-suppressor cells in the workers with < 10 or > 10 years' exposure to Hg0. Lower increase count of (CD3+)T-cells and (CD4+)T-helper cells than (CD8+)T-suppressor cells was the cause of decreased values in the (CD3+)T/(CD8+)T-suppressor ratio and (CD4+)T-helper/(CD8+)T-suppressor ratio in the workers with < 10 or > 10 years' of exposure. Moreover, no changes were observed in the T-cell populations between workers with < 10 and those with > 10 years' exposure. In addition, statistical analysis of the effects of age and duration of exposure to Hg0 on the studied immunological parameters indicates that exposure duration may affect some of the values. These quantitative changes of T-cell population as well as changes of the (CD3+)T/(CD8+)T-suppressor and (CD4+)T-helper/(CD8+)T-suppressor ratio have been proposed as immunological indicators of exposure to Hg0, which can be used for monitoring and to explain the origin of autoimmunity disorders induced by metallic mercury.

Role of Leukocyte Activation in Patients with Venous Stasis Ulcers

Alteration in leukocyte activation has been implicated as an etiological factor in the development of chronic venous stasis ulcers (CVSU). The purpose of this study was to determine differences in expression of cell surface activation markers on circulating leukocytes and systemic, soluble, serum cytokine levels between healthy controls and patients with CVSU. Twenty-three patients were separated into two groups. Group I consisted of 12 healthy, adult, age-matched male patients with no venous disease. Group II consisted of 11 adult male patients with CVSU who underwent air plethysmography (APG) and duplex scanning to determine the severity of venous insufficiency. All patients had measurements of systemic, serum-based, soluble IL-1β, IL-2, IL-6, TNF-α, and β2 microglobulin levels. Using fluorescence flow cytometry, we measured the percentage of lymphocytes (CD3), monocytes (CD14), and granulocytes (CD15) expressing various cell surface activation markers. By APG and duplex scan, all group II patients exhibited venous insufficiency, with a mean venous filling index of 6.9 ± 3.9 sec. Relative to group I, group II patients demonstrated a decreased expression of the CD3+/DR+ (13.3 ± 1.5, P ⩽ 0.01) and CD3+/CD38+ (31.1 ± 2.1, P ⩽ 0.04) markers on T-lymphocytes and an increased expression of CD14+/CD38+ (99.6 ± 0.2, P ⩽ 0.008) markers on monocytes. Circulating neutrophils showed no evidence of activation. In addition, a significant elevation in the T-helper to T-suppressor ratio (2.9 ± 0.6, P ⩽ 0.0001) between groups I and II was observed. IL6 was elevated in group II, while TNF-α, IL-1β, IL-2, and β-2 microglobulin demonstrated no significant difference between groups. Our data demonstrate a down-regulation of CD3+/DR+ and CD3+/CD38+ markers on circulating T-lymphocytes, increased activation of CD14+/CD38+ circulating monocytes, and increased levels of soluble serum IL-6 in the systemic circulation of group II patients. The lack of systemic neutrophil activation suggests that their involvement in the pathogenesis of CVSU occurs locally in the microcirculatory environment of the affected limb. These observations also suggest that the ulcer itself may cause cellular dysfunction.

The possible role of fungal infections in AIDS

The acquired immunodefficiency syndrome (AIDS) is characterized by a gross defect in the cell-mediated immune response. However, infection with human immunodeficiency virus (HIV), which is the generally accepted etiological factor of AIDS, cannot explain by itself the following problems: why do not some of the seropositive subjects develop AIDS or AIDS-related complex; why are some of the patients with AIDS seronegative for HIV and its corresponding antibodies; what is the reason why some of the healthy seronegative subjects from groups at a high risk for AIDS (homosexuals, hemophiliacs and drug abusers) have low T-helper to T-suppressor ratios. We suggest that some additional factor is necessary for the development of AIDS. We propose that the factor needed is a ‘partial functional thymectomy’. We suspect that slow fungal infections, producing thymotoxic metabolites, may be a major cause for the latter.

Lymphocyte Subpopulations in ‘Normal’ Lymph Nodes Harvested From Cadavers

Lymphocyte suspensions from 23 mesenteric lymph nodes harvested from clinically normal cadaveric kidney donors were examined for surface markers by flow cytometry. Mononuclear cells were isolated from nodal tissue by density gradient centrifugation and stained by an indirect immunoftuorescent method. A mean T-cell value of 71.0% was obtained using the pan T-cell marker CD3 (Leu 4); a T-helper / T-suppressor ratio of 3.3 was found using the monoclonal antibodies CD4 (Leu 3a+3b) andCDS (Leu la). With the pan B-cell marker CD19 (Leu 12), a B-cell value ofl 8.0% was measured. The κ/λ ratio was 1.6. This study describes a reference range forthe distribution of lymphocyte subsets in mesenteric nodes and compares these data with published reports on the matter.

Alterations in T-helper and T-suppressor lymphocyte populations after multiple injuries

Fifteen patients with multiple injuries and an Injury Severity Score (ISS) ranging from 2 to 57 (median 25) were studied for variations in lymphocyte populations on the day of injury and the three following days. Nine of the patients had an ISS above 16. In all patients the total number of lymphocytes fell during the first 24 hours after the injury ( P < 0.01), mainly due to a reduction in the number of circulating T-lymphocytes from a median of 1.8 to 0.6 × 10 9 cells/l ( P < 0.01). No reduction in the T-helper T-suppressor cell ratio could be demonstrated for the group as a whole, but in the 9 patients with an Injury Severity Score (ISS) of more than 16 a significant reduction in ratio from median 1.5 to 0.8 was found. Due to clinical observations patients with an ISS of more than 16 are considered severely injured and at risk of developing complications such as infection and septicaemia. The fall in T-helper T-suppressor ratio indicates impaired immunity in these patients.

Immunoregulatory mechanisms in cyclosporine-treated renal allograft recipients.

Cyclosporine (CsA)-treated recipients of a primary cadaveric (CAD) renal allograft were postoperatively evaluated for their donor and nonspecific immune responsiveness. Recipients with posttransplant (Tx) T helper (TH):T suppressor (TS) cell ratios less than 1.0 (averaged for the first 0-30 post-Tx days) had significantly better one-year serum creatinines (SCr) of 1.8 +/- 0.7 vs. 2.3 +/- 0.6 for recipients with TH:TS ratios greater than 1.0, P less than 0.05. Significantly fewer rejection episodes (30 vs. 57) and immune graft losses (10 vs. 19) were experienced by recipients with TH:TS ratios less than 1.0 vs. greater than 1.0, P less than 0.001 and 0.05, respectively. Recipients with TH:TS ratios less than 1.0 vs. greater than 1.0 displayed significantly lower post-Tx panel mixed lymphocyte culture (PMLC) stimulation indices (SI) of 24 +/- 11 vs. 38 +/- 6, P less than 0.05 and donor MLC SI of 15 +/- 6 vs. 31 +/- 8, P less than 0.05, respectively. Moreover, the post-Tx:pre-Tx donor MLC ratio of 0.58 +/- 0.2 vs. 1.1 +/- 0.32 was significantly lower in recipients with TH:TS ratios less than 1.0 vs. greater than 1.0, P less than 0.05. The suggested donor hyporesponsiveness in recipients with post-Tx TH:TS ratios less than 1.0 was further investigated by studying 46 CsA-treated allograft recipients for their ability to display regulatory T cell or adherent monocyte MLC suppressor activity. With a mean follow-up time of 5 +/- 4 months (range 0.5-14 months) we observed that 46% (21/46) of the patients displayed T cell suppressor activity, including 35% (16/46) with T-donor-specific and 46% (21/46) with T non-specific MLC suppressor activity. Additionally, 59% (27/46) of the patients also displayed nonspecific adherent monocyte MLC suppression. Recipients displaying either T cell or adherent monocyte suppression experienced significantly fewer rejection episodes than patients with no suppressor cell activity (P less than 0.05). Moreover, patients with T cell suppressor activity displayed a significantly lower panel and donor MLC vs. patients not displaying T suppressor activity (P less than 0.05. and 0.05, respectively). Finally, there was a significant correlation between the display of T cell suppressor activity in patients who were matched with their donors at the HLA-DR locus vs. no display of T suppressor activity in those patients unmatched with their donors at the HLA-DR locus.

Spectrum of HTLV‐III infection in a hemophilic cohort treated with blood products from a single manufacturer

One hundred fifty-eight hemophilia A, B, and von Willebrand disease (VWD) patients treated with clotting factor concentrates from a single manufacturer were tested for antibody to the human T-lymphotropic virus type III (HTLV-III). Antibody was detected in 63% and 40% of those with severe hemophilia A and B, respectively, 12% and 0% of those with mild hemophilia A and B, and two patients with recessive VWD. Forty-two antibody-positive and 20 antibody-negative patients were studied for clinical and laboratory features of infection. Eleven seropositive patients had clinical signs of infection including Pneumocystis carinii pneumonia, lymphadenopathy, splenomegaly or diarrhea; however, only one patient had developed acquired immune deficiency syndrome (AIDS), and only two had significant impairment of their performance status. Thirty-one patients remained totally asymptomatic. Eight patients had a history suggestive of acute HTLV-III infection. Thrombocytopenia was observed in 18% of seropositive patients, lymphopenia in 60%, depressed T-helper cells in 43%, reduced T-helper:T-suppressor ratios (TH:TS) in 33%, and elevated platelet-bound immunoglobulin in 53%. The antibody-negative group had normal T-helper cell levels (except one patient) and TH:TS ratios, and normal platelet immunoglobulin levels. Both groups demonstrated a significant elevation of immunoglobulin levels and a high prevalence of antinuclear factor and antismooth muscle antibodies. The mean level of IgG was significantly higher in the antibody-positive group. This study confirms the correlation between HTLV-III infection and reduced T-helper cells in hemophiliacs but demonstrates a low incidence of clinical symptomatology. There was evidence of polyclonal B-cell hyperactivity in the antibody-negative group as well as the seropositive group.

Effects of Exposure to Factor Concentrates Containing Donations From Identified AIDS Patients

We compared recipients of eight lots of factors VIII and IX voluntarily withdrawn from distribution because one donor was known to have subsequently developed the acquired immunodeficiency syndrome with a nonexposed cohort matched by age, sex, and factor use. The factor VIII recipient cohorts did not differ in prevalence of antibody to human immunodeficiency virus (HIV) (exposed, 75%; nonexposed, 86%), T-cell subset numbers (median: exposed, 619 T-helper cells per cubic millimeter; nonexposed, 659 T-helper cells per cubic millimeter), T-helper to T-suppressor ratios, or immunoglobulin levels. Exposed individuals had higher levels of immune complexes by C1q binding and staphylococcal binding assays and lower responses to phytohemagglutinin and concanavalin A. However, only the staphylococcal binding assay values were outside the normal range for our laboratory. Factor IX recipient cohorts did not differ in HIV antibody prevalence (exposed, 30%; nonexposed, 40%) or any immune tests. Although exposed and nonexposed individuals did not differ from each other in a clinically meaningful fashion at initial testing, both the exposed and nonexposed cohorts had high rates of HIV seroprevalence. Market withdrawals were clearly insufficient means of limiting the spread of HIV in hemophilic patients; however, the currently available methods of donor screening and viral inactivation of blood products will prevent continued exposure within this population.

Decreased T-Helper/T-Suppressor Ratios in Homosexual Men: A Nonspecific Finding

Although decreased T-lymphocyte helper/suppressor ratios are uniformly present in homosexuals with AIDS, this finding is not specific for AIDS and has been documented in many asymptomatic homosexuals. In AIDS patients, the abnormal ratio is due to a decrease in both the percentage and absolute number of lymphocytes staining with OKT4 (Leu 3) and an increased percentage of cells positive for OKT8 (Leu 2). The total number of T lymphocytes is diminished. Other conditions or variables to which certain homosexuals are exposed (venereal, viral, and parasitic pathogens and recreational drugs) may result in a decreased T-helper T-suppressor ratio secondary to increased numbers of suppressor cells with normal or increased total numbers of T lymphocytes.

ABNORMAL IMMUNE RESPONSES IN HOMOSEXUAL MEN WITH CHRONIC GENERALIZED LYMPHADENOPATHY

Chronic generalized lymphadenopathy (CGL) in homosexual men may be a prodrome of acquired immunodeficiency syndrome (AIDS). Depressed cell mediated immunity including low T-helper:T-suppressor ratios are commonly detected. To evaluate humoral immune function we immunized 9 CGL patients with pneumococcal polysaccharide (PPS) vaccine and the T-dependent neoantigen bacteriophage ØX 174 (ØX 174). Antibody responses to PPS were abnormal in 7 of 8 patients immunized; baseline antibody titers were absent or low, post immunization titers rose minimally and titers declined rapidly. Three patients had abnormal primary and secondary and five patients had abnormal secondary responses to ØX 174 including failure to switch from IgM to IgG. One patient with a very low primary response to ØX 174 developed pneumocystis carinii pneumonia 5 months later. Peripheral blood mononuclear cells (PBM) of patients with abnormal antibody responses in vivo showed reduced antigen induced antibody synthesis in vitro. The direct hemolytic plaque assay was abnormal in all patients: 2 had excessive suppression; 1 lacked T help; 5 showed increased antibody synthesis suggesting a state of immune activation which might explain the reported hyperimmunoglobulinemia.These studies indicate that homosexual males with CGL have both cellular and humoral immune deficiency, predisposing such persons to the opportunistic infections which characterize AIDS.

The prognosis of asymptomatic homosexual men with decreased T-helper to T-suppressor ratio.

Screening of 70 asymptomatic homosexual men in Copenhagen revealed that 13 (19%) had T-helper to T-suppressor (H/S) ratios less than or equal to 1.0. Clinical and immunological follow-up examinations for 2-7 months (mean, 5.2 months) disclosed that none of the 13 men developed the acquired immunodeficiency syndrome (AIDS) or AIDS-like symptoms. An increase in H/S ratios to greater than 1.0 was observed in 11 of the 13 men during the time of observation. The decreased H/S ratios were due to an increase in the T-suppressor population. The T-helper population did not at any time differ from that found in 31 male control subjects. The biological relevance of the observed decrease in H/S ratios was supported by the demonstration of a positive correlation to a decrease in the proliferative response of the lymphocytes. Serological studies did not reveal any specific infectious background for the low H/S ratio found in the 13 men, and the reason for the 'spontaneous' increase during the time of observation remains unknown. The present results indicate that most asymptomatic homosexual men with a decreased H/S ratio will experience normalization of the immunological variables.

Development of B-cell lymphoma in homosexual men. Clinical and immunologic findings.

Serious infections, neoplasms, and immunologic abnormalities have been found in homosexual men. We describe the development of malignant lymphoma in six such patients, three of whom had persistent, generalized lymphadenopathy. In biopsies done before the lymphoma developed, the lymphadenopathy was characterized morphologically by a distinctive pattern of B-cell follicular hyperplasia. All lymphomas were of B-lymphocytic origin, including B-cell immunoblastic sarcoma; small noncleaved, Burkitt-like lymphoma; and plasmacytoid lymphocytic lymphoma. Extranodal presentation with B symptoms occurred in five patients. Median age of our patients was 33 years. Three patients had histories of repeated systemic infections. The peripheral blood lymphocyte count was depressed in four, with depression of OKT 4+ (helper phenotype) cell levels and reversal of the T-helper: T-suppressor ratio in all. We conclude that these patients are at risk for the development of abnormalities of the B-lymphocytic system, manifested by abnormal hyper-B-cell response in enlarged reactive lymph nodes and aggressive, extranodal B-cell lymphomas.

National case-control study of Kaposi's sarcoma and Pneumocystis carinii pneumonia in homosexual men: Part 2. Laboratory results.

The Centers for Disease Control conducted a case-control study to investigate an outbreak of Kaposi's sarcoma and Pneumocystis carinii pneumonia in homosexual men. The occurrence of these diseases was found to be associated with certain aspects of lifestyle, including a greater number of male sex partners per year, exposure to feces during sex, history of syphilis and non-B hepatitis, treatment for enteric parasites, and use of various illicit substances. Laboratory studies reflected both this lifestyle and the probable underlying cause of the Kaposi's sarcoma and P. carinii pneumonia--cellular immune deficiency. Patients were found to have lymphopenia, specifically a deficiency of the T-helper subpopulation, resulting in a reversal of the T-helper to T-suppressor ratio. Levels of IgG and IgA were increased. When compared with controls, patients were also found to have significantly higher titers of antibody to Epstein-Barr virus and cytomegalovirus, a higher prevalence of antibody to hepatitis A virus and Treponema pallidum, a lower prevalence of antibody to varicella zoster virus, and a higher frequency of isolation of cytomegalovirus.

Spontaneous and interferon resistant natural killer cell anergy in AIDS.

The acquired immunodeficiency syndrome (AIDS) is characterized by severe unrelenting opportunistic infections and/or Kaposi's sarcoma associated with a dysfunction of cell mediated immune responses. In addition to cutaneous anergy and inversion of T-helper/inducer to T-suppressor cell ratios usually observed in AIDS, we have observed in three AIDS cases with multiple opportunistic infections that spontaneous and interferon (IFN) stimulated natural killer (NK) cell activity against K-562 cells is absent or severely depressed as compared to controls. Spontaneous and IFN stimulated NK cell activity in promiscuous male homosexual controls was similar to that observed in heterosexual controls. The control subjects had T-helper:T-suppressor ratios ranging from 1.1 to 2.4 in contrast to the AIDS subjects who had typical inverted ratios of T-cells ranging from 0.17 to 0.54. HNK-1, a monoclonal antibody that identifies NK and antibody-dependent cytotoxic cells, marked 3-22% of peripheral blood lymphocytes from AIDS patients in comparison to 8-38% of lymphocytes from controls. A larger series will be required in order to ascertain the true incidence of NK cell anergy in AIDS and whether or not subgroups exist based on the association of Kaposi's sarcoma in the disease process.