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Indoleamine 2,3-dioxygenase (IDO) is one of the initial rate-limiting enzymes of the kynurenine pathway (KP), which causes immune suppression and induction of T cell anergy. It is associated with the imbalance of immune homeostasis in numerous diseases including cancer, chronic viral infection, allergy, and autoimmune diseases. Recently, IDO has extended its role to liver field. In this review, we summarize the dysregulation and potentials of IDO in the emerging field of liver injuries, as well as current challenges for IDO targets. In particular, we discuss unexpected conclusions against previous work published. IDO is induced by pro-inflammatory cytokines in liver dysfunction and exerts an immunosuppressive effect, whereas the improvement of liver injury may require consideration of multiple factors besides IDO.

Betsch and Sprengholz (1) address the issue of supposedly increased severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) testing frequency in allergic patients during the pollen season because of the misinterpreted similar symptoms of allergic and viral rhinitis. We (2) had previously reported a significant and positive relationship between SARS-CoV-2 infections and airborne pollen concentrations in early Spring 2020, with potential mechanism of a previously discovered immunosuppressive effect of pollen on the nasal epithelium (3), possibly more pronounced in allergics due to a known intrinsic reduction of antiviral type I and type III interferon responses (4, 5). In this study (1), several parameters may have influenced the conclusion drawn. First, “allergic” participants were identified based on self-reported “hay fever” (yes/no) without further stratification for the type of pollen allergy; it … [↵][1]1To whom correspondence may be addressed. Email: thanos.damialis{at}tum.de. [1]: #xref-corresp-1-1

Tumor xenograft models can create a high capacity to study human tumors and discover efficient therapeutic approaches. Here, we aimed to develop the gamma-radiated immunosuppressed (GIS) mice as a new kind of tumor xenograft model for biomedical studies. First, 144 mice were divided into the control and treated groups exposed by a medical Cobalt-60 apparatus in 3, 4, and 5 Gy based on the system outputs. Then, 144 BALB/c mice were divided into four groups; healthy, xenograft, radiation, and radiation + xenograft groups. The animals in the xenograft and radiation + xenograft groups have subcutaneously received 3 × 106 MCF-7 cells 24 h post-radiation. On 3, 7, 14, and 21 days after cell injection, the animals were sacrificed. Then, the blood samples and the spleen and tumor tissues were removed for the cellular and molecular analyses. The whole-body gamma radiation had a high immunosuppressive effect on the BALB/c mice from 1 to 21 days post-radiation. The macroscopic and histopathological observations have proved that the created clusters' tumor structure resulted in the xenograft breast tumor. There was a significant increase in tumor size after cell injection until the end of the study. Except for Treg, the spleen level of CD4, CD8, CD19, and Ly6G was significantly decreased in Xen + Rad compared to the Xen alone group on 3 and 7 days. Unlike IL-4 and IL-10, the spleen level of TGF-β, INF-γ, IL-12, and IL-17 was considerably decreased in the Xen + Rad than the Xen alone group on 3 and 7 days. The spleen expressions of the VEGF, Ki67, and Bax/Bcl-2 ratio were dramatically increased in the Xen + Rad group compared to the Xen alone on 3, 7, 14, and 21 days. Our results could confirm a new tumor xenograft model via an efficient immune-suppressive potential of the whole-body gamma radiation in mice.

Catgut implantation at acupoints (CIA) has a long history as a medical treatment for a wide variety of diseases, including autoimmune diseases. However, the effect and mechanism of this therapy in autoimmune uveitis is still largely unknown. The aim of this study was to explore the immunity-inhibitory effect of CIA in an experimental autoimmune uveitis (EAU) rat model. EAU was established in Lewis rats by the injection of IRBP1177–1191 peptide. The rats were randomly divided into control and CIA groups. Phenotypic and histological assessments were performed days 9, 13, 18, 23 post-immunization. The percentage of Th1 and Th17 lymphocytes isolated from lymph nodes were determined by flow cytometry. The expression of IL-17 and IFN-γ was detected by real-time quantitative PCR and enzyme-linked immunosorbent assay (ELISA). In the CIA group, delayed mild inflammation was observed. Pathological investigation found alleviated infiltration of lymphocytes and ocular damage. Flow cytometry showed significantly decreased Th17 lymphocytes at day 9, 13, and 18 post-immunization (P

Supplemental Digital Content is available in the text., The efficacy of adoptive cellular immunotherapy against cancer cells is limited due to the presence of immunosuppressive cells within the solid tumor microenvironment. The upregulation of certain coinhibitory receptors may lead to exhaustion of the immune effector cells. T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immune inhibitory receptor expressed by regulatory T cells and activated T cells and natural killer cells. The aim of this study was to determine the immunosuppressive effects of CD155/TIGIT signaling on CD8+ T cells of adoptive cellular immunotherapy in hepatocellular carcinoma (HCC). Our studies found that CD155 was overexpressed in HCC, and CD155hi HCC cells upregulated TIGIT on CD8+ T cells, which decreased the secretion of interferon-γ, tumor necrosis factor-α, and interleukin-17A and increased that of interleukin-10 from the effector cells. However, TIGIT blockade or CD155-knockdown reversed the inhibitory effect of HCC cells on CD8+ T-cell effector function. These results indicate that TIGIT can exert an immunosuppressive effect on CD8 T cells by modulating cytokine production through CD155, and is a promising target to optimize adoptive cellular immunotherapy against HCC.

Anti-thymocyte globulin (ATG) is a polyclonal antiserum introduced into clinical medicine more than 30 years ago. It induces a broad non-specific immunosuppression. In haematology, standard indications are severe aplastic anaemia and prophylaxis and treatment of graft-versus-host disease (GVHD) (after allogeneic transplantation). For aplastic anaemia, ATG from horses has been found to be superior to ATG from rabbits. In the situation of allogeneic transplantation, ATG lessens the risk of chronic GVHD but may not improve survival. There is current controversy regarding which patients benefit most from ATG and what the ideal dosage is. It is likely that in the coming years a more specific immunosuppressive will be developed that will minimize GVHD while maintaining the graft-versus-malignancy effect.

It has been demonstrated that mesenchymal stem cells (MSCs) have potent immunosuppressive capacities. But it is controversial whether differentiated mature stromal cells (SCs) share the immunosuppressive capacities. A previous study examined the ability of SCs from different human tissue sites to inhibit the proliferation of lymphocytes. The results are all positive but the mechanism isn't clear, and few mouse data have been published on this topic. Using an efficient mixed cell culture assay, our in vitro data show that the anti-proliferative ability of murine MSCs on lymphocytes is shared by mature murine SCs, i.e. chondrocytes and fibroblasts. Though conflicting results have been published, our results suggest that nitric oxide and IFN-γ are critical to the immunosuppressive effect. We also demonstrate that murine MSCs cultivated in chondrogenic differentiation medium still possess the anti-proliferative capacities on lymphocytes in vitro.

This article discusses the need to implement effective methods for monitoring immune status and rehabilitation of patients after kidney transplantation. Induction of immunological tolerance which allows minimizing or even completely canceling supportive immunosuppressive therapy is one of the key tasks in the field of organ transplantation. Regulatory T-cells (TREGs) play an important role in maintaining immunological homeostasis, including limiting kidney transplant rejection, and potentially contribute to the development of immunological tolerance. At the same time, for the introduction of TREG therapy into clinical practice, it is necessary to overcome a number of unsolved problems, such as induction and cultivation of a sufficient number of TREG cells for therapeutic action as well as reducing the risks associated with TREG conversion to effector lymphocytes or an undesirable non-specific immunosuppressive effect. This review examines both the impact of common post-transplant pharmacological immunosuppression approaches on TREGs and the therapeutic potential of TREG cell cultures in prevention of kidney transplant rejection. The questions of ex vivo TREG manufacturing process and possible threats of applying cell technologies in this branch of transplantology were considered.Индукция иммунологической толерантности, позволяющей минимизировать или полностью отменить поддерживающую иммуносупрессивную терапию, — одна из ключевых задач в области трансплантации органов. Т-регуляторные клетки (Трег) играют важную роль в поддержании иммунологического гомеостаза, в том числе в ограничении отторжения трансплантата почки, и потенциально способствуют развитию иммунологической толерантности. В то же время, чтобы внедрить клеточную терапию Трег в клиническую практику, необходимо преодолеть ряд нерешенных проблем, таких как индукция и культивирование достаточного количества Трег для терапевтического действия, и снизить риски, связанные с конверсией Трег в эффекторные лимфоциты либо с нежелательным неспецифическим иммуносупрессивным эффектом. Рассмотрены влияние распространенных методов посттрансплантационной фармакологической иммуносупрессии на Трег, возможности терапевтического применения клеточных культур Трег для предотвращения отторжения трансплантата почки, а также технология получения ex vivo Трег и риск применения клеточных технологий в данной области трансплантологии.

Mesenchymal stromal cells derived from amnion (AM-MSCs) can be easily obtained in large quantity by less invasive method in comparison to bone marrow-derived MSCs (BM-MSCs). However, the biological and immunosuppressive properties of AM-MSCs are still poorly characterized. Previous studies demonstrated that BM-MSCs expressed indoleamine 2,3-dioxygenase (IDO) to suppress T-cell responses. This study was designed to address whether IDO contributes to the immunosuppressive function of AM-MSCs. MSCs isolated from amnion were cultured in complete medium similar to BM-MSCs. After culture, AM-MSCs exhibited spindle shape morphology and expressed MSC markers similar to that of BM-MSCs. In addition, AM-MSCs were able to differentiate into adipocytes and osteoblasts. Fascinatingly, AM-MSCs and BM-MSCs exhibited comparable degree of immunosuppressive effect when they were co-cultured with activated T-cells. In addition, IDO secreted by AM-MSCs was responsible for induction of immunosuppressive activities in the same manner as BM-MSCs. Taken together; the results of the present study demonstrate that while AM-MSCs and BM-MSCs show similar immunosuppressive effect, AM-MSCs may have additional advantage over the BM-MSCs in terms of availability. Therefore, AM-MSCs might be considered a potential source for therapeutic applications especially for treatment of immune related diseases., Highlights • Cells isolated from amnion possess MSC characteristics. • AM-MSCs displayed a similar degree of immunosuppression to that of BM-MSCs. • Immunosuppression of AM-MSCs relies on a highly complex mechanism. • The key immunosuppressive mechanism of AM-MSCs centers on the IFNγ-mediated IDO expression.

We described the development of multiple melanocytic nevi within long-standing MF patches in four young patients. Mycosis fungoides (MF) patches are characterized by a regulatory-like cytokine profile leading to local immune suppression. The proliferation of nevomelanocytes is regulated by cellular senescence mechanisms mediated by immune system. The immunosuppressive effect of MF infiltrate in conjunction with the systemic effect of treatments may play a specific role in the nevomelanogenesis of the patients herein described.

Glucocorticoids are hormones that regulate several functions in living organisms and synthetic glucocorticoids are the most powerful anti-inflammatory pharmacological tool that is currently available. Although glucocorticoids have an immunosuppressive effect on immune cells, they exert multiple and sometimes contradictory effects on neutrophils. From being extremely sensitive to the anti-inflammatory effects of glucocorticoids to resisting glucocorticoid-induced apoptosis, neutrophils are proving to be more complex than they were earlier thought to be. The aim of this review is to explain these complex pathways by which neutrophils respond to endogenous or to exogenous glucocorticoids, both under physiological and pathological conditions.

A 66-year-old woman who had rheumatoid arthritis and underwent a long-term treatment with methotrexate and etanercept developed Pneumocystis jirovecii pneumonia (PCP) 3 months after iguratimod add-on. Although most rheumatologists might have the impression that iguratimod has less toxicity and immunosuppressive effect compared with methotrexate and biologic disease-modifying antirheumatic drugs, this case suggests that iguratimod may increase the risk of PCP, especially in combination with other drugs.

In recent years there has been considerable effort to understand the interaction of nanomaterials with the skin. In this study we use an in vivo mouse model of allergic contact dermatitis to investigate how nanoparticles (NPs) may alter allergic responses in skin. We investigate a variety of NPs that vary in size, charge and composition. Results show that small (

The standard therapy for some autoimmune diseases consists of a combination of corticosteroids and thiopurines. In non-responders to thiopurine drugs, the measurement of the metabolites of azathioprine, 6-thioguanine, and 6-methylmercaptopurine, can be a useful tool. The measurement has been used during the treatment of inflammatory bowel diseases and, less commonly, in autoimmune hepatitis. Many patients preferentially metabolize thiopurines to 6-methylmercaptopurine (6-MMP), which is potentially hepatotoxic, instead of 6-thioguanine, the active immunosuppressive metabolite. The addition of allopurinol shifts the metabolism of thiopurine towards 6-thioguanine, improving the immunosuppressive effect. We present the case of a 51-year-old female with autoimmune hepatitis who had a biochemical response after azathioprine and prednisone treatment without histological remission, and who preferentially shunted to 6-MMP. After the addition of allopurinol, the patient’s 6-thioguanine levels increased, and she reached histological remission with a reduction of 67% of the original dose of azathioprine. The patient did not develop clinical manifestations as a consequence of her increased immunosuppressive state. We also review the relevant literature related to this issue. In conclusion, the addition of allopurinol to thiopurine seems to be an option for those patients who do not reach histological remission and who have a skewed thiopurine metabolite profile.

Pasaulyje yra net dvidešimt aštuonios infekcinės ligos, nuo kurių efektyviausia apsaugos priemonė yra skiepijimas [1]. Lietuvoje Nacionalinė imunoprofilaktikos programa įgyvendinama nuo 1992 m., vaikų profilaktinių skiepijimų kalendorius Lietuvoje patvirtintas 2007 m. Šiuo metu didžiausias dėmesys skiriamas suaugusiųjų skiepijimo rekomendacijų kūrimui ir patvirtinimui. Suaugusiųjų skiepijimo rekomendacijos apima visų suaugusiųjų skiepijimus ir suaugusiųjų, priklausančių tam tikroms rizikos grupėms, skiepijimus [2]. Šiuo metu vienas svarbiausių ir sudėtingiausių uždavinių – rizikos grupių pacientų skiepijimo rekomendacijų sukūrimas, apimantis rizikos grupių identifikavimą, vakcinų, kuriomis galėtų būti taikoma imunoprofilaktika, parinkimas, rekomendacijų, kada imunoprofilaktika turėtų būti taikoma, patvirtinimas, bei naudos-rizikos santykio įvertinimas. Viena sudėtingiausių identifikuojamų rizikos grupių – autoimuninėmis uždegiminėmis reumatinėmis ligomis (AURL) sergantys žmonės, kurie turi padidėjusią riziką sirgti infekcinėmis ligomis, jų eiga dažnai yra sunkesnė, komplikacijos dažnesnės, todėl tai lemia padidėjusį pacientų sergamumą ir mirtingumą. Nustatyta, kad reumatoidiniu artritu (RA) sergantys pacientai turi du kartus didesnę riziką sirgti sunkiomis infekcinėmis ligomis, o tarp sergančių sistemine raudonaja vilklige (SRV) pacientų apie 25 proc. mirties atvejų yra sąlygoti infekcinių ligų [3,4]. Skiriamos kelios padidėjusio imlumo infekcinėms ligoms priežastys: imunodeficitinė būklė dėl autoimuninio uždegiminio proceso, skiriamo gydymo ligos eigą modifikuojančiais medikamentais (LMV), slopinančiais imuninę sistemą, gydymo biologine terapija, ilgalaikio gliukokortikosteroidų vartojimo, gretutinių ligų kiekio, organų ir organų sistemų pažeidimo. Būtina paminėti, jog vakcinos efektyvumas šios rizikos grupės pacientams gali būti sumažėjęs ar net sukelti ligos paūmėjimus.

Allograft rejection continues to be the biggest hurdle in successful organ transplantation. This application (WO2012106634A1) claims the use of blocking CD200 antibody to achieve long-term survival of allografts. CD200 is the ligand for the inhibitory CD200 receptor (CD200R).In mouse allograft transplantation models, a blocking CD200 antibody was used to improve renal and cardiac graft survival. Similarly, in humans a blocking CD200 antibody would be administered to the organ recipient in combination with currently used immunosuppressive drugs or even as a monotherapy.In the presented animal experiments, anti-CD200 antibody application to the allograft recipient decreases SHIP expression in splenocytes. This is accompanied by a significant increase in renal or cardiac graft survival. Furthermore, anti-CD200 antibody has an immunosuppressive effect manifested by an increased production of T regulatory and myeloid-derived suppressor cells (MDSC) and a decrease in B cells and activated T cells.In vivo administration of anti-CD200 antibody has a remarkable positive effect on allograft survival. However, since this finding contradicts all previous effects of in vivo CD200 manipulation described in transplantation settings, future development of this invention is highly uncertain.

Objective: To assess the immunosuppressive effect of R-CHOP in patients with B-cell lymphoma at 2 years. Methods: Parameters of humoral and cell-mediated immunity were assessed in 89 patients with diffuse large B-cell lymphoma or follicular lymphoma before and after 6-8 cycles of R-CHOP-14 or R-CHOP-21 regimen. Results: Data on pre- and posttreatment serum IgG (sIgG) levels were available for all 89 patients, while the corresponding data on serum CD20+, CD3+, CD4+, and CD8+ lymphocyte counts were available in only 43. Median sIgG levels significantly decreased from 1,221 mg/dl (baseline) to 733 mg/dl (after chemotherapy) (p < 0.001). Although CD20+ and CD4+ cell counts decreased (p < 0.001), no significant effect of chemotherapy on CD3+ and CD8+ cell counts was observed. CD20+ cell counts were restored to baseline levels at the 12-month follow-up. sIgG levels and CD4+ cell counts were not completely restored at 24 months, indicating a sustained immunosuppressive effect of R-CHOP in these patients. The incidence of infections over the 2-year period was 16.3-23.6%. Conclusion: The immunosuppressive effect of R-CHOP in newly diagnosed cases of B-cell lymphoma tends to persist for >2 years, although sIgG levels were restored more quickly than CD4+ cell counts.

The immunomodulatory effect of the probiotic (Saccharomyces cerevisiae) on Trypanosoma brucei brucei infected rats was studied. Thirty (30) rats divided into five groups (A-E) of 6 rats each were used for the study. Groups A, B and C rats received feed supplemented with S. cerevisiae (at 0.08, 0.12 and 0.16/kg of feed, respectively) for the duration of the study. Groups D and E diets were not supplemented. All the rats in the 5 groups were immunized with 0.3 ml of 10% sheep red blood cells (SRBC) at day 7 pre-supplementation, and booster doses given every 14 days thereafter. On day 28 post supplementation (PS), rats of groups A-D were infected with 1 × 10(6) of T. brucei brucei intraperitoneally. Supplementation resulted in increases in antibody titres to SRBC which later declined following T. brucei brucei infection, but remained higher than the pre supplementation titres. At termination of the study (i.e. day 49 PS) supplemented groups had significantly (p0.05) higher antibody titres than either the infected or the non infected controls. The total and differential leucocyte counts followed a similar pattern with initial increases in counts following supplementation followed by reductions after T. brucei brucei infection. Supplementation also resulted in decline in parasitaemia with significant difference between the supplemented groups and the un-supplemented controls on day 42 post infection. The results are indication that probiotics can be used to ameliorate the immunosuppressive effect of T. brucei brucei infections.

Contains fulltext : 138866.pdf (Publisher’s version ) (Open Access) A study in mice implicates a cholesterol derivative in damping down the inflammatory response mediated by interleukin-1beta and explaining, at least in part, the immunosuppressive effect of type I interferon, which is used in the treatment of multiple sclerosis.

Days ago, the Nobel Prize in Physiology or Medicine 2018 was awarded jointly to James P. Allison and Tasuku Honjo “for their discovery of cancer therapy by inhibition of negative immune regulation„. This news has increased the attention on immunotoxicity and immune evasion mechanisms, which are once again hot research topics. Actually, increasing lines of evidence show that trichothecene mycotoxins have a strong immunosuppressive effect. These mycotoxins suppress the host immunity and make them more sensitive to the infection of pathogens, including bacteria and viruses. However, the underlying mechanism(s) in this context is still poorly understood. Interestingly, recent work showed that an immune evasion mechanism might be involved in trichothecene immunotoxicity. In this work, we discuss the potential immune evasion mechanism in trichothecene immunotoxicity. More importantly, under these circumstances, we are pleased to compile a Special Issue entitled “Biochemistry, Molecular Biology, and Toxicology of Natural and Synthetic Toxins„ for the International Journal of Molecular Sciences (IJMS). Researchers are encouraged to share their latest interesting findings with the readers of IJMS.

Resume Influence de L'«Imarun» sur le thymus et la bourse de Fabricius chez des poules On a examine l'influence d'un traitement a l' «Imuran» sur les organes lymphatiques centraux (thymus et bourse de Fabricius) chez des poules et sur la reponse immunitaire contre un antigene E. coli. Les resultats ont montre de nets changements dans le metabolisme des proteines (proteines totales, taux en ARN et en ADN) qui sont plus etendus dans la bourse de Fabricius que dans le thymus. L' «Imuran» active les glandes surrenales, ce qui se manifest par une chute du taux de l'acide ascorbique. Un traitement de longue duree avec cette preparation presente un effet immuno-suppresseur qui determine une reponse imlunitaire de defense diminued vis-a-vis d'un antigene E. coli. Summary The effect of Imuran on the Thymus and Bursa of Fabricius in Chickens The effect of Imuran treatment on the central lymphatic organs (thymus and bursa of Fabricius) in chickens as well as on the immune response to E. coli antigen were studied. Data show important changes in the protein metabolism (total protein, RNA and DNA content) which are more pronounced in the bursa of Fabricius than in the thymus. The drug induced in activation of the adrenals suggested by a decrease of their ascorbic acid content. A prolonged treatment with the drug had also an immunosuppressive effect expressed by the lowering of the immuno-biological capacity of chicken tested against E. coli antigen. Zusammenfassung Die Auswirkungen von Imuran auf den Thymus und die Vursa Fabricus von Huhnern Untersucht wurde der Einflus einer Imuran-Behandlung auf die zentrajen lymphatischen Organe (Thymus und Bursa Fabricius) bei Huhnern und die Immunantwort gegen E. coli Antigen. Es traten Veranderungen im Protein Metabolismus (Gesamtprotein, RNS und DNS Gehalt) auf, die in der Bursa deutlicher ausgepragt sind als im Thymus. Imuran aktiviert die Nebennieren, was sich durch einen Abfall des Ascorbin Saure Gehaltes feststellen lies. Eine Langzeit-Behandlung mit diesem Praparat fuhrte zu einem Immun-suppressiven Effekt, der sich in einer verminderten immunologischen Abwehrkapazitat gegenuber E. coli Antigen aus-druckt. Resumen Los efectos de Imuran sobre el timo y la bolsa de Fabricio en las gallinas Se examino el influjo de un tratamiento con Imuran sobre los organos linfaticos centrales (timo y bolsa de Fabricio) en gallinas y la respuesta inmunologica frente a antigeno de E. coli. Aparecieron modificaciones en el metabolismo proteico (proteina total, contenido en ARN y ADN), las cuales eran mas manifiestas en la bolsa que en el timo. Imuran activa las anterrenales, lo cual se pudo establecer mediante un descenso del contenido en acido ascorbico. Un tratamiento a plazo largo con esta especialidad conducia a un efecto inmunosupresivo, que se expresa en una capacidad reducida de defensa inmunologica frente al antigeno de E. coli.

To probe into immunosuppressive effect and cell cycle arrest effect of different dose of FTY720.we study immunosuppressive effect and cell cycle arrest effect of different dose of FTY720 and time and dose dependence of FTY720 with control and random method in vivo, respectively.(i) survival time of graft in rat cardiac transplantation model is prolonged in group treated with FTY720. It is longer in group treated with FTY720 10 mg/kg than that in group treated with FTY720 2 mg/kg. (ii) The mean sum of lymphocyte in periphery blood decrease obviously 2 h after administration, reaches its peak 4 h after administration, and then maintain at low level stably. The mean sum of lymphocyte shows a linear relationship with dose of FTY720 and decrease with increasing of dose of FTY720. (iii) The percent of cell in G1-G0 increased in group treated with FTY720, not only in thymus but also in lymph node; this is more prevalent in the group treated with FTY720 10 mg/kg than that in group treated with FTY720 2 mg/kg. Similarly, the percent of cell in S and G2-M decreased in group treated with FTY720, not only in thymus but also in lymph node, and this decrease is more associated with group treated with FTY720 10 mg/kg than the one treated with FTY720 2 mg/kg.FTY720 is an effective immunosuppressant and immunosuppressive effect of FTY720 show a tendency of time and dose dependent. Effect of cell cycle arrest of FTY720 is related to dose of this new immunosuppressant.

Experiments with rats showed that ionophoretic delivery of alpha1-adrenoblocker into the skin does not change effects of superficial and deep cooling and did not affect the amount of the antibody producing cells in spleen and a blood level of circulating antibodies under thermoneutral conditions. Meanwhile alpha1-adrenoblocker abolished inhibitory effect of fast deep cooling on antigen-binding properties of spleen cells and peritoneal extraction cells, and markedly stimulated it. beta-Adrenoblocker had no effect on immunogenesis under thermoneutral conditions and changes modulating effect of cooling on immune response. It abolished immunosuppressive effect of deep cooling and enhanced the stimulating effect of superficial cooling. It was true both for antigen-binding processes in spleen and peritoneal cavity and for antibody production in spleen. The results obtained indicate an involvement of alpha1--and beta-adrenoreceptors in immune response inhibition after deep cooling. Adrenoblockers effects on various immune competent cells are ambiguous and depend on temperature.

It has been suggested that elderly people are more susceptible to infectious diseases because of immunosenescence. The well-described transient immunosuppressive effect of exercise may increase health risks in such populations. Although resistance training has been recommended to older individuals, little is known regarding its acute effects on immune indexes. This study examined the acute effects of resistance exercise sessions performed at different intensities (50 vs. 80% of one-repetition maximum [1RM]) on salivary immunoglobulin A (IgA), total leukocytes, lymphocytes and their subsets, and the cortisol levels of older women. Fifteen physically independent elderly women (mean age = 67.5 +/- 3.9 years) underwent, in a randomized manner, two experimental sessions comprising resistance exercise for the major muscular groups or one control session without exercise. Session 1 consisted of two sets of 13 repetitions at 50% 1RM, whereas session 2 consisted of two sets of eight repetitions at 80% 1RM. Blood and saliva samples were collected at rest, immediately after, and at 3 and 48 hours after the completion of the sessions. Blood cortisol, total leukocytes, lymphocytes and their subpopulations, and salivary IgA were measured by standard techniques. Overall, resistance exercise sessions failed to provoke significant decline on the examined immune function indexes. Instead, resistance exercise sessions induced significant elevation in salivary IgA levels, but this was not observed after the control session. Also, experimental sessions did not induce significant elevations in blood cortisol. It was concluded that resistance exercise sessions performed at 50 or 80% of 1RM do not present suppressive effects on the studied immune parameters. Conversely, a transient elevation was observed in salivary IgA levels, which requires support in future investigations. Taken together, the observed results suggest that elderly women can engage in resistance training programs without negative acute effects on the studied parameters of the immune system.

Prodigiosin was isolated from marine bacteria Hahella chejuensis which has been recently discov- ered from Marado, Cheju Island, Republic of Korea. Immunosuppressive properties have been reported for pro- digiosin members such as undecylprodigiosin, metacycloprodigiosin, prodigiosin, and its synthetic analogue PNU156804 (PNU). However, the effect of this agent on the function of macrophage and splenocyte has not been characterized in detail. In the present study, we examined the effects of prodigiosin for its ability to alter the function of murine macrophage and NK cell, and the proliferation of splenocytes. When thioglycollate-elicited macrophages pre-exposed to prodigiosin (1-50 ng/ml) were stimulated with LPS/IFN-γ, pretreatment with prodi- giosin resulted in the inhibition of tumoricidal activity of macrophage in a concentration-dependent manner. Tumoricidal activity of NK cell was also inhibited by prodigiosin. Moreover, we found that prodigiosin was able to cause a dose-dependent inhibition of murine lymphocyte responsiveness to Con A and LPS although T-mitoge- nic response was the more sensitive one. Taken together, the present results point out that prodigiosin has a suppressive effect on the mitogen-induced proliferation of murine lymphocytes and the function of macrophage and NK cell.

Mesenchymal stem cells (MSC) have recently received centre stage attention because of their potent immunosuppressive effect which has also been successfully exploited in the clinical setting to treat graft-versus-host disease (GVHD); however, the path to clinical efficacy is hindered by the limited understanding of how MSC work and how best to use their potential. In this issue of the European Journal of Immunology, it is shown, using an animal model, that MSC can treat GVHD only if administered in the presence of active disease and that this requirement is strictly related to the presence of IFN-gamma. Here we summarise the knowledge regarding MSC mediated tolerance and the evidence supporting the notion that MSC must be 'licensed' to exert their effects. We also propose the idea that the instrumental effect of IFN-gamma activity on MSC-mediated immunomodulation relies upon IFN-gamma's ability to gather and retain suppressive and effector cells in the same anatomical compartment.

Oridonin is an ent-kaurene diterpenoid extracted from Isodon Serra, and we have previously demonstrated its immunosuppressive effect. Our goal was to study how Oridonin impacts CD4+/CD25+ regulatory T cells (Tregs) and Th1/Th2 balance, as well as its effect on the anti-inflammatory target HO-1.Splenic lymphocytes were prepared from male 6-8-week-old SD rats.Cells were cultured in four groups as Oridonin-L (Oridonin 12.5 micromol/l), Oridonin-H (Oridonin 25 micromol/l), Cobalt protoporphyrin (Copp 50 micromol/l) and control (DMSO) with stimulation of ConA (5 microg/ml) for 48 h or with no stimulation for 12 h.We set up a model of Th1 polarization in vitro using ConA stimulation; ratios of CD4+/CD25+ Tregs (confirmed by the expression of Foxp3) were measured by flow cytometry, and levels of IL-2, IFN-gamma, TGF-beta and IL-10 were measured by ELISA. In addition, HO-1 expression was measured without stimulation with ConA by RT-PCR and Western blotting, and HO-1 level in vitro was then measured by enzyme activity assay. p0.05 (t-test) was taken as the level of statistical significance.Oridonin promoted differentiation towards CD4+/CD25+ Tregs, inhibited IL-2 and IFN-gamma but induced TGF-beta and IL-10, thus rectified the Th1 polarization. Moreover, Oridonin induced the expression of HO-1 mRNA and protein, and HO-1 activity in vitro was enhanced accordingly.The results suggest that Oridonin has a distinct effect on promoting CD4+/CD25+ Treg differentiation and modulating Th1/Th2 balance, and this effect may be achieved via inducing the anti-inflammatory target HO-1.

Xenotransplantation remits the severe shortage of human organs and tissues for transplantation, which is a problem that severely limits the application of transplantation to the treatment of human disease. However, severe immune rejection significantly limits the efficacy of xenotransplantation. In this study, we systematically investigated the immunosuppressive effect and mechanism of action of As2 O3 and leflunomide using a hamster-to-rat heart xenotransplantation model. We initially examined heart xenograft survival following As2 O3 and leflunomide treatment alone or combined treatment. We found that treatment with As2 O3 combined with leflunomide can significantly prolong the survival of heart xenograft by inhibiting Th1 and Th2 differentiation and reducing the production of IgG and IgM. Interestingly, As2 O3 and leflunomide showed low toxicity to the organs of the recipient. Taken together, these observations indicate that treatment with As2 O3 combined with leflunomide may be a promising immunosuppressive schedule for xenotransplantation.

Regulatory T cells (Tregs) play a critical role in preventing autoimmunity but can be co-opted by cancer cells to block immune surveillance of tumors. One immunosuppressive mechanism of Tregs is the contact-dependent release of transforming growth factor–β1 (TGF-β1), which is bound to the Treg surface by the protein GARP. Cuende et al. reported that GARP also contributes to the release of active TGF-β1 and that monoclonal antibodies targeting GARP blocked release of TGF-β1, thereby blocking immunosuppressive activity. In a xenogeneic mouse model of graft-versus-host disease (GVHD), coadministration of Tregs with the xenografted cells delays the onset of GVHD and injection with the monoclonal antibodies targeting GARP blocked this immunosuppressive effect. Thus, blocking GARP, either alone or in combination with other checkpoint inhibitors, could add to our arsenal for cancer immunotherapy. J. Cuende, S. Lienart, O. Dedobbeleer, B. van der Woning, G. De Boeck, J. Stockis, C. Huygens, D. Colau, J. Somja, P. Delvenne, M. Hannon, F. Baron, L. Dumoutier, J.-C. Renauld, H. De Haard, M. Saunders, P. G. Coulie, S. Lucas, Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo. Sci. Transl. Med.7, 284ra56 (2015). [Abstract]

Although the prevailing concept has been that mortality in sepsis results from an unbridled hyper-inflammatory cytokine-mediated response, the failure of more than 30 clinical trials to treat sepsis by controlling this cytokine response requires a 'rethink' of the molecular mechanism underpinning the development of sepsis. As we discuss here, remarkable new studies indicate that most deaths from sepsis are actually the result of a substantially impaired immune response that is due to extensive death of immune effector cells. Rectification of this apoptotic-inflammatory imbalance using modulators of caspases and other components of the cell-death pathway have shown striking efficacy in stringent animal models of sepsis, indicating an entirely novel path forward for the clinical treatment of human sepsis.

The authors' aim was to evaluate the efficacy of immunosuppression with monoclonal anti-CD40 ligand antibodies (aCD40L) or nonspecific polyclonal intravenous immunoglobulin (IVIG) in the pig-to-rat islet xenotransplantation model.Fetal porcine islet-like cell clusters were transplanted under the kidney capsule of nondiabetic rats. All antibodies were administered alone or in combination with cyclosporine A (CsA). In addition, some animals were administered antibodies plus tacrolimus (TAC) or sirolimus (SIR). Twelve days after transplantation, islet xenograft survival and rejection were evaluated using immunohistochemistry.aCD40L plus CsA had a pronounced inhibitory effect on islet xenograft rejection for up to 12 days after transplantation. Unexpectedly, treatment with a monoclonal control antibody (anti-keyhole limpet hemocyanin [aKLH]) plus CsA had a similar inhibitory effect. Furthermore, a similar inhibition of islet xenograft rejection was observed also in animals administered IVIG plus CsA. Monotherapy with aCD40L, aKLH, IVIG, or CsA had no effect on the rejection process. Also, when aCD40L or aKLH was administered together with TAC, islet xenograft rejection was inhibited. There was no marked difference compared with rats treated with aCD40L or aKLH and CsA. Immunosuppression with aCD40L or aKLH in combination with SIR also inhibited pig-to-rat islet xenograft rejection, but the protective effect was not as pronounced.Immunosuppression with high doses of antibodies, monoclonal or polyclonal, in combination with CsA or TAC inhibits pig-to-rat islet xenograft rejection. No specific effect of co-stimulatory blockade with aCD40L could be observed. Instead, the results indicate a nonspecific immunosuppressive effect of high doses of antibodies in this model.

Until recently, patients with rheumatoid arthritis (RA) were treated with monotherapy using conventional drugs such as sulfasalazine, antimalarials, intramuscular gold and methotrexate, which often leads to persistent arthritis, loss of functional capacity and decreased quality of life. The use of high-dose glucocorticoids (GCs) and active RA are both associated with generalised bone loss and fractures, while GCs have a strong immunosuppressive effect. With the introduction of very effective tumour-necrosis factor-blockers and other biologics, clinical remission is a realistic target in around half of the early patients with RA; the same appears true for the use of methotrexate with chronic low dose or initially high-dose GCs. With the use of a treat-to-target strategy focusing on clinical remission or low disease activity in early patients with RA, the negative effects of systemic inflammation on bone can be inhibited and local bone loss (in the joints), and generalised bone loss at the spine and hips, can be limited or prevented. Whether this also leads to a reduction in vertebral and non-vertebral fractures remains to be demonstrated. Another issue is, in other systemic rheumatic diseases in which treatment options are smaller and less effective than in RA, local and systemic bone loss may still occur.

T helper (Th)17 cells have been proposed to play important roles in several human diseases. The literatures about Chinese medicine studies, which related to inhibiting Th17, were reviewed, and the Chinese medicine which could inhibit Th17 cells was summarized in this paper.

1. Protective action of an enzyme-linked polyvinylpolypyrrolidone (PVPP, Mycofix ® Plus) against the immunosuppressive effect of afatoxins (AF) was evaluated by determination of peripheral blood T-lymphocyte proportions and splenic plasma cell counts. Histological changes in lymphoid organs were also investigated by light microscopy. One-d-old broiler chicks (Hybro) received 2·5 mg/kg diet AF (83·06% AFB1, 12·98% AFB2, 2·84% AFG1, 1·12% AFG2) with or without PVPP (3 g/kg diet) until 21 d of age. 2. When compared with the controls, AF treatment significantly decreased peripheral T-lymphocyte counts. AF caused a slight decrease in splenic plasma cell counts. The addition of PVPP to an AF-containing diet significantly increased T-lymphocyte counts. Splenic plasma cell counts were numerically intermediate between control and AF groups. 3. The dietary addition of PVPP to AF-free diet did not significantly alter either T-lymphocyte or splenic plasma cell counts.

We have shown previously that increased levels of hsp70, and antibodies reactive with hsp70 parallel the onset and severity of graft-versus-host disease (GVHD) in a parent → (DA × LEW)FI rat modelIn this study we have assessed the effect of reducing the levels of the 70 kDa heat shock protein (hsp70), on the morbidity and mortality of acute GVHD in (DA × LEW)FI ratsThe reduction was accomplished by the administration of 15-deoxyspergualin (DSG), an immunosuppressive agent which binds to a constitutively expressed member of the 70 kDa heat shock protein familyDSG administered via three different protocols reduced GVHD-associated morbidityOne of the regimens, which consisted of intermittent DSG administration, also significantly reduced GVHD associated mortalityThis DSG treatment reduced hsp70 levels in spleen and lymph nodes, inhibited anti-hsp70 antibody production, and diminished the serum levels of IL-2, IFN-γ, TNF-α, and IL-I0IL-4 levels in the serum did not change during GVHD and were not effected by DSGThese results show that the mechanism of DSG immunosuppressive effect in rat GVHD may involve DSG's capacity to bind to hsp70, which in turn may lead to a decrease in levels of circulating anti-hsp70 antibodies, and reduced production of cytokines.

Despite advances in prophylaxis and treatment, cytomegalovirus (CMV) infection remains a significant problem in the solid-organ transplant recipient. In addition to the clinical manifestations of CMV infection, there is also the immunosuppressive effect of CMV, which confers increased risk for fungal and other opportunistic infections. In reference to heart transplant recipients, the possible connection between CMV infection and rejection or CMV infection and allograft vasculopathy are areas of active research. Recent diagnostic advances, such as the CMV antigenemia assay and CMV-DNA detection by polymerase chain reaction or direct hybrid capture, have enabled early detection and monitoring of CMV infection and have raised the question of the implications of asymptomatic viremia. A wide variety of prophylactic strategies have been evaluated in heart and other solid-organ transplant recipients, including antiviral agents, globulin preparations, combinations of these therapies, and pre-emptive treatment strategies based on early detection or identification of a high-risk subset of patients. Many of these regimens have demonstrated efficacy in certain groups of patients, but a consensus has yet to emerge in terms of a single preferable strategy. Future advances on the horizon include the development of newer antiviral agents and a vaccine.

Cassytha filiformis L. and Piper borbonense C. DC. are used as ethnical medicine for diverse diseases in Comoros islands. This study aims to evaluate the potential immunomodulator properties ex-vivo of the phenolic fraction provided of the methanol extract of these plants by flow cytometer. The results highlighted an immunosuppressive effect on lymphocyte subpopulations for all doses administered intraperitoneally (i.p.) compared to the control group. The most immunosuppressive activity was observed at doses of 25 and 100 mg/kg b.w. respectively for Cassytha filiformis and Piper borbonense. However, an interesting immunostimulant activity was noted on monocytes for all doses and on granulocytes for doses of 50 and 100 mg/kg b.w. in treated group with Cassytha filiformis. The same result was observed for P. borbonense on granulocytes for all doses. This immunostimulant effect observed on granulocytes can suggest a possible anti-inflammatory potency of these plants and an eventual use of these plants in the treatment of inflammatory symptoms diseases.

Transforming growth factor-β1 (TGF-β1) exerts broad anti-inflammatory and immunosuppressive effects and plays a key role in self-tolerance. Complete knockout of TGF-β1 in mice results in autoimmunity and multi-organ inflammatory syndrome. The aim of the present study was to determine TGF-β1 serum levels in healthy individuals and in patients with typical systemic or organ-specific autoimmune disorders such as systemic lupus erythematosus (SLE) and Hashimoto's thyroiditis (HT) in an attempt to elucidate the importance of TGF-β1 in human autoimmunity.Serum concentrations of TGF-β1 were determined using an enzyme-linked immunosorbent assay in a group of 53 patients with SLE (87% women) and 123 with HT (95% women). Results were compared with those from 66 healthy controls (HC; 80% women).Significantly lower levels of serum TGF-β1 were found in patients with SLE and HT than those found in HC (mean ± SD: SLE: 8.7 ± 2.5 ng/mL; HT: 18.74 ± 8.2 ng/mL; HC: 33.01 ± 2.4.8 ng/mL; SLE versus HC: p0.001; HT versus HC: p0.001). Also, serum levels of TGF-β1 were significantly lower in patients with SLE compared to patients with HT (p0.001). The serum levels TGF-β1 were significantly higher in men than in women in the HC group (63.4 ± 28.1 ng/mL versus 26.6 ± 17.5 ng/mL, P0.001), but were similar for men and women in both patients groups (p0.05).Our data demonstrate that altered TGF-β1 levels are associated with the presence of autoimmune disorders, and that TGF-β1 concentrations seem to be more profoundly depressed in systemic autoimmune diseases than in autoimmune thyroid disorders. Autoimmunity may have been triggered as a result of a decreased immunosuppressive effect induced by depressed TGF-β1 levels in patients with SLE and Hashimoto's thyroiditis.

15-Deoxyspargualin (DSG) is a synthetic analogue of spergualin isolated from the culture filtrate of Bacillus laterosporus. It shows a strong immunosuppressive effect by antiproliferating action inhibiting the IL-2-stimulated maturation of T cells from the G0/G1 phases to the S and G2/M phases. Hsc70, a constitutive member of Hsp70 was identified as the immunophilin of DSG by Nadlar et al. In allogeneic transplantation of rat heart and dog kidney, DSG was definitely proved to prevent rejection and to rescue ongoing rejection. Our multicenter clinical trials on DSG showed that the percent efficacy to reverse acute rejection was 70-80%, and 600 days graft survival was 90% in the cases effectively treated with DSG at acute rejections. The combined use of DSG with methylprednisolone to treat acute rejection and the use of DSG to treat rejections in chronic phases were reported as the beneficial uses of DSG.

The efficacy of rapamycin (RAPA) was tested on small bowel transplantation in the mouse and compared with cyclosporine (CsA). Four groups were involved, each one included three combinations (n > or = 6) for evaluation of host-versus-graft (HVG, C57BL/6 X BALB/c F1 (CB6F1)-to-BALB/c), graft-versus-host (GVH, BALB/c-to-CB6F1), and combined HVG and GVH responses (C57BL/6-to-BALB/c). Grafts were transplanted to recipients heterotopically. Groups were as follows: group 1: naive controls; groups 2 and 3: recipient mice treated with RAPA 2 mg/kg/day and 4 mg/kg/day orally for 14 days, respectively; group 4: recipient mouse treated with CsA 4 mg/kg/day orally for 14 days. In the HVG model, the mean survival time (MST) of recipients was significantly longer in group 2 (32.9 +/- 17.7 days, P=0.006), group 3 (32.7 +/- 10.4 days, P=0.0001), and group 4 (37.9 +/- 11.8 days, P=0.0001), compared with naive controls in group 1 (8.5 +/- 1.6 days). In the GHV model, the MST of recipients in group 2 (41.8 +/- 19.9 days, P=0.002), group 3 (48.2 +/- 21.4 days, P=0.001) and group 4 (56.5 +/- 30.6 days, P=0.003) were significantly prolonged compared with control group 1 (8.5 +/- 1.6 days). In combined HVG and GVH responses, MST of recipient in group 2 (20.9 +/- 4.9 days, P=0.0001), group 3 (27.0 +/- 4.3 days, P=0.008), and group 4 (35.2 +/- 23.9 days, P=0.0001) were also significantly longer than that in controls (6.9 +/- 1.4 days), but in all three combinations, there were no statistically significant differences between groups 2 and 3, groups 2 and 4, or groups 3 and 4 (P>0.05). RAPA is a potent immunosuppressant able to significantly prolong small bowel allograft survival in mice using a short-term treatment. There is no statistically significant difference in recipient survival between low and high doses of RAPA treatment and the CsA standard dose used in this study.

The experiments were carried out on normothermal rabbits and rabbits exposed to cold stress (hypothermia). The animals of the latter group were submerged in ice-water for 20 s and then placed in a freezer at -15 degrees C for 8 min until their body temperature dropped by 3 degrees C. Both the normothermal and hypothermal rabbits were immunized i.p. with 3 ml of 10% sheep red blood cells (SRBC). Levamisole (2 mg/kg), DTC (sodium diethyldithiocarbamate, 20 mg/kg) or mechlorethamine (mustine; 5 micrograms/kg) were injected i.v. three times at 24-h intervals. The number of PFC, total (19S + 7S) and 2-mercapthoethanol resistant (7S) serum haemagglutination titres were determined. It was found that, in normothermal rabbits, all three agents potentiated the number of plaque-forming cells (PFC); the impact of DTC was the strongest, while the weakest influence was observed for mechlorethamine. Furthermore, DTC increased anti-SRBC haemagglutinin titre, whereas mechlorethamine did not. Levamisole, on the other hand, reduced total serum haemagglutinin titre. Cold stress reduced humoral response to SRBC, which was reflected in the decreased number of PFC and serum haemagglutination titres (19S + 7S and 7S). Each agent showed a different way of action. Pretreatment with DTC prevented the immunosuppression caused by cold stress, while levamisole and mechlorethamine only reduced the immunosuppressive effect.