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SUMMARY Using a double-labelling immunoperoxidase technique and monoclonal antibodies raised against T helper and T suppressor cells and Langerhans cells, we have found that the clinically involved skin of seventeen mycosis fungoides (MF) patients shows an increase in number of Langerhans cells which are in contact with T helper lymphocytes. T suppressor lymphocytes are also present, but are generally seen singly and situated at a distance from the T helper/Langerhans cell clusters.

Despite intensive research, autoimmune-disease pathogenesis is still an enigma, but in the past decade Ts-cell defects have assumed a central role in this pathogenesis. Ts-cell dysfunctions have been reported in numerous autoimmune diseases (e.g. SLE, autoimmune thyroid disease, myasthenia gravis) and in animal models of autoimmune diseases. Therefore, it is currently believed that Ts cells are responsible for maintaining self-tolerance and that perturbations in suppressor functions may initiate development of autoimmune diseases. Ts-cell abnormalities can result from LCTA production, intrinsic biochemical alterations, genetic susceptibility, or environmental factors. Since Ts-cells dysfunctions are believed to initiate autoimmunity, it may be possible to treat autoimmune diseases by correcting the suppressor defects, and indeed, preliminary trials in this direction are promising.

This study was performed to investigate the cell-mediated immune response in burned patients with no septic episodes. The results show that burned patients with percentage body burn higher than 20 had an impaired lymphocyte reactivity to phytohaemagglutinin and conconavalin A. This hyporesponsiveness appeared on day 3–4 and in all cases reached its maximum on day 7–8 post burn, while recovery occurred between day 11 and 29 depending on the severity of the injury. The serum from immunodepressed patients was able to inhibit the response to phytohaemagglutinin and conconavalin A of normal lymphocytes. This immunosuppressive activity was present very early after injury (on day 1–2) and before the onset of lymphocyte hyporesponsiveness to mitogens and was no longer detectable on day 7–8 post burn, when patient lymphocytes showed the greatest hyporesponsiveness to mitogens. This late depression was due to T suppressor cells.

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 less than 0.01), mainly due to a reduction in the number of circulating T-lymphocytes from a median of 1.8 to 0.6 x 10(9) cells/l (P less than 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.

75 patients with various types of hepatitis B were studied by the assay of Gattringer’s spontaneous suppressor T cell (STs) function. 24 of them with chronic hepatitis B infection were simultaneously investigated by enumeration of OKT3+, OKT4+, OKT8+ T cell subsets in peripheral blood with staphylococci-conjugated IgG rosette forming technique. Patients with chronic active hepatitis B (CAHB) had a significantly decreased STs function while all but one asymptomatic HBsAg carriers had normal, or even higher than normal, STs function. OKT4/OKT8 ratio was obviously low both in CAH and in chronic persistent hepatitis B (CPHB). Positive relationship between STs function and the proportion of OKT8+ cells was identified while most patients with CAH showed higher proportion of OKT8+ cells and destroyed STs function simultaneously. It is suggested that OKT8+ cells in CAHB and CPHB are not of the same entity. In other words, in CAHB OKT8+ cells include mostly cytotoxic T cells, while in CPH, mostly T suppressors.

• Effects of mucosa-derived T-suppressor cells on induction of IgG-mediated otitis media with effusion (OME) were investigated in mice, since antigenantibody reactions in the tympanic cavity are pathogenic mechanisms of OME. Splenic T-suppressor cells from strain C 3 H/HeN female mice, to which ovalbumin (OVA) had been orally administered, were transferred intravenously to syngeneic mice. The mice receiving the T-suppressor cells were immunized with OVA intraperitoneally and then injected with OVA into the tympanic cavity. Nine of ten control mice, to which splenic T cells from saline-fed mice were administered, developed OME, while OME was seen in only one of ten mice receiving splenic T cells from OVA-fed mice. The results show that IgG-mediated OME can be suppressed to a certain extent by the induction of antigen-specific, mucosa-derived, T-suppressor cells. (Arch Otolaryngol Head Neck Surg 1988;114:878-882)

The hypothesis presented envisages dengue virus infection in a host with preexisting parasitic infection. The dual infections may produce alterations in the immunoregulatory system that would lead to depletion of T suppressor cells. The resultant augmented production of IgG and IgE may be responsible for type III and type I hypersensitivity reactions, respectively.

The influence of thymic preparations on the kinetics of the development of PFC response to sheep erythrocytes was tested in mice 0 to 4 weeks old. Soluble thymic factor (STF) or thymic epithelial culture supernatant (TES) was prepared from the thymuses of C57B1/6 mice. STF was injected to gravid mice on day 13 or on day 18 of gestation. A marked acceleration in the appearance of PFC to SRBC was noted only in the offspring from those mothers having received STF on day 18. The ability to generate anti-SRBC response in vitro by splenocytes from 1-to 4-week-old mice was significantly improved in the presence of TES. The accelerated appearance of the response to a T-dependent antigen is attributed to increase in the ratio of T helper/T suppressor cells resulting from differentiation and/or clonal expansion under the influence of STF crossing of the placental barrier in the materno-fetal direction.

T helper (Th) and T suppressor (Ts) functions on the induction of specific antibody response have been studied in 80 aged individuals by means of a plaque-forming cell assay. Of the subjects 45.2% exhibited a reduction of Ts activity on Ig production by adding Concanavalin A (Con A) to cultures on day 0, while 35.7% of aged donors showed a decrease of Th functions by supplementation of Con A on day 2. A small number of individuals displayed a combined deficit (Th + Ts). Furthermore, these defects seem to be related to soluble suppressive factors which might adhere to cell surface. In fact, preincubation of peripheral blood mononuclear cells (PBMC) before their addition to cultures and resuspension in fresh medium normalized the immunoregulatory defects. On the other hand, overnight supernatants from old PBMC transferred to young PBMC cultures induced the same deficit observed in the aged cell suspensions. Finally, Zinc chloride supplementation to cultures was able to correct the deficient Th activity only. These data suggest an additional defect of immunoregulation in the elderly.

In 40 patients diagnosed as having head and neck region malignant tumors, we studied the changes of peripheral blood lymphocyte and its subpopulation using OK and T series monoclonal antibody.We divided the patients into three classes: good prognostic cases (13 cases), cancerous cases (16 cases) and death cases (11 cases).Peripheral blood lymphocyte showed tendencies of decreases in the following order: good prognostic cases, cancerous cases and death cases (p

Opsoclonus and other cerebellar symptomatology developed in a patient who underwent mastectomy for adenocarcinoma of the breast. No evidence for metastases was found. Immunological studies demonstrated decreased function of T suppressor cells and hyperreactivity of T helper cells in spite of a normal suppressor/ helper ratio. The clinical condition, as well as the immunological abnormalities normalized under steroid treatment. An autoimmune process as etiopathogenesis of this paraneoplastic syndrome is proposed.

SUMMARY Monoclonal antibodies recognizing specific antigenic determinants of peripheral T-lymphocytes (OKT3PAN), helper T-cells (OKT4IND) and suppressor T-cells (OKT8SUP) were used to study the immune regulation in autoimmune thyroiditis. An indirect immunofluorescence microscopy method was employed to quantify the number of different subtypes. In addition, B-lymphocytes were also studied using a fluorescent surface Ig detection technique. Patients with autoimmune thyroiditis—independent of their clinical status—show a decrease in the number of suppressor T-lymphocytes. This finding, in agreement with other functional tests, indicates that the autoimmune phenomenon is linked to a decreased T-suppressor activity.

Treatment with Vi antigen followed after 46–48 h by cyclophosphamide induces a state of specific areactivity in mice which persists through adoptive transfer. Only trace amounts of Vi antigen were found in the blood and spleen of the tolerant mice after 2–3 weeks. No T suppressors were found in the spleen of the tolerant animals: Cells of the tolerant mice did not depress the immune response of normal lymphocytes when cultured togetherin vivo and they did not induce tolerance in intact recipients; the cells of normal donors partially restored the immunoreactivity of the tolerant animals. The results suggest that this form of tolerance is due to elimination or prolonged inactivation of the immunocompletent cells.

Functional activity of spleen and thymus cells of mice tolerant to sheep's red blood cells was studied 1 and 4 days after induction of tolerance. Tolerance was obtained with the aid of cyclophosphamide. Complete restoration of the immunocompetence of the thymus cells was found after 4 weeks. The functional activity of splenic T and B lymphocytes also was partly restored 4 weeks after induction of tolerance. Preliminary thymectomy weakened but did not prevent complete restoration of competence of splenic T cells. No T suppressors were found in the thymus and spleen of the tolerant animals.

Autoradiographic studies have revealed that stimulation of rabbit spleen lymphocytes by various ConA doses involves two subpopulations responding successively when ConA concentration rises from 0.5 to 5 μg/ml. Equilibrium density sedimentation analysis of DNA replicated in the presence of BUdR is performed after stimulation by these different ConA concentrations. It is shown that at optimal doses to which each of these subpopulations responds, profiles of sedimentation correspond to a normal replication followed by cellular division and a second round of replication. After stimulation by minimal doses, sedimentation profiles indicate a discontinuous process of replication in which initiating events are numerous, but elongations partially blocked. This pattern suggests that the number of stimuli necessary to produce elongations is higher than that necessary to initiate replication. Comparison with effects produced by drugs like FUdR or HU on replication in continuous cultures suggests also that DNA synthesis in lymphocytes cultures could be regulated by a precise balance between stimulating and inhibiting factors. Finally equilibrium density analysis supports the autoradiographic finding that the duration of the S phase varies with the doses of ConA used. Different problems concerning replication in lymphocytes are discussed.

T gamma and T mu lymphocytes and haemolytic plaque-forming cells (PFC) were quantitatively determined in peripheral blood and uterine draining lymph nodes ( DLN ) from 36 nonpregnant and 45 pregnant sows. A considerable increase in the number of T gamma cells occurred both in the blood and the DLN during pregnancy (P less than 0.001). This increase was higher at the beginning of pregnancy (20th-40th day) and lower at the end (80th- 110th day). No significant quantitative changes were found in T mu cells. During pregnancy there was a marked drop in the number of cells in the peripheral blood manifesting direct erythrocytolytic activity (DECA), as well as of haemolysin-producing cells.

A patient with Guillain-Barre syndrome was successfully treated by plasma exchange (without any other therapy), and the relationship between changes in his peripheral blood lymphocyte subpopulations and the clinical improvement induced by plasma-pheresis was studied. At the recovery, the most interesting findings were an increase in T suppressor lymphocytes, and in Fc receptor-bearing lymphocytes (above normal values), together with a decrease in B lymphocytes. In this patient, plasma exchange not only removed toxic humoral factors, but also restored a normal balance among peripheral lymphocytes.

Administration to mice of repeated small doses of glutaraldehyde-polymerized ovalbumin (OA-POL) results in drastic suppression of the IgE antibody response. The high anamnestic IgE antibody responses usually obtained after 2 injections of native OA in alum were completely abrogated when OA-POL was administered between the 2 immunizations. Treatment with OA-POL prior to a primary immunization with 2 μg DNP-OA in alum induced a profound suppression of both anti-DNP and anticarrier IgE responses. The suppression, which was detectable for at least 7 months, was antigen-specific, selective for the IgE class and was sensitive to treatment of spleen cells with anti-Thy-1.2 antibody and complement. Adoptive transfer of spleen cells from donors treated with OA-POL 200 days, 16 days or 200 and 16 days prior to transfer, resulted in different kinetics of suppression in the recipient. The results are consistent with the presence of long-lived IgE-selective T suppressor cell memory. The possibility that separate Ts and Ts memory cell populations are generated is discussed.

Aging effect on immunoregulatory processes in Peyer's patches (PP) from BALB/c mice of 3-4 months and 24-28 months was studied in vitro. The magnitude of isotype-specific Ig production by aged or young PP B cells in co-culture with young or old fresh PP T cells strongly suggested that the suppressor activity of PP T cells was impaired in aged mice. Further studies on in vitro induction of concanavalin A-activated T helper cells, T suppressor-inducer cells and T suppressor cells from aged PP indicated that the generation of T suppressor cells was largely impaired, in contrast to a minor defect(s) in that of T helper cells. The findings obtained here at least suggest that in aged PP, a T suppressor-inducer cell subset appears to be more selectively impaired in the aging process than the other lymphocyte subpopulations, which possess minor intrinsic functional defects. Thus, these abnormal T and B cell responses in PP could be responsible for the senescence-associated gut mucosal immunologic dysfunction.

The writers showed previously that mice of the inbred line I/St are highly susceptible to infection with tuberculosis, whereas those of inbred line A2G are resistant [2]. Parameters of immunity to tuberculosis, such as the level of the delayed-type hypersensitivity (DTH) reaction and of antibody synthesis to tuberculin, were opposite in mice of these lines at the same times after infection: a high level of DTH and a low level of antibodies in A2G mice and the opposite picture in I/St mice [i]. These data confirm the earlier concept [3] of immunological causes of sensitivity and resistance to tuberculosis and the protective role of cellular immunity in this disease.

The homologous, monoclonal antiidiotope, MB, induced idiotope suppression that was remarkably stable and could be transferred by B lymphocytes. Marked depletion of T cell function, confirmed by limiting diluting analysis, did not affect the ability of MB to suppress the corresponding idiotope. Suppression induced by MB appears to result from direct interaction with idiotope-positive B cells, without the intervention of idiotope-specific T suppressor cells.

Two principal human immunoregulatory T cells have been defined. T helper/inducer (Th/i) lympho- cytes are recognized by monoclonal antibodies to CD4 (T4 or Leu 3) antigen and T suppressor (Ts) and cytotoxic (Tc) lymphocytes by monoclonal anti- bodies to CD8 (T8 or Leu 2) antigen• Antigen- specific

Monoclonal antibodies reacting with specific determinants on lymphocytes and their subpopulations were used to study the influence of surgery under general or epidural anaesthesia on the number of T-cells (T11), T-suppressor cells (T8), and T-helper cells (T4). The T-cell fraction decreased significantly during surgery, but was only moderately reduced on the first postoperative day. The change in the T-cell fraction was the same under both types of anaesthesia. The helper and suppressor cell fractions were not significantly altered at any time during the study, and again there was no difference between the two anaesthetic regimens. The ratio of helper cells to suppressor cells (the T4/T8 ratio), which is widely used as an indicator of immunosuppression, showed no significant variations during the study, even though there were individual variations. Changes in the T4/T8 ratio were not correlated to the amount of blood transfusions, nor was there any correlation between the T4/T8 ratio and the thymidine uptake in mitogen-(PHA)-stimulated lymphocytes. T-lymphocytes are depressed during and after surgery under general anaesthesia. From the present study, this does not seem to be due to changes in the balance between helper- and suppressor T-cells.

Experimental autoimmune uveoretinitis (EAU) was induced in rats by immunization with bovine interphotoreceptor retinoid-binding protein (IRBP) and studied by immunohistochemistry. In general, the IRBP induction of inflammatory cellular components and expression of immune-related antigens on various non-lymphoid cells resembled those provoked by S-antigen (S-Ag). However, differences were found between the two diseases, including: 1) The increase in T suppressor/cytotoxic cells occurred in IRBP EAU more rapidly than in S-Ag EAU. 2) Fewer numbers of non-lymphoid cells expressed major histocompatibility complex class II surface antigens in IRBP EAU than in S-Ag EAU. The immunopathogenic mechanisms of EAU induced by these two retinal antigens are discussed.

Lymphocyte subpopulations were determined in 13 patients, recipients of kidney allografts, 7 of them during an acute rejection episode (ARE). Monitoring of the T lymphocyte suppressor or T helper cells was performed by aid of the theophylline sensitivity test and the local xenogeneic graft-versus-host reaction (GVHR). An absence or a striking decrease of theophylline-sensitive T suppressor cells was found in all patients during ARE. Incubation of the lymphocytes of these patients with a thymic hormone, THF, raised the number of TS lymphocytes from nil or from a very low level to normal or above. The therapeutic use of THF in selected renal allograft recipients is proposed.

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder, occurring predominantly in women. We studied by flow cytofluorimetry the T cell subsets in men and women with ITP and compared them with healthy sex-matched volunteers. In healthy controls, women were found to have higher proportions of T helper/inducer (Th/i) and lower T suppressor/cytotoxic (Ts/c) lymphocytes and consequently higher Th/i:Ts/c ratios than men. Accordingly, in clinical surveys, patients and controls should be matched for sex for proper comparisons. In patients with ITP in its active phase, an imbalance in T cell subsets was found in both sexes. The perturbation was more severe in women who had a marked decrease in number and proportion of Th/i lymphocytes and an increase in the proportion of Ts/c lymphocytes, whereas in men only, the proportion of Th/i lymphocytes was decreased. When patients with active disease were compared to those with ITP in remission, the decrease in Th/i subsets still persisted in both sexes but the Ts/c subset in women had returned to normal proportions. Therefore, the immune imbalance in ITP is more marked in women than men; imbalances in both Th/i and Ts/c are present in women while Ts/c appears not to be involved in men.

The cause of the abnormal T lymphocyte subsets reported in healthy homosexual men is not known. Frequent sexually transmitted infections including human T cell lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) are possible causes. To determine if the T lymphocyte subsets were abnormal in this population in an area without endemic acquired immune deficiency syndrome (AIDS), T lymphocyte subsets of 52 homosexual men in Rochester, New York, were enumerated, and evidence of infections known to cause these abnormalities was sought. Unlike the findings in previous reports, relative numbers of T helper and T suppressor cells and helper/suppressor T cell ratios were normal. Prevalence of cytomegalovirus infection (86 percent) was similar to that found in analogous populations, but only 9 percent had seropositive results for HTLV-III/LAV. Men with serologic evidence of nonprimary cytomegalovirus disease had lower helper/suppressor T cell ratios (1.5 +/- 0.2 versus 2.2 +/- 0.2; p less than 0.01). Hence, despite frequent infections with cytomegalovirus and other sexually transmitted pathogens, T cell subsets are normal in homosexual men in an area without endemic AIDS. Therefore, HTLV-III/LAV is primarily responsible for the T cell abnormalities observed elsewhere.

Peripheral blood lymphocytes from patients with multiple sclerosis (MS) and two control groups, patients with neurologic diseases other than MS and healthy individuals, were examined for their cellular response to basic protein (BP), suppressor cell activity elicited by concanavalin A (ConA) and enumeration of T gamma cells. Lymphocytes from patients with active and chronic progressive MS showed the highest blastogenic stimulation in response to BP, the lowest ConA-induced suppression and the lowest absolute and relative number of T gamma cells. Lymphocytes from patients with nonactive or slowly progressive MS showed BP blastogenic stimulation similar to or slightly higher than that of the control groups. The ConA suppressor activity and the absolute and relative number of T gamma cells in the nonactive MS group were within normal ranges. The results indicate that although hypersensitivity to BP may be accompanied by deficient immunoregulatory activity, there is no pattern in the sequence of events. In addition, in some instances, changes in the immunoregulatory cells occurred with little or no effect on the cellular response to the neural antigen.

The role of T suppressor (Ts) cells in low zone tolerance (LTZ) to bovine serum albumin (BSA) has been analyzed. LZT induced in adult CBA mice (aLZT) is carrier specific and accompanied by activation of Ts cells as demonstrated by adoptive transfer into 200-R-irradiated syngeneic recipients. Anti-Thy-1.2 antiserum and complement eliminates Ts cells. Injection of adult mice with cyclophosphamide (Cy) at time of tolerogenic treatment with BSA prevents induction of LZT and activation of transferable Ts cells. Neonatally induced LZT (nLZT) to BSA is also carrier specific and accompanied by activation of Ts cells as demonstrated by Cy sensitivity and adoptive transfer. Concommitant induction of neonatal tolerance to fluorescein-conjugated human IgG (FITC-HGG) and nLZT to BSA, followed by challenge of adult mice with FITC-BSA, shows that BSA-specific Ts cells maintain nLZT even if the FITC-specific B-cell repertoire has recovered. These findings suggest that both aLZT and nLZT are to a large extent maintained by Ts cells. The data confirm and extend our previous findings on LZT to phage fd.

Local exposure of the sites of elicitation (ears) of contact hypersensitivity (CHS) in mice to relatively modest doses of ultraviolet radiation (FS40 sunlamps) daily for 4 days prior to challenge in previously immunized animals results in significant enhancement of the CHS response as measured by 24-h swelling. This effect was seen in both C3H/HeJ and A/J mice and with the use of both trinitrochlorobenzene and dinitrofluorobenzene as contact sensitizers. Doses of PUVA (parenteral administration of 8-methoxypsoralen followed by exposure to UVA, 320-400 nm, radiation) up to that which can systemically suppress the induction of CHS failed to affect the elicitation of CHS. Irritation of the sites of elicitation of CHS by applications of turpentine also failed to affect the CHS elicitation reaction. Enhancement of the CHS elicitation response by local ultraviolet radiation exposure prior to challenge appears to be a specific photobiologic event.

During the last i0 years the nature of immunologic tolerance has been extensively discussed in the literature. It has not been shown that tolerance may be based on two fundamentally different processes: elimination or inactivation by an antigen of the corresponding clone of immunocompetent cells [6, 9, i0, 16] or increased activity of antigen-specific T or B suppressors, secondarily inhibiting effector cells or their precursors [8, 14, 15]. The concrete conditions under which a particular form of tolerance arises and the possibility of their coexistence and mutual transition are items for discussion [3].

The effect of combined application of thymalin and plaferon in the prophylaxis and treatment of traumatic syndrome has been investigated in rats. The survival rate was taken as the criterion of efficiency, the mechanism of the effect obtained being estimated at the level of immunological protective factors. Traumatic shock was induced by Kennon's method in Wistar male rats weighing 200-250 g. Post-traumatic syndrome has been observed within 7 days. The combined application of thymalin and plaferon has increased the survival rate twice within the first 7 days. Immunomodulating effect of the combined application of thymalin and plaferon on the 7th day of traumatic syndrome was most marked at the level of total T-lymphocyte population, theophylline-sensitive T suppressors and lysozyme blood serum activity.