Search

Immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1) have recently revolutionized anti-cancer therapy and are nowadays used in different metastatic cancers. These treatments may induce immune-related adverse events which frequently involve the digestive tract and, to a less extent the liver. The tissular injuries, which are still poorly characterized from a morphological and physiopathological point of view, may lead on one side to the interruption of a life-saving treatment and on the other side to the development of severe complications, if not death. Therefore, it is crucial to diagnose as early as possible and treat these digestive and hepatic adverse effects in an optimal way. This article aims to describe the clinical and pathological presentations of digestive and hepatic adverse events induced by these immunotherapies., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Costimulatory molecules allow the full lymphocyte activation, whereas co-inhibitory molecules are negative counterparts that act as immune regulators, avoiding excessive response. In some context of chronic inflammation such as cancer, co-inhibitory immune checkpoint as CTLA-4, PD-1, Lag-3, Tim-3 can accumulate at the membrane of T cells leading to a state of anergy and therefore the loss of tumor growth control. Consequently, these immune checkpoints are considered as potential target in the treatment of cancer. Immunotherapy by anti-CTLA-4 and anti-PD-1/PD-L1 early demonstrated very good proof of efficacy in the setting of several cancers types, supporting the role of these molecules in tumor immune escape. The aim of this review is to summarize the pathophysiology of immune checkpoints and their therapeutic applications in cancer., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Most anticancer agents are thought to act through direct induction of tumoral, stromal and endothelial cell death by apoptosis or necrosis. In a 2008 issue of Bulletin de l'Académie Nationale de Médecine, we described an alternative (or complementary) theory whereby the immune system participates in the antitumoral effects of some chemotherapy or radiotherapy regimens by promoting an immunogenic cell death pathway. In particular, we showed the critical importance of two pre-mortem stressors that determine the immunogenicity of dying tumor cells. The first, an ER stress response culminating in calreticuline exposure at the tumor cell surface, is mandatory for the uptake and efficient phagocytosis of apoptotic bodies by dendritic cells. In the second, autophagy leads to the release of ATP by dying tumor cells, resulting in the recruitment of inflammatory phagocytes and antigen-presenting cells, and also triggering the inflammasome that causes IL-1beta release and CD8+ T cell polarization. The tumor microenvironment changes following chemotherapy, favoring sequential accumulation of a series of innate and cognate effectors that act in a coordinated fashion to promote tumor eradication. These findings will help to identify immune predictors of the response to conventional anticancer treatments and to design innovative combinatorial immunochemotherapy regimens.

The standard immunosuppression protocol after liver transplantation (LT) is based on an anticalcineurin (ACN) (tacrolimus or cyclosporine microemulsion) combined with mycophenolate and corticosteroids. Corticosteroids are usually stopped between 6 and 12 months after LT, except for patients whose transplantations were necessitated by autoimmune disease. ACN and mycophenolate must be monitored to verify the dose, with a residual blood assay (for tacrolimus), at 2hours (for cyclosporine microemulsion), or by a simplified area under the curve (for mycophenolate). The first-line treatment for rejection calls for increasing the dosage of tacrolimus (or switching to tacrolimus for patients treated with cyclosporine). Second-line treatment for refractory rejection is corticosteroid bolus (500-1000 mg of methylprednisolone, one to three times). Antibodies blocking the interleukin 2 receptors (basiliximab) or lymphocytes (thymoglobulin) make it possible to reduce the incidence of rejection, decrease corticosteroid doses rapidly and introduce ACN later on (useful in cases of kidney failure). The mTOR inhibitors (sirolimus and everolimus) have different side effects (hyperlipidemia, thrombocytopenia, and pulmonary, cutaneous, and articular events) than ACNs. The absence of any renal or vascular effect is interesting for patients with kidney failure, and the antiproliferative effect can be useful for patients transplanted because of cancer. The current objective of immunosuppression is to reduce the adverse effects (kidney failure, metabolic complications, cancer and infections, in particular, which reduce the survival of patients and grafts), and in the future, to promote the establishment of tolerance that ideally will allow the patient to stop prophylactic immunosuppressant treatment. New chemical agents, capable of acting on new and more specific pathways, are in phase II/III testing.

Unlabelled: AIM OF THIS WORK: Aziridines have been shown to possess marked immunotropic activity. In this study, the in vitro effects of a new aziridine, 2-hydroxy-methyl-1-(N-phtaloyltryptophyl) aziridine, were determined on the proliferative responses of human lymphocytes stimulated by mitogens and on interleukin (IL-2, IL-6) secretion., Material and Methods: Peripheral blood lymphocytes were isolated using differential centrifugation on a density gradient of Ficoll-Paque. They were cultured with or without mitogens (Concanavalin A and lipopolysaccharide), and with different concentrations of the aziridine. Proliferation was monitored by direct cell counts and confirmed by MTT [3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. After different incubations, IL-2 and IL-6 were determined by using commercially available Elisa kits., Results: The aziridine tested significantly stimulated the resting and mitogen T and B lymphocyte proliferation at concentrations between 1 microM and 1 mM, in a dose-dependent manner. It also increased IL-2 and IL-6 secretion., Conclusion: 2-hydroxy-methyl-1-(N-phtaloyltryptophyl) aziridine displayed immunomodulatory properties and is potentially immunostimulant. It could be used to provide non-specific cell-mediated immune responses.

Psoriasis is a frequent chronic disease with a typical cutaneous expression described as erythemato-squamous lesions, and sometimes, joint involvement. This disorder rarely causes death in patients, but often alters their quality of life. A better understanding of the pathophysiology of psoriasis has led to the development of new therapeutic options among which are treatments targeted on blocking T-cell activation. Thanks to these therapies we can offer the patients long lasting remission, albeit not a curative approach. The therapeutic approach towards psoriasis will be selected in a multidisciplinary spirit, and after considering the patient himself, his disease and his lifestyle.

Over the past decade, new biological therapies have been developed to treat systemic autoimmune diseases. These new treatments, which target various steps of the immune response, include: B lymphocyte (BL) inhibitors, such as anti-CD20 monoclonal antibodies, BlyS antagonists, and tolerogens that inhibit specific BLs that produce pathogenic antibodies; inhibitors of costimulation between antigen-presenting cells and T lymphocytes (TL), such as monoclonal antibodies against CD40 ligand and CTLA4-Ig (abatecept); TL antagonists, which can inhibit proliferation of autoreactive T cells; cytokine antagonists; chemokine and adhesin antagonists, which inhibit trafficking of immunocompetent cells to target organs. These new approaches are based on a deeper understanding of the autoimmune response.

Lymphocytes from patients treated with immunosuppressive agents were cultured for 48 hours either with or without concanavalin A. Phospholipid synthesis was then studied using 32p pulse-incorporation (5-hours pulses). Phosphatidylethanolamine synthesis was strongly decreased under immunosuppressive treatment: 1.5-fold in resting lymphocytes and 3- to 4-fold in concanavalin A-stimulated lymphocytes. Phosphatidylinositol synthesis also decreased about 2-fold in stimulated lymphocytes. These results indicate a loss of sensitivity of immunodeficient lymphocytes to the mitogen and an alteration of the G0 and the late G1 cell cycle phases. In parallel, but after a 72-hours incubation, lymphocytes were analysed by flow-cytofluorimetry with propidium iodide. Under concanavalin A-triggered stimulation, the entry into the S phase was much lower in immunodeficient lymphocytes as compared to standard. The characteristics of the G0-G1 population of lymphocytes were also modified. More importantly, after incubation in the culture medium in the absence of mitogen, we observed, among the immunodeficient lymphocytes, a high level of apoptotic cells, about 20 to 30%. This susceptibility to spontaneous apoptosis seems inherent to the status of immunodeficiency itself, whatever its origin. It may be related to the inhibition of phosphatidylethanolamine synthesis in the G0 phase.

Voltage-gated potassium channels (Kv channels) are ion channels, openings of which provide an outward flow of potassium ions repolarising the cell. In neurons, Kv channels play a crucial role in action potential repolarisation and in shaping neuronal excitability. In non-excitable cells, such as T lymphocytes, Kv channels and calcium-activated K+ channels (KCa channels) determine the driving force for Ca2+ entry. During T cell activation the calcium entry depolarises the cell and increases the cytosolic calcium concentration, which in return activates Kv and KCa channels. K+ channel opening repolarises the cell and drives the membrane potential to a negative voltage. The roles of Kv channels in nervous and immune systems have been investigated here by means of a rat experimental autoimmune disease of the central nervous system, the experimental autoimmune encephalomyelitis (EAE). EAE is characterised clinically by paralysis, and pathologically by inflammatory cell infiltrations into the brain and the spinal cord. Among the inflammatory cells, T lymphocytes play a major role. Hence, EAE can be adoptively transferred into syngenic animals by the injection of T cells reactive to myelin antigens. During adoptive-EAE, somato-sensory evoked potentials recorded along the spinal tracts decrease in amplitude and axonal propagation is disrupted. We have analysed the consequences of Kv channels blockade by peptidyl toxins on central nerve conduction, on T cell activation and on the time course of EAE. In rat optic nerves, Kv channels have been identified up from postnatal day 1. Their blockade by kaliotoxin (a scorpion toxin) or by dendrotoxin-I (a snake toxin) enlarges the compound action potentials, demonstrating the participation of Kv channels to spike repolarisation. This effect disappears at adult age due to the sequestration of Kv channels under the myelin, in the paranodal regions. During acute demyelination by lysophosphatidyl-choline, the surface area of compound action potential decreased probably because conduction block occurred. Demyelination unmasked Kv channels, which are again accessible to toxins. Their blockade by dendrotoxin-I or kaliotoxin favoured a slow delayed conduction suggesting that those Kv channel blockers exert a neurological benefit during demyelinating diseases. In a T-cell line reactive to myelin basic protein antigen, which is used to adoptively transfer experimental autoimmune encephalomyelitis, Kv1.3 channels are constitutively expressed. Their blockade leads to a pronounced reduction of the T cell proliferative response, cytokine production and Ca2+ influx. In the rat, blockade of Kv1.3 inhibits the delayed type hypersensitivity response to myelin basic protein prevents and treats adoptive experimental autoimmune encephalomyelitis. Blockade of Kv channels alone or in combination with KCa channels improves the symptoms of the disease. These results demonstrate that K+ channel blockers displaying high selectivity are potent immunosuppressive agents with beneficial symptomatic effects in experimental autoimmune encephalomyelitis.

Unlabelled: AN EFFICIENT AETIOLOGICAL TREATMENT: Specific immunotherapy or allergen vaccination currently constitutes the only aetiological treatment for allergic respiratory diseases and is more effective in children than in adults. Since its introduction in 1911, it has been much disparaged in spite of its effectiveness demonstrated in double blind placebo controlled studies, for the treatment of both allergic rhinoconjunctivitis and stable and controlled asthma., Mechanism of Action: Its mechanism of action varies depending on the type of allergen (venoms or pneumallergenes) and its administration route (subcutaneous or local) and recent studies indicate that the prevalent mechanism proceeds from a modification of the T cell response by an immunological deviation (stimulation of the Th0/Th1 lymphocytes) or T lymphocyte anergy (reduction in Th0/Th2) or both at same time. The IL-10, immunosuppressive cytokine secreted by the third population of T-Tr1 lymphocytes, would have an important role., In Practice: The indications for specific immunotherapy have been specified in international consensuses, and its practical administration must respect preconditions and a certain number of rules. Improvement in quality of allergenic extracts by standardization, better knowledge of its mechanism of action and the availability of local administration routes reinforce its place in the global therapeutic strategy for the management of respiratory allergies. A greater use of the sublingual route, together with biological and clinical research will allow the widening of its indications.

This work is devoted to the study of 22 dossiers of persons who have presented with clinical signs following taking a drug. The study was confined to patients in whom the symptoms had as origin a hypersensitivity (true or non-specific by histamine release). This study has allowed analysis of the value of several serological tests (measurement of leukotrienes, activation of basophils and T specific lymphocytes) in diagnosis and so to define the path to take that is best adapted to each case. The conclusion presents an agreement between the suspected diagnosis, after allergy enquiry and prick-tests, and the results of serological tests.

Aim: Since an increase in the generation of free radicals has been shown in diabetes, we were interested on its involvement in changes in microvascular permeability during diabetes., Methods: Intravital microscopy was used to study changes in microvascular permeability during diabetes. The extravasation of a fluorescent macromolecular tracer (FITC-Albumin) was measured for one hour and, after computer-aided image analysis, was expressed as variations of normalized grey levels (arbitrary units)., Results: The extravasation of the tracer was increased in diabetic rats. An intravenous bolus of probucol (an other anti-oxidant) inhibits this increase (fig. 1). The increase of the extravasation of the macromolecular tracer can also be inhibited when both superoxide dismutase, (which dismutates superoxide to hydrogen peroxide) and catalase (which reacts with hydrogen peroxide to form water and molecular oxygen) are administered simultaneously (fig 2). When administered separately, these enzymes failed to inhibit the increase of the extravasation of the macromolecular tracer. Five-week treatment of diabetic rats by pentoxifyllin, a drug which inhibits leukocyte activation did not have any effect on the increase of albumin extravasation (fig. 3a). In addition, no difference was found in adherent leukocytes or in the leukocyte rolling flux between diabetic and normoglycemic rats (fig. 3b)., Conclusion: Reactive oxygen species are responsible for an increase in microvascular permeability likely by leukocyte-independent mechanisms.

In vitro lymphocyte mitogenic stimulation by phytohemagglutinin A was determined in 20 subjects, comparing tritiated thymidine incorporation and nuclear propidium iodide fluorescence. Unexpectedly, no correlation could be found between the two measures. The pitfalls of both methods are reviewed and discussed. The inability to validate one test by the other restricts the interpretation of the results obtained with one method and prevents their generalization. Without another gold-standard at the present time, specific and limited method-dependent norms should be defined.

The aim of the work reported here was to evaluate the effects of an adjuvant treatment composed of an association of vitamins with an amino acid: beta-alanine, in cancer patients. This adjuvant therapy has been given to 17 subjects with a squamous cell carcinoma of upper aerodigestive tract treated by radiotherapy most cases were T3 (according to the TNM-UICC). After a 63 months follow-up, 7 patients are alive and sterilized, 4 are alive but no sterilized, 2 died, 4 were excluded from the study. Besides a physical comfort improved in all our patients, we note a restoration of the immune defenses, both humoral and cellular, disturbed by radiotherapy. At last, we note an increase of survival in the patients treated by the adjuvant therapy, compared to a reference population of patients with squamous cell carcinoma of upper aerodigestive tract. Despite the limits of the study, it was interesting to report the positive effects of the therapeutical association, vitamins and beta-alanine, after a combined radio-surgical treatment of patients with squamous cell carcinoma of upper aerodigestive tract.

Drug allergy has been studied by flow cytometry with the technique of cellular cycle, of which the principle is based on cellular activity. There were four groups of patients in the study: The first reference groups (A:20 patients) gave evaluation of phase S + G2-M without antigenic stimulation of monodisperse lymphocyte cultures. This was 4%. The second group (B:15 patients) presented a phase S + G2-M of 14.1% with PHA compared with the reference response significant at 2.5%. The third group (C) was composed of 5 wasp venom allergic subjects with cellular activity phase of 17.3% and 5 nonallergic subjects with an almost identical response of around 15%. The fourth group was 5 subjects who were allergic to drugs with clinical history that strongly indicated an allergy. The response to stimulation in these subjects was much greater for each of the drugs than that of a reference subject who was taking the same drug without problem. Wasp venom seems to behave like PHA, as a mitogen. In contrast, the subjects who were objectively and clinically sensitive to drugs, had an overall greater response to them than those shown by references. It is important to have a control for each drug used.

In schizophrenia, various modifications of the immune system have been reported. A decrease of interleukin-2 production by T lymphocytes and an increase of IL-2 receptors were observed by several authors. Not only cellular but humoral immunity seems to be modified: apart from the viral hypothesis, an auto-immune hypothesis holds that auto-antibodies may play a role in the biology of schizophrenia. Natural auto-antibodies, preexisting any antigenic stimulation, may also be involved, particularly in the response to neuroleptic drugs.

This study aims to test the lymphocyte response in normal subjects and patients who presented an anaphylactoid shock to various anaesthetic and muscle relaxant drugs, by using the lymphoblast transformation test (LTT). The results show that, although the LTT is a specific test, which can be carried out in vitro, it is badly adapted to the biological diagnosis of anaphylactic drug accidents on the whole, because of a possible non specific lymphoblastic transformation in controls or, on the contrary, of false negative results in anaphylaxis. As a consequence of this, and some comparative studies, the diagnosis of drug induced anaphylaxis must rely on skin tests, human basophil degranulation test (HBDT) and the Prausnitz-Küstner test.

The influence of different concentrations of ornithine phosphate and ornithine alpha ketoglutarate on pokeweed mitogen stimulation of immunoglobulin production in vitro was tested. Lymphocyte response of normal subjects was compared with lymphocyte response of undernourished patients. Our results indicate that IgG and IgM synthesis, under usual culture conditions of PWM stimulation, can be optimized in certain normal subjects by adding low concentrations (10(-5)M/l) of ornithine in culture medium. Moreover, in this culture system, the deficit observed in undernourished patients can be partially corrected by adding physiological (close to serum) concentrations of ornithine. More data are necessary in order to find out in vivo the effect of administration of ornithine on the immune system which is influenced by many (specially hormonal) factors.

The alpha2 H globulin, a glycoferroprotein, has been found in the serum of patients with malignant diseases. Its level varies according to the evolution of the disease. The activity of this protein has been studied on the normal lymphocytes cultivated in presence of phytohemagglutinin. This study has showed that 5 mug/ml of alpha2 H globulin can inhibit the blastic transformation. The inhibitory effect is proportional to the amount of alpha2 H globulin added as judged by the tritiated thymidin incorporation. The study of morphological aspects of the lymphocytes shows that alpha2 H globulin acts upon the synthesis of the cytoplasmic proteins.

Dysimmune lymphadenopathies during carbamazepine treatment. A report of two cases. We report on two cases of dysimmune lymphadenopathies with histological aspect of angio immunoblastic lymphadenopathy (AIL) developing after administration of carbamazepine. Clinical manifestations consisted of fever, erythroderma, generalized pruritus, facial edema, lymphadenopathy, liver enlargement. The two patients had anemia, hypogammaglobulinemia, impaired liver function and a negative Coomb's test. Lymphocyte stimulation test with carbamazepine in vitro was positive in both cases. Lymph node biopsy disclosed the angioimmunoblastic proliferation characteristic of AIL. After discontinuing carbamazepine, a complete remission was obtained.

The action of isoprinosine on lymphocytes stimulated by optimal or suboptimal concentrations of polyclonal mitogens (ConA and PWM) was studied in 3, 5 and 7-days cultures. In some experiments, varying concentrations of isoprinosine were added to lymphocyte cultures at variuos times. Isoprinosine exerted no effect on non stimulated cells but enhanced the proliferative response in the presence of mitogens. The optimal response was obtained with a dose of 1 000 micrograms (/10(6) cells) of isoprinosine and on the 5th day in the cultures stimulated by ConA or PWM, but an enhancing effect could still be detected on the 7th day of culture. The effect seems stronger when isoprinosine is introduced earlier in the course of the cultures. Preliminary experiments suggest that isoprinosine increase the proliferation of both T and B cells and that its activity on B cells could be due to the potentiating action of helper T cells.

The authors describe a new technique of biological quantitative determination of the somatomedin activity in human plasma by incorporation of tritiated thymidine into human lymphocytes treated by specific activator. This method is more simple, faster, and more sensitive than the biological assays described so far.

Mild periodate treatment is mitogenic for T lymphocytes. With murine spleen cells periodate oxidation is effective between C8 and C9 on sialyl acid residues. With human blood lymphocytes this oxidation occurs between C7 and C8 of these residues. In vitro immune response is inhibited by periodate treatment. Activation of an immunosuppressive T lymphocyte population is obtained. Similar results are performed with human blood lymphocytes.

The present work studies the effect of the placental hormones HCG and HCS on cellular immunity in vitro. These two hormones used in identical or greater concentrations than found in circulating blood inhibit lymphoblastic changes in mixed cultures of lymphocytes. It is possible that HCG and HCS have the same inhibiting effect in vivo on immunity by cellular mediation in the pregnant woman. This inhibition could be of the greatest importance at the surface of the trophoblast where their concentration is probably raised, and where contact between fetal antigens and maternal blood also takes place.

Rabbits issued from a closed colony which was genetically homogenous were used to investigate the capacity of streptolysin O and streptococcal M-protein to induce both cellular immune and autoimmune responses with respect to autologous cardiac tissue. The presence of immune response was indicated by positive responses of two tests of cellular immunity: blastogenesis of splenic T lymphocytes and inhibition of splenic macrophage migration. By thing into account that a nonspecific direct effect is produced by certain components of the streptococcal cell wall (lipoteichoic acid) but not by streptolysin O or M-protein on splenic lymphocytes, and according to the data on the modifications of lymphocyte populations during the autoimmune processes, it was possible to presume that anti-cardiac autoimmunity was as much due to a modification of cardiac tissue towards "non-self" status caused by experimental inductive factors as to he presence of a functional imbalance of the immunomodulatory lymphocyte system due to a predominance of auxiliary T lymphocytes.

Inhibition of circulating antibody production by steroids has been repeatedly shown in steroid-sensitive animals such as mice or rabbits. It is well known that after a single injection of 5 mg of cortisone acetate, mouse spleen cells loose their ability to be transformed by B cell mitogens such as lipopolysaccharides or Nocardia water soluble mitogen. Therefore it was of interest to study in the rabbit the influence of cortisone on the reactivity of spleen cells to a B cell mitogen (blast transformation and polyclonal strimulation) and their ability to be cytotoxic in the antibody-dependent cell-mediated cytotoxicity assay. Our data demonstrate that the cells which mediate such a cytotoxicity are cortisone-resistant whereas the B lymphocytes--which can be transformed and polyclonally activated by these mitogens--are sensitive to cortisone treatment.

Mild oxidation of mouse spleen cells by sodium periodate induces blastogenesis. Concomitantly, the in vitro response of these cells to sheep red blood cells is inhibited. Exposure of spleen cells to sodium borohydride following periodate treatment reduces blastogenesis and restores the immune response.

Most of the body's histamine is stored in the granules of tissue mast cells and blood basophils. Free histamine regulates gastric acid secretion, acts as a neurotransmitter in the central nervous system and is a potent mediator of allergic inflammation. Histamine may also exert negative influences on human inflammatory cells in vitro. Evidence is provided here that the administration of histamine in man may depress the chemotactic response of the PMNs and spontaneous or pulsed T-lymphocyte proliferation. Thus, histamine has indeed, in man, some antiinflammatory actions which may explain the increased sensitivity of asthmatics to respiratory infections.

Some vegetable extract have haemagglutinating activity and are able to transform lymphocytes in culture. The comparative activities of lectin from Pisum sativum and other lectins already used (phytohaere shown. This lectin can be isolated in a highly purified form which is described. Purification of the human blood lymphocytes is obtained through nylon columns and measurement of transformation and proliferation by means of 3 H thymidine incorporation. Normal lymphocyte stimulation can be obtained within a range of concentrations of stimulants can be obtained within a range of concentrations of stimulants and the curves with PHA or lectin from Pisum show a peak of blastogenic activity. The activity of lectin from Pisum sativum was studied in this way on blood cultures of 8 chronic lymphocytic leukaemias and 5 immunodeficient patients. It appeared that lectin from Pisum and PHA have the same activity. The response of human peripheral lymphocytes to various mitogenic agents in vitro does not point out the proliferative abnormal cell and may not be used to detect different populations of human lymphocytes.