Inhibition of T cell responses by activated human CD8+ T cells is mediated by interferon-gamma and is defective in chronic progressive multiple sclerosis.

The autologous mixed lymphocyte reaction (AMLR) involves the activation of T cells by autologous antigen presenting cells. Cells are generated during the course of the AMLR that have suppressive properties in vitro. In the present study we investigated the induction of CD8+ T cells in the AMLR with suppressive properties and the mechanism by which these cells downregulate in vitro proliferative responses. Purified CD8+ but not CD4+ T cells activated in the AMLR in conditioned medium inhibited proliferation of autologous T cells by anti-CD3 or PPD. Nonactivated CD8+ T cells did not suppress. The CD8+ T cells activated in the AMLR in the presence of conditioned medium (CD8+ Tact) were CD11b negative and were noncytotoxic. The inhibitory effect of CD8+ Tact cells was completely abrogated by anti-IFN-gamma antibody, but not by anti-IL-4, anti-IL-10, or anti-TGF-beta antibody. The induction of CD8+ Tact cells in the AMLR was blocked by anti-IL-2 or by anti-GM-CSF antibody and the combination of these two recombinant cytokines could support the induction of suppressive CD8+ Tact cells. CD8+ Tact cells were defective in patients with chronic progressive multiple sclerosis (MS) as compared to patients with relapsing-remitting MS or normal controls. Our studies provide a basis for understanding the mechanism of suppression by human CD8+ T cells in terms of specific cytokines, and demonstrate the potential importance of these cells in a human autoimmune disease as their function is defective in patients with progressive MS.

Predictive cytokine biomarkers of clinical response to glatiramer acetate therapy in multiple sclerosis.

A prospective study of 62 patients with relapsing-remitting multiple sclerosis (RRMS) treated with Glatiramer acetate (GA) was conducted to evaluate the value of baseline and treatment-modulated cytokines in predicting the clinical response to the drug after 2years of therapy. There were 32 responders and 30 non-responders. GA upregulated Th2/regulatory cytokines and inhibited Th1 cytokines in sera or PBMC supernatants 3 and 6months into treatment. We found two prognostic models with clinical utility. A model based on IL-18 at baseline, the change in TNFa from baseline to 3months, the change in IL-4 from baseline to 6months, and the change in the log of the ratio of TNFa/IL-4 from baseline to 6months had an area under the curve (AUC) of 0.80. A high IL-18 level at baseline and a reduction of TNF-alpha over time are associated with a response to GA. Although the study identified predictive biomarkers of clinical response to GA, the results will need to be validated in other data sets.

Defective regulation of IFNgamma and IL-12 by endogenous IL-10 in progressive MS.

BACKGROUND: MS is a chronic inflammatory disease of the CNS postulated to be a Th1 type cell-mediated autoimmune disease. There is increased interferon-gamma (IFNgamma) secretion in MS, and IFNgamma administration induces exacerbations of disease. IFNgamma expression is closely regulated by a number of cytokines produced by different cells of the immune system. Interleukin-12 (IL-12) is a major factor leading to Th1-type responses, including IFNgamma secretion, and there is increased secretion of IL-12 in MS. IL-10 is a potent inhibitor of both IL-12 and IFNgamma expression. METHODS: The authors investigated cytokine production and proliferative responses of peripheral blood mononuclear cells stimulated with soluble anti-CD3 in healthy controls and patients with stable relapsing-remitting MS or progressive MS. RESULTS: The authors found that T cell receptor-mediated IFNgamma and IL-10 secretion were increased in progressive MS, whereas IL-4 and IL-2 secretion and lymphocyte proliferative responses were normal. Anti-IL-12 antibody suppressed raised IFNgamma in progressive MS but did not affect raised IL-10. In addition, neutralization of endogenous IL-10 upregulated IFNgamma in controls but not progressive MS. IL-10 was produced by CD4+ cells whereas IFNgamma was produced by both CD4+ and CD8+ cells. There were no differences in IL-10 receptor expression in MS patients. CONCLUSIONS: These abnormalities in IL-10 regulation were not seen in the relapsing-remitting form of MS. Thus, the defect in regulation of both IL-12 and IFNgamma production by endogenous IL-10 in progressive MS could be an important factor involved in the transition of MS from the relapsing to the progressive stage and has implications for treating MS patients with exogenous IL-10.

Application of anti-CD3-treated lymphocytes as stimulator cells in human autologous mixed lymphocyte cultures for generation of autorestricted CD8+ suppressor T cells.

The purpose of the present study was to investigate the application of anti-CD3-treated lymphocytes as stimulator cells in human one-way autologous mixed lymphocyte cultures (MLC) for the generation of suppressor cells. MLC-activated CD4-CD8+ CD16- T cells were non-cytotoxic, while they down-regulated the proliferation of autologous (but not allogeneic) responder lymphocytes in allogeneic test MLC.

[Scanning electron microscopic method for studying the interaction of normal peritoneal macrophages with tumor cells]. / Izuchenie metodom skaniruiushchei élektronnoi mikroskopii vzaimodeistviia normal'nykh peritoneal'nykh makrofagov s opukholevymi kletkami.

It is shown that the damage action of normal peritoneal macrophages of mice includes inhibition of the proliferating activity of the mastocytoma P-815 cells and their complete destruction accompanied by the breaks of their cytoplasmic membrane. Scanning electron microscopy was used to reveal two types of contacts between peritoneal macrophages and cells P-815; the loss of microvilli and the appearance of blebs on cell surface in the case of adsorption of P-815 cells on macrophages; the contact through long filopodia which are sent forth by macrophages in the case when contacting cells are at some distance from each other.

[Isolation from the human peripheral blood of a fraction of mononuclear cells with high cytotoxicity against K-562 and HeLa target cells]. / Vydelenie iz perifericheskoi krovi cheloveka fraktsii mononuklearov s vysokoi tsitotoksichnost'iu protiv kletok-mishenei linii K-562 i HeLa.

Adherent cells were released from human peripheral blood mononuclears and the remaining mononuclears were separated by the density gradient centrifugation on percoll. Five fractions obtained were tested for cytotoxicity against K-562 and HeLa tumour target cells. Cell morphology and reactivity to some monoclonal antibodies were also studied. Fractions 2 and 3 were enriched by large granular lymphocytes (LGL) and BMA-070 positive cells and showed increased cytotoxicity only to K-562 target cells, while fraction 1 contained 9.5% of monocytes, but no LGL, and showed increased cytotoxicity against both K-562 and HeLa target cells.

[Immunologic aspects of migraine headaches and autonomic prosopalgias]. / Immunologicheskie aspekty pri migrenoznykh tsefalgiiakh i vegetativnykh prozopalgiiakh.

The paper presents the results of an immunological screening of patients with facial vegetative neuralgia, Horton's syndrome, and migraines prior to and following therapy. The patients with migraines were found to have an activated local humoral immunity. Those from all the groups showed lower serum immunoglobulin A concentrations after therapeutic interventions.

[Immunologic status in autonomic prosopalgias]. / Immunologicheskii status pri vegetativnykh prozopalgiiakh.

The authors describe the results of immunological examination of patients suffering from vegetative prosopalgias. A study was made of the initial status of immunity and of its dynamics after treatment. The majority of patients manifested an increase of immunoglobulin A concentration and activation of local humoral immunity. The treatment brought about a reduction of immunoglobulin A concentration in blood serum.

[Local and general humoral immunity in patients with migraine, Horton's syndrome and autonomic pain]. / Opredelenie mestnogo i obshchego gumoral'nogo immuniteta u bol'nykh s migreniami, sindrom Khortona i vegetalgiiami.

Patients with migraines, Horton syndrome and autonomic pains were subjected to immunological investigation that revealed different degrees of local and general immunity disorders: increase in blood serum IfA and salival IgAc concentrations. These changes are believed to be capable of serving as diagnostic and prognostic indices.

[Characteristics of cellular immunity in multiple sclerosis]. / Osobennosti kletochnogo immuniteta pri rasseiannom skleroze.

In 30 patients with definite multiple sclerosis a combined clinicoimmunological investigation was performed. The results of estimation of T-lymphocyte subpopulations by means of flow cytometry and monoclonal antibodies; of proliferative responses to PHA, PWM and Con A, to PHA with autoserum; of synthesis and reception of IL-2 containing material is discussed. A hypothesis of a cyclic course of the immunopathologic process is suggested (autoimmune and immunodeficiency stages).

[Study of cellular immunity and the opioid peptide system in patients with multiple sclerosis]. / Issledovanie kletochnogo immuniteta i sistemy opiatnykh peptidov u bol'nykh rassiannym sklerozom.

Twenty-five patients with chronic progressing multiple sclerosis were examined for the content of beta-endorphin in blood serum, supernatants of activated lymphocytes and CSF by RIA. At the same time the parameters of cellular immunity were appraised. Different relations were discovered between cellular immunity and the content of beta-endorphin in biological fluids which may play a material part in the pathogenesis of multiple sclerosis.

[Immunological aspects of trigeminal neuralgia]. / Immunologicheskie aspekty nevralgii troinichnogo nerva.

Immunological investigation was performed in patients with trigeminal neuralgies and painful myofascial temporomandibular joint dysfunction before and after treatment. The data suggest a connection between the state of humoral immunity and the peculiarities of pain syndrome in trigeminal neuralgia and clinically related prosopalgies that was most probably due to different mechanisms of realization of pain syndrome.

[Natural antitumor cytotoxicity of the whole blood of donors and cancer patients]. / Estestvennaia protivoopukholevaia tsitotoksichnost' tsel'noi krovi donorov i onkologicheskikh bol'nykh.

Natural antitumor resistance of cancer patients and healthy subjects was studied on the basis of whole blood natural cytotoxicity (WBNC) assay. A correlation between WBNC and mononuclear leukocyte cytotoxic activity in healthy donors was established (r = 0.912; p less than 0.001). WBNC levels in colonic, breast and gastric cancer patients were decreased as compared with healthy controls.

[The levels of the main classes of immunoglobulins in the serum and saliva of patients with trigeminal neuralgia]. / Issledovanie urovnei immunoglobulinov osnovnykh klassov v syvorotke i sliune bol'nykh s nevralgiei troinichnogo nerva.

The results of immunologic investigation of patients with trigeminal neuralgia evidence that this condition involves impairments of local and central humoral immunity parameters: increased serum IgA and salivary secretory IgA. Such measurements may become a diagnostic test.

[Basic cellular indices of immunity in patients with various pain syndromes of the face and head]. / Osnovnye pokazateli kletochnogo immuniteta u bol'nykh s razlichnymi bolevymi sindromami v oblasti litsa i golovy.

Studies of the major cell-mediated immunity parameters in patients with painful syndromes involving the face and neck have shown a reduction of the peripheral lymphocyte count.

Seasonal prevalence of MS disease activity.

OBJECTIVE: This observational cohort study investigated the seasonal prevalence of multiple sclerosis (MS) disease activity (likelihood and intensity), as reflected by new lesions from serial T2-weighted MRI, a sensitive marker of subclinical disease activity. METHODS: Disease activity was assessed from the appearance of new T2 lesions on 939 separate brain MRI examinations in 44 untreated patients with MS. Likelihood functions for MS disease activity were derived, accounting for the temporal uncertainty of new lesion occurrence, individual levels of disease activity, and uneven examination intervals. Both likelihood and intensity of disease activity were compared with the time of year (season) and regional climate data (temperature, solar radiation, precipitation) and among relapsing and progressive disease phenotypes. Contrast-enhancing lesions and attack counts were also compared for seasonal effects. RESULTS: Unlike contrast enhancement or attacks, new T2 activity revealed a likelihood 2-3 times higher in March-August than during the rest of the year, and correlated strongly with regional climate data, in particular solar radiation. In addition to the likelihood or prevalence, disease intensity was also elevated during the summer season. The elevated risk season appears to lessen for progressive MS and occur about 2 months earlier. CONCLUSION: This study documents evidence of a strong seasonal pattern in subclinical MS activity based on noncontrast brain MRI. The observed seasonality in MS disease activity has implications for trial design and therapy assessment. The observed activity pattern is suggestive of a modulating role of seasonally changing environmental factors or season-dependent metabolic activity.

Different conditions for generation of non-cytotoxic autorestricted CD4-CD8+ human suppressor T cells and allospecific cytotoxic T lymphocytes in one-way mixed lymphocyte cultures: the role of adherent mononuclear cells.

The purpose of the present study was to investigate the role of adherent mononuclear cells (AMC) in generation of suppressor T lymphocytes (T-Lph) in one-way allogeneic mixed lymphocyte cultures (MLC). Alloantigen-specific cytotoxic T-Lph were generated in MLC predominantly in the presence of stimulator AMC, but not responder AMC. The presence of responder AMC and the absence of stimulator AMC were optimal conditions for generation of non-cytotoxic (through the whole duration of MLC) suppressor T-Lph. These CD4-CD8+ suppressor T-Lph were allononspecific but autorestricted (with responders in test MLC).

The role of T lymphocytes in the immunotherapy of tumours.

The interactions of tumour cells with membrane molecules of T-cell subsets, as well as methods directed towards the enhancement of antitumour immunity, are reviewed in this paper. Special attention is given to the cytotoxic function of lymphokine-activated tumour-infiltrating lymphocytes, to tumour-specific suppressor T cells, and to various causes of decreased expression of histocompatibility antigens on the surface of tumour cells. The different mechanisms underlying selective antitumour immunodeficiencies and possible approaches to the correction of immunodeficiency, to the enhancement of tumour immunogenicity, and to specific immunotherapy are considered in more detail.