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1
McDevitt, Lisa M. "Immunosuppressive Agents on the Horizon." Journal of Pharmacy Practice 16, no. 6 (December 2003): 434–41. http://dx.doi.org/10.1177/0897190003259384.
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The evolution of immunosuppression in organ transplantation has resulted in decreasing rates of rejection and improved allograft survival. The current successes, however, comes at the price of intense drug monitoring, frequent adverse affects, and long-term toxicity. New immunosuppressive agents offer the hope for decreased toxicity and improved long-term results. This article highlights those novel agents that are currently in late-stage clinical studies including new calcineurin inhibitor analogs and formulations, mycophenolate acid sodium, everolimus, FK-778, FTY720, and various monoclonal antibodies. The diverse mechanisms of action of these agents, coupled with promising efficacy and adverse effect profiles, may land each of them a unique niche for immunosuppression in organ transplantation.
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Grbovic, Leposava, and Miroslav Radenkovic. "Therapeutic use of glucocorticoids and immunosuppressive agents." Srpski arhiv za celokupno lekarstvo 133, Suppl. 1 (2005): 67–73. http://dx.doi.org/10.2298/sarh05s1067g.
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Pharmacotherapy of autoimmune thyroid disease (AITD) is complex. Apart from the replacement hormone therapy, antithyroid agents, beta adrenoceptor blockers and other drugs, in regard to the present symptoms, it also includes the administration of glucocorticoids and immunosuppressive agents. Physiological actions of glucocorticoids are significant in number, well known and described in details. The most prominent pharmacological properties of glucocorticoids, that are important for their clinical use, are antiinflammatory and immunosuppressive actions. In this article, the most notable clinical pharmacology aspects of glucocorticoids have been presented, including the basic principles of their therapeutic use, as well as the most important indications with the examples of dosing regiments (rheumatic disorders, renal diseases, allergic reactions, bronchial asthma, gastrointestinal inflammatory diseases, thrombocytopenia, organ transplantation, and Graves? ophthalmopathy). In addition, adverse and toxic effects of glucocorticoids as well as their interactions with other drugs have been described. Immunosuppressive agents have important role in treatment of immune disorders, including the reduction of immune response in autoimmune diseases and organ transplantation. Apart from glucocorticoids, immunosuppressive agents consist of calcineurin inhibitors (cyclosporine, tacrolimus), antiproliferative and antimetabolic agents (sirolimus, azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide), monoclonal antibodies: anti-CD3 antibody (muromonab-CD3), anti- CD25 antibody (daclizumab), anti-TNF-alpha antibody (infliximab). In this part, the most updated facts about mechanism of action, rational therapeutic use, as well as adverse and toxic effects of immunosuppressive agents have been reviewed.
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Robak, Tadeusz, Ewa Lech-Maranda, Anna Korycka, and Ewa Robak. "Purine Nucleoside Analogs as Immunosuppressive and Antineoplastic Agents: Mechanism of Action and Clinical Activity." Current Medicinal Chemistry 13, no. 26 (November 1, 2006): 3165–89. http://dx.doi.org/10.2174/092986706778742918.
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Valdoleiros, Sofia R., Isabel Furtado, Carolina Silva, Inês Correia Gonçalves, André Santos Silva, Olga Vasconcelos, Ana Aboim Horta, et al. "Protocolo de Prevenção e Tratamento de Infeções Associadas à Terapêutica Imunossupressora de Doenças Autoimunes." Acta Médica Portuguesa 34, no. 6 (June 1, 2021): 469. http://dx.doi.org/10.20344/amp.15625.
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We propose a guideline about the risk, prevention and treatment of infection in the patient under immunomodulatory or immunosuppressive therapy in the context of autoimmune or autoinflammatory disease. It is divided into three sections: drugs and associated risk of infection; immunizations; risk, prevention, and treatment of specific infections. The treatment of autoimmune diseases involves the use of immunosuppressive or immunomodulatory therapies, with an increasing number of new drugs being used. It is associated with an increased risk of infection, which may be present globally or only for specific agents, varying widely depending on the pharmacological class and even within the same class. The prevention strategy and clinical management need to be individually tailored and there are several key factors: characterization of the disease that prompts the immunosuppression, understanding of the mechanism of action of the immunosuppressive drug, knowledge of previous infections, recognition of risk factors, laboratory test results, vaccine administration, monitoring of clinical signs and symptoms and patient education.
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Bauer, Andrea C., Rodrigo F. Franco, and Roberto C. Manfro. "Immunosuppression in Kidney Transplantation: State of the Art and Current Protocols." Current Pharmaceutical Design 26, no. 28 (August 31, 2020): 3440–50. http://dx.doi.org/10.2174/1381612826666200521142448.
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Currently, kidney transplantation is the best treatment option for kidney failure for a majority of eligible patients. It is associated with a better quality of life and reduced mortality as compared to staying on dialysis. Many of the improvements in kidney transplant outcomes, observed in recent decades, are due to more efficient immunosuppression strategies. Therefore, developing expertise in the management of immunosuppressive drugs is key to the success of kidney transplantation. In this review, the historical aspects of organ transplant immunosuppression are briefly addressed and the basis of the allograft immune response to contextualize the main topic is provided, which is a deeper view of the immunosuppressive agents, including their known mechanisms of action, pharmacokinetics, interactions, toxicities, and clinical use. The most commonly used immunosuppressive protocols employed based on patients' and donors' characteristics are also presented here.
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Gorantla, Vijay S., John H. Barker, Jon W. Jones, Kaustubha Prabhune, Claudio Maldonado, and Darla K. Granger. "Immunosuppressive agents in transplantation: Mechanisms of action and current anti-rejection strategies." Microsurgery 20, no. 8 (2000): 420–29. http://dx.doi.org/10.1002/1098-2752(2000)20:8<420::aid-micr13>3.0.co;2-o.
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Taylor, Anna L., Christopher J. E. Watson, and J. Andrew Bradley. "Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy." Critical Reviews in Oncology/Hematology 56, no. 1 (October 2005): 23–46. http://dx.doi.org/10.1016/j.critrevonc.2005.03.012.
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Stepkowski, Stanislaw M. "Molecular targets for existing and novel immunosuppressive drugs." Expert Reviews in Molecular Medicine 2, no. 4 (June 21, 2000): 1–23. http://dx.doi.org/10.1017/s1462399400001769.
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Anti-neoplastic cytostatic antiproliferative agents, such as methotrexate, 6-mercaptopurine and cyclophosphamide, were originally used as immunosuppressive drugs. Although these agents induced only modest anti-rejection activity, they caused serious non-specific bone marrow suppression, impairing host resistance and increasing the incidence of infections. Unlike these non-selective agents, cyclosporine A, tacrolimus and sirolimus act more selectively on different stages of the T-lymphocyte (T-cell) and B-lymphocyte (B-cell) activation cycles; however, cyclosporine and tacrolimus are nephrotoxic, whereas sirolimus causes hypertriglyceridaemia. Thus, despite this progress, continued efforts must be made to develop and test new, potentially very selective agents. The agent 15-deoxyspergualin moderately inhibits both mitogen-stimulated T-cell proliferation and the generation of cytotoxic T lymphocytes (CTLs) but does not affect the production of interleukin 2 (IL-2). Another drug, FTY720, has a unique action to prevent rejection, by altering the homing of lymphocytes to the lymphoid compartments. The newest members of the family of antiproliferative agents, namely mycophenolate mofetil, leflunomide and brequinar, are potentially more selective than their predecessors. However, the most promising agents are produced using antisense technology. This approach involves the design of antisense oligodeoxynucleotides; these novel drugs are designed to block allograft rejection by blocking selected messenger RNA (mRNA). This review outlines the mechanisms of action, the limitations of application and the molecular or cellular targets of traditional agents, newly developed drugs and also antisense technology, which is an example of a new application of molecular medicine.
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Tan, Marcus, Thurston Heng, and Anselm Mak. "The Potential Use of Metformin, Dipyridamole, N-Acetylcysteine and Statins as Adjunctive Therapy for Systemic Lupus Erythematosus." Cells 8, no. 4 (April 6, 2019): 323. http://dx.doi.org/10.3390/cells8040323.
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Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune condition that can potentially affect every single organ during the course of the disease, leading to increased morbidity and mortality, and reduced health-related quality of life. While curative treatment is currently non-existent for SLE, therapeutic agents such as glucocorticoids, mycophenolate, azathioprine, cyclosporine, cyclophosphamide and various biologics are the mainstay of treatment based on their immunomodulatory and immunosuppressive properties. As a result of global immunosuppression, the side-effect profile of the current therapeutic approach is unfavourable, with adverse effects including myelosuppression, infection and malignancies. Hydroxychloroquine, one of the very few Food and Drug Administration (FDA)-approved medications for the treatment of SLE, has been shown to offer a number of therapeutic benefits to SLE patients independent of its immunomodulatory effect. As such, it is worth exploring drugs similar to hydroxychloroquine that confer additional clinical benefits unrelated to immunosuppressive mechanisms. Indeed, apart from hydroxychloroquine, a number of studies have explored the use of a few conventionally non-immunosuppressive drugs that are potentially useful in the management of SLE. In this review, non-immunosuppressive therapeutic agents, namely metformin, dipyridamole, N-acetylcysteine and statins, will be critically discussed with regard to their mechanisms of action and efficacy pertaining to their potential therapeutic role in SLE.
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Nelson, R. D., N. Shibata, R. P. Podzorski, and M. J. Herron. "Candida mannan: chemistry, suppression of cell-mediated immunity, and possible mechanisms of action." Clinical Microbiology Reviews 4, no. 1 (January 1991): 1–19. http://dx.doi.org/10.1128/cmr.4.1.1.
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The ability of Candida albicans to establish an infection involves multiple components of this fungal pathogen, but its ability to persist in host tissue may involve primarily the immunosuppressive property of a major cell wall glycoprotein, mannan. Mannan and oligosaccharide fragments of mannan are potent inhibitors of cell-mediated immunity and appear to reproduce the immune deficit of patients with the mucocutaneous form of candidiasis. However, neither the exact structures of these inhibitory species nor their mechanisms of action have yet been clearly defined. Different investigators have proposed that mannan or mannan catabolites act upon monocytes or suppressor T lymphocytes, but research from unrelated areas has provided still other possibilities for consideration. These include interference with cytokine activities, lymphocyte-monocyte interactions, and leukocyte homing. To stimulate further research of the immunosuppressive property of C. albicans mannan, we have reviewed (i) the relationship of mannan to other antigens and virulence factors of the fungus; (ii) the chemistry of mannan, together with methods for preparation of mannan and mannan fragments; and (iii) the historical evidence for immunosuppression by Candida mannan and the mechanisms currently proposed for this property; and (iv) we have speculated upon still other mechanisms by which mannan might influence host defense functions. It is possible that understanding the immunosuppressive effects of mannan will provide clues to novel therapies for candidiasis that will enhance the efficacy of both available and future anti-Candida agents.
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Lu, C. Y., S. C. Sicher, and M. A. Vazquez. "Prevention and treatment of renal allograft rejection: new therapeutic approaches and new insights into established therapies." Journal of the American Society of Nephrology 4, no. 6 (December 1993): 1239–56. http://dx.doi.org/10.1681/asn.v461239.
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Renal transplantation is the preferred treatment modality for patients with ESRD who are good surgical risks and able to comply with chronic immunosuppressive medications. Clinical transplantation has advanced significantly, with most transplant centers reporting 1-yr renal allograft survival rates of better than 80%. Nevertheless, rejection and a progressive loss of allografts over time continue to occur. The immunosuppressive agents currently used may lead to the development of life-threatening infections, malignancies, and advanced atherosclerosis as a consequence of some of their side effects. This review examines the mechanisms involved in allograft rejection as currently understood. The recent knowledge into the mechanism of action of cyclosporine, FK506, and rapamycin on T cell activation is presented. Information recently available on some of the established therapies such as steroids, antimetabolites and monoclonal antibodies as well as the newer agents is also discussed. The interaction between clinical transplantation and basic research in immunology continues to result in exciting advances in both fields.
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Allard, David, Bertrand Allard, and John Stagg. "On the mechanism of anti-CD39 immune checkpoint therapy." Journal for ImmunoTherapy of Cancer 8, no. 1 (February 2020): e000186. http://dx.doi.org/10.1136/jitc-2019-000186.
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With the coming of age of cancer immunotherapy, the search for new therapeutic targets has led to the identification of immunosuppressive adenosine as an important regulator of antitumor immunity. This resulted in the development of selective inhibitors targeting various components of the adenosinergic pathway, including small molecules antagonists targeting the high affinity A2A adenosine receptor and low affinity A2B receptor, therapeutic monoclonal antibodies (mAbs) and small molecules targeting CD73 and therapeutic mAbs targeting CD39. As each regulator of the adenosinergic pathway present non-overlapping biologic functions, a better understanding of the mechanisms of action of each targeted approach should accelerate clinical translation and improve rational design of combination treatments. In this review, we discuss the potential mechanisms-of-action of anti-CD39 cancer therapy and potential toxicities that may emerge from sustained CD39 inhibition. Caution should be taken, however, in extrapolating data from gene-targeted mice to patients treated with blocking anti-CD39 agents. As phase I clinical trials are now underway, further insights into the mechanism of action and potential adverse events associated with anti-CD39 therapy are anticipated in coming years.
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MONAGHAN, PAUL, DARREN B. LENEGHAN, WESLEY SHAW, and ANGUS BELL. "The antimalarial action of FK506 and rapamycin: evidence for a direct effect on FK506-binding protein PfFKBP35." Parasitology 144, no. 7 (March 9, 2017): 869–76. http://dx.doi.org/10.1017/s0031182017000245.
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SUMMARYFK506 and rapamycin (Rap) are immunosuppressive drugs that act principally on T-lymphocytes. The receptors for both drugs are FK506-binding proteins (FKBPs), but the molecular mechanisms of immunosuppression differ. An FK506–FKBP complex inhibits the protein phosphatase calcineurin, blocking a key step in T-cell activation, while the Rap –FKBP complex binds to the protein kinase target of rapamycin (TOR), which is involved in a subsequent signalling pathway. Both drugs, and certain non-immunosuppressive compounds related to FK506, have potent antimalarial activity. There is however conflicting evidence on the involvement of Plasmodium calcineurin in the action of FK506, and the parasite lacks an apparent TOR homologue. We therefore set out to establish whether inhibition of the Plasmodium falciparum FKBP PfFKBP35 itself might be responsible for the antimalarial effects of FK506 and Rap. Similarities in the antiparasitic actions of FK506 and Rap would constitute indirect evidence for this hypothesis. FK506 and Rap acted indistinguishably on: (i) specificity for different intra-erythrocytic stages in culture, (ii) kinetics of killing or irreversible growth arrest of parasites and (iii) interactions with other antimalarial agents. Furthermore, PfFKBP35's inhibitory effect on calcineurin was independent of FK506 under a range of conditions, suggesting that calcineurin is unlikely to be involved in the antimalarial action of FK506.
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Shanahan, Fergus, Gerald C. O'’Sullivan, and J. Kevin Collins. "Immunosppressive Agents in Inflammatory Bowel Disease: Current Status and Future Prospects." Canadian Journal of Gastroenterology 8, no. 6 (1994): 383–87. http://dx.doi.org/10.1155/1994/580410.
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Inflammatory bowel disease involves an interaction between genetic susceptibility factors and environmental triggers, and the intestinal injury is mediated by the host immunoinflammatory response. Identification of the mechanisms and mediators that contribute to the tissue injury has provided a sound rationale for the therapeutic use of immunosuppressive and immunomodulatory agents. The efficacy of traditional immunosuppressive drugs, such as the purine analogues in both Crohn’s disease and ulcerative colitis, is well established. The major limitation of the use of these drugs is the delayed clinical response associated with their use. This has prompted an evaluation of other immunosuppressivcs, such as cyclosporine and related drugs, that have a more rapid onset of action. Convincing data indicate a distinct role for cyclosporine in certain patients with acute severe ulcerative colitis. However, despite early promising results with cyclosporine in Crohn’s disease, recent results have been less encouraging. There is also uncertainty about the exact clinical role of cyclosporine because of concerns regarding long term toxicity. At present, many investigators regard cyclosporine as an interim measure for acutely ill patients. The challenge that remains is the development of novel immunomodulatory strategies that are specific for the mucosal immune system and that are based on recent advances in our understanding of the pathogenesis of mucosal inflammation.
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GROSU-BULARDA, Andreea, Oana VERMEŞAN, Luana LĂZĂRESCU, and Ioan LASCĂR. "Immunosuppression in transplant of vascularized composite allografts." Romanian Journal of Medical Practice 11, no. 2 (June 30, 2016): 160–71. http://dx.doi.org/10.37897/rjmp.2016.2.11.
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Since 1998, when the first successful hand transplant was performed in France, at Lyon, an unpredicted development of reconstructive transplant surgery (transplant of VCA: vascularized composite allografts) occurred. Those procedures represents the only option for patients having extensive, complex tissue defects, involving multiple anatomical layers, impossible to approach using conventional reconstructive techniques. More than two hundred VCA procedures were reported worldwide, including: upper and lower limbs, face, larynx, trachea, abdominal wall, penis, uterus, knee allotransplant. Important aspects arise in the study of immunological mechanisms of acceptance and rejection of the allograft, the mode of action of immunosuppressive agents and protocols currently used in transplant programs for vascularized composite allografts. Immunosuppressive regimens that are used for solid organ transplantation (kidney, heart) are also effective for VCA transplants with good results regarding survival and functionality of the allografts. Current goal is the minimization of immunosuppression, composite tissue allotransplantation procedures being addressed for functional recovery (are not life-saving interventions like solid organ transplants). The ideal situation, which would allow a large scale utilization of VCA procedures, is the possibility of induction the donor-specific tolerance, allowing allograft acceptance without the need of immunosuppressive therapy. Currently this circumstance is difficult to achieve in clinical practice, resulting in large transplant centers ongoing research focusing on immunological difficult aspects.
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Klintmalm, Goran B., and Björn Nashan. "The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence." Journal of Transplantation 2014 (2014): 1–45. http://dx.doi.org/10.1155/2014/845438.
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Despite the success of liver transplantation, long-term complications remain, includingde novomalignancies, metabolic syndrome, and the recurrence of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). The current mainstay of treatment, calcineurin inhibitors (CNIs), can also worsen posttransplant renal dysfunction, neurotoxicity, and diabetes. Clearly there is a need for better immunosuppressive agents that maintain similar rates of efficacy and renal function whilst minimizing adverse effects. The mammalian target of rapamycin (mTOR) inhibitors with a mechanism of action that is different from other immunosuppressive agents has the potential to address some of these issues. In this review we surveyed the literature for reports of the use of mTOR inhibitors in adult liver transplantation with respect to renal function, efficacy, safety, neurological symptoms,de novotumors, and the recurrence of HCC and HCV. The results of our review indicate that mTOR inhibitors are associated with efficacy comparable to CNIs while having benefits on renal function in liver transplantation. We also consider newer dosing schedules that may limit side effects. Finally, we discuss evidence that mTOR inhibitors may have benefits in the oncology setting and in relation to HCV-related allograft fibrosis, metabolic syndrome, and neurotoxicity.
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Yang, Fan, Yang Li, Qian Zhang, Liang Tan, Longkai Peng, and Yong Zhao. "The Effect of Immunosuppressive Drugs on MDSCs in Transplantation." Journal of Immunology Research 2018 (July 3, 2018): 1–16. http://dx.doi.org/10.1155/2018/5414808.
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Myeloid-derived suppressor cells (MDSCs) are a group of innate immune cells that regulates both innate and adaptive immune responses. In recent years, MDSCs were shown to play an important negative regulatory role in transplant immunology even upstream of regulatory T cells. In certain cases, MDSCs are closely involved in transplantation immune tolerance induction and maintenance. It is known that some immunosuppressant drugs negatively regulate MDSCs but others have positive effects on MDSCs in different transplant cases. We herein summarized our recent insights into the regulatory roles of MDSCs in transplantation specially focusing on the effects of immunosuppressive drugs on MDSCs and their mechanisms of action. Studies on the effects of immunosuppressive drugs on MDSCs will significantly expand our understanding of immunosuppressive drugs on immune regulatory cells in transplantation and offer new insights into transplant tolerance. We hope to emphasize our concern for the negative effects of immunosuppressive agents on MDSCs, which may potentially attenuate the immune tolerance induction in transplanted recipients.
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Ingawale, Deepa K., Satish K. Mandlik, and Snehal S. Patel. "An emphasis on molecular mechanisms of anti-inflammatory effects and glucocorticoid resistance." Journal of Complementary and Integrative Medicine 12, no. 1 (January 1, 2015): 1–13. http://dx.doi.org/10.1515/jcim-2014-0051.
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AbstractGlucocorticoids (GC) are universally accepted agents for the treatment of anti-inflammatory and immunosuppressive disorders. They are used in the treatment of rheumatic diseases and various inflammatory diseases such as allergy, asthma and sepsis. They bind with GC receptor (GR) and form GC–GR complex with the receptor and exert their actions. On activation the GC–GR complex up-regulates the expression of nucleus anti-inflammatory proteins called as transactivation and down-regulates the expression of cytoplasmic pro-inflammatory proteins called as transrepression. It has been observed that transactivation mechanisms are notorious for side effects and transrepressive mechanisms are identified for beneficial anti-inflammatory effects of GC therapy. GC hampers the function of numerous inflammatory mediators such as cytokines, chemokines, adhesion molecules, arachidonic acid metabolites, release of platelet-activating factor (PAF), inflammatory peptides and enzyme modulation involved in the process of inflammation. The GC resistance is a serious therapeutic problem and limits the therapeutic response of GC in chronic inflammatory patients. It has been observed that the GC resistance can be attributed to cellular microenvironment changes, as a consequence of chronic inflammation. Various other factors responsible for resistance have been identified, including alterations in both GR-dependent and GR-independent signaling pathways of cytokine action, hypoxia, oxidative stress, allergen exposure and serum-derived factors. The present review enumerates various aspects of inflammation such as use of GC for treatment of inflammation and its mechanism of action. Molecular mechanisms of anti-inflammatory action of GC and GC resistance, alternative anti-inflammatory treatments and new strategy for reversing the GC resistance have also been discussed.
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Holt, Curtis D., Gordon Ingle, and Theodore M. Sievers. "Inhibitors of Calcineurin." Journal of Pharmacy Practice 16, no. 6 (December 2003): 414–33. http://dx.doi.org/10.1177/0897190003260317.
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Before the early 1980s, patient and allograft survival for solid organ transplant recipients was dismal. By 1983, the first calcineurin blocker, cyclosporine (Sandimmun), had been introduced, and outcomes were dramatically improved. However, cyclosporine macroemulsion had suboptimal pharmacokinetics, significant drug interactions, and several adverse effects, including nephrotoxicity, neurotoxicity, hyperlipidemia, and hypertension. Recent advances with cyclosporine include the introduction of modified dosage formulations: Neoral, a microemulsion, and several generic microemulsion products. The potent second-generation calcineurin blocker tacrolimus (Prograf) was introduced in 1994 and has become the drug of choice for several types of transplant recipients. Although tacrolimus has improved pharmacokinetics and therapeutic drugmonitoring parameters, it has adverse effects such as nephrotoxicity, neurotoxicity, and diabetes. Thus, current immunosuppressive regimens implementing calcineurin blockers often involve additional immunosuppressive agents to “spare” the use of these agents, minimizing their adverse effects. This article reviews the mechanisms of action, pharmacokinetics, clinical use, therapeutic drug monitoring, drug interactions, adverse effects, and dosing of cyclosporine and tacrolimus in solid organ transplant recipients.
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Muraille, Eric, Fabienne Andris, Bernard Pajak, K. Martin Wissing, Thibaut De Smedt, Fabrice Desalle, Michel Goldman, et al. "Downregulation of Antigen-Presenting Cell Functions After Administration of Mitogenic Anti-CD3 Monoclonal Antibodies in Mice." Blood 94, no. 12 (December 15, 1999): 4347–57. http://dx.doi.org/10.1182/blood.v94.12.4347.
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Abstract Antibodies against CD3ɛ are widely used as immunosuppressive agents. Although it is generally assumed that these reagents exert their immunomodulatory properties by inducing T-cell deletion and/or inactivation, their precise mechanism of action remains to be elucidated. Using a murine model, we demonstrate in this report that administration of anti-CD3ɛ antibodies causes the migration and maturation of dendritic cells (DC) in vivo, as determined by immunohistochemical analysis. This maturation/migration process was followed by selective loss of splenic DC, which resulted in a selective inhibition of antigen-presenting cell (APC) functions in vitro. Spleen cells from anti-CD3ɛ–treated animals were unable to productively stimulate naive alloreactive T cells and Th1-like clones in response to antigen, while retaining the ability to present antigen to a T-cell hybridoma and Th2 clones. Anti-CD3ɛ treatment was found to induce a selective deficiency in the ability of spleen cells to produce bioactive interleukin-12 in response to CD40 stimulation. APC dysfunction was not observed when nonmitogenic forms of anti-CD3ɛ antibodies were used, suggesting that splenic DC loss was a consequence of in vivo T-cell activation. Nonmitogenic anti-CD3ɛ monoclonal antibodies were found to be less immunosuppressive in vivo, raising the possibility that APC dysfunction contributes to anti-CD3ɛ–induced immunomodulation. Collectively, these data suggest a novel mechanism by which mitogenic anti-CD3ɛ antibodies downregulate immune responses.
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Muraille, Eric, Fabienne Andris, Bernard Pajak, K. Martin Wissing, Thibaut De Smedt, Fabrice Desalle, Michel Goldman, et al. "Downregulation of Antigen-Presenting Cell Functions After Administration of Mitogenic Anti-CD3 Monoclonal Antibodies in Mice." Blood 94, no. 12 (December 15, 1999): 4347–57. http://dx.doi.org/10.1182/blood.v94.12.4347.424k31_4347_4357.
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Antibodies against CD3ɛ are widely used as immunosuppressive agents. Although it is generally assumed that these reagents exert their immunomodulatory properties by inducing T-cell deletion and/or inactivation, their precise mechanism of action remains to be elucidated. Using a murine model, we demonstrate in this report that administration of anti-CD3ɛ antibodies causes the migration and maturation of dendritic cells (DC) in vivo, as determined by immunohistochemical analysis. This maturation/migration process was followed by selective loss of splenic DC, which resulted in a selective inhibition of antigen-presenting cell (APC) functions in vitro. Spleen cells from anti-CD3ɛ–treated animals were unable to productively stimulate naive alloreactive T cells and Th1-like clones in response to antigen, while retaining the ability to present antigen to a T-cell hybridoma and Th2 clones. Anti-CD3ɛ treatment was found to induce a selective deficiency in the ability of spleen cells to produce bioactive interleukin-12 in response to CD40 stimulation. APC dysfunction was not observed when nonmitogenic forms of anti-CD3ɛ antibodies were used, suggesting that splenic DC loss was a consequence of in vivo T-cell activation. Nonmitogenic anti-CD3ɛ monoclonal antibodies were found to be less immunosuppressive in vivo, raising the possibility that APC dysfunction contributes to anti-CD3ɛ–induced immunomodulation. Collectively, these data suggest a novel mechanism by which mitogenic anti-CD3ɛ antibodies downregulate immune responses.
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Löwenberg, Mark, Jurriaan Tuynman, Meike Scheffer, Auke Verhaar, Louis Vermeulen, Sander van Deventer, Daniel Hommes, and Maikel Peppelenbosch. "Kinome Analysis Reveals Nongenomic Glucocorticoid Receptor-Dependent Inhibition of Insulin Signaling." Endocrinology 147, no. 7 (July 1, 2006): 3555–62. http://dx.doi.org/10.1210/en.2005-1602.
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Glucocorticoids (GCs) are powerful immunosuppressive agents that control genomic effects through GC receptor (GR)-dependent transcriptional changes. A common complication of GC therapy is insulin resistance, but the underlying molecular mechanism remains obscure. Evidence is increasing for rapid genomic-independent GC action on cellular physiology. Here, we generate a comprehensive description of nongenomic GC effects on insulin signaling using peptide arrays containing 1176 different kinase consensus substrates. Reduced kinase activities of the insulin receptor (INSR) and several downstream INSR signaling intermediates (i.e. p70S6k, AMP-activated protein kinase, glycogen synthase kinase-3, and Fyn) were detected in adipocytes and T lymphocytes due to short-term treatment with dexamethasone (DEX), a synthetic fluorinated GC. Western blot analysis confirmed suppressed phosphorylation of the INSR and a series of downstream INSR targets (i.e. INSR substrate-1, p70S6k, protein kinase B, phosphoinositide-dependent protein kinase, Fyn, and glycogen synthase kinase-3) after DEX treatment. DEX inhibited insulin signaling through a GR-dependent (RU486 sensitive) and transcription-independent (actinomycin D insensitive) mechanism. Overall, we postulate here a molecular mechanism for GC-induced insulin resistance based on nongenomic GR-dependent inhibition of insulin signaling.
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Shustov, E. B., A. E. Kim, and M. B. Ivanov. "Molecular targets of immunotoxic action of drugs." Toxicological Review, no. 2 (May 15, 2020): 11–17. http://dx.doi.org/10.36946/0869-7922-2020-2-10-16.
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The aim of the article is to generalize information on possible molecular targets that ensure the implementation of the immunotoxic effects of drugs for the subsequent improvement of the methodological apparatus of immunotoxicological studies of new drugs and assess the prospects of the development of new directions of immunopharmacology. The results of the information search for official data provided by manufacturers of medicines registered in the Russian Federation (guidelines for use, clinical recommendations, reports on biomedical and clinical research), as well as data from pharmacological monitoring of the safety of their use conducted by Roszdravnadzor of the Russian Federation are summarized.Guidelines for the use of 524 current international non-patent medicines, covering a total of more than 5000 generics in various forms, releases and dosages, were analyzed. The object of the search was data on undesirable side effects of medicines related to the human immune system.The analysis showed that the immunotoxic effect is described for 40,6% of 524 active pharmacological agents. Clinical and pathogenetic characteristics allowed us to identify several cluster groups that can be characterized as immunotoxic syndromes: allergic, immunosuppressive, lymphotropic, generalized cytokine reaction, reactivation of the immune response, and immune activation of oncogenesis. Molecular targets of immunotoxic action were determined based on the known mechanisms of action of the analyzed drugs.
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Colby, Christine, Cheryl A. Stoukides, and Thomas R. Spitzer. "Antithymocyte Immunoglobulin in Severe Aplastic Anemia and Bone Marrow Transplantation." Annals of Pharmacotherapy 30, no. 10 (October 1996): 1164–74. http://dx.doi.org/10.1177/106002809603001016.
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OBJECTIVE: To review antithymocyte immunoglobulin (ATG) and its current role in the treatment of severe aplastic anemia (SAA), focusing on ATG in immunosuppressive therapy compared with bone marrow transplantation (BMT). DATA SOURCES: A MEDLINE search (1966 to 1996) of English-language literature and human subjects pertaining to ATG and BMT therapy in SAA was performed. Additional literature was obtained from reference lists of pertinent articles identified through the search. STUDY SELECTION AND DATA EXTRACTION: All articles were considered for possible inclusion in the review. Pertinent information, as judged by the authors, was selected for discussion. DATA SYNTHESIS: The hallmark of SAA is pancytopenia and bone marrow hypoplasia. Although the etiology in a majority of cases remains unknown, current data implicate an immune-mediated destruction of stem cells. ATG is a potent immunosuppressive agent and has emerged as an important therapy for patients with SAA. The exact mechanism of immunosuppressive action is not fully understood, although ATG appears to disrupt cell-mediated immune responses resulting in inhibition or altered T-cell function. Numerous trials have evaluated the use of ATG both as monotherapy and in combination with other immunosuppressive agents. Treatment with ATG in SAA has demonstrated a 40–70% response rate. Data suggest that intensive immunosuppressive therapy with ATG in combination with cyclosporine may provide the optimal immunosuppressive treatment. Questions still remain concerning complications and long-term survival of the patients. Although more than a 2-year follow-up shows a decline in mortality, a plateau in the survival curve was not achieved. BMT is a potential treatment for SAA. Although there is a high initial mortality due to treatment-related toxicities, successful marrow engraftment provides a cure for SAA. Many patients (75–90%) experience long-term survival after allogenic BMT. Age, donor availability, and severity of disease limit the number of eligible patients. CONCLUSIONS: Due to excellent results with BMT, it has become the therapy of choice for selected patients with SAA. For patients who are not eligible for BMT, intensive immunosuppressive therapy with ATG and cyclosporine is recommended. Further study to better understand the pathogenesis of SAA and prevent treatment-related complications is essential to provide the best care to all patients.
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Blaess, Julien, Julia Walther, Arthur Petitdemange, Jacques-Eric Gottenberg, Jean Sibilia, Laurent Arnaud, and Renaud Felten. "Immunosuppressive agents for rheumatoid arthritis: a systematic review of clinical trials and their current development stage." Therapeutic Advances in Musculoskeletal Disease 12 (January 2020): 1759720X2095997. http://dx.doi.org/10.1177/1759720x20959971.
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Aims: With the arrival of conventional synthetic (csDMARDs), biological (bDMARDS) and then targeted synthetic (tsDMARDs) disease-modifying anti-rheumatic drugs, the therapeutic arsenal against rheumatoid arthritis (RA) has recently expanded. However, there are still some unmet needs for patients who do not achieve remission and continue to worsen despite treatments. Of note, most randomized controlled trials show that, for methotrexate-inadequate responders, only 20% of patients are ACR70 responders. With our better understanding of RA pathogenesis, finding new treatments is a necessary challenge. The objective of our study was to analyse the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development. Methods: We conducted a systematic review of all drugs in clinical development in RA, in 17 online registries of clinical trials. Results: The search yielded 4652 trials, from which we identified 243 molecules. Those molecules belong to csDMARDs ( n = 22), bDMARDs ( n = 118), tsDMARDs ( n = 103). Twenty-four molecules are already marketed in RA in at least one country: eight csDMARDs, 10 bDMARDs and six tsDMARDs. Molecules under current development are mainly bDMARDs ( n = 34) and tsDMARDs ( n = 33). Seven of those have reached phase III. A large number of molecules (150/243, 61.7%) have been withdrawn. Conclusion: Despite the availability of 24 marketed molecules, the development of new targeted molecules is ongoing with a total of 243 molecules in RA. With seven molecules currently reaching phase III, we can expect an increase in the armamentarium in the years to come.
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Fernández-Villa, Aguilar, and Rojo. "Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications." International Journal of Molecular Sciences 20, no. 20 (October 9, 2019): 4996. http://dx.doi.org/10.3390/ijms20204996.
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: Bacterial, protozoan and other microbial infections share an accelerated metabolic rate. In order to ensure a proper functioning of cell replication and proteins and nucleic acids synthesis processes, folate metabolism rate is also increased in these cases. For this reason, folic acid antagonists have been used since their discovery to treat different kinds of microbial infections, taking advantage of this metabolic difference when compared with human cells. However, resistances to these compounds have emerged since then and only combined therapies are currently used in clinic. In addition, some of these compounds have been found to have an immunomodulatory behavior that allows clinicians using them as anti-inflammatory or immunosuppressive drugs. Therefore, the aim of this review is to provide an updated state-of-the-art on the use of antifolates as antibacterial and immunomodulating agents in the clinical setting, as well as to present their action mechanisms and currently investigated biomedical applications.
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Suuring, Maaike, and Aurélie Moreau. "Regulatory Macrophages and Tolerogenic Dendritic Cells in Myeloid Regulatory Cell-Based Therapies." International Journal of Molecular Sciences 22, no. 15 (July 26, 2021): 7970. http://dx.doi.org/10.3390/ijms22157970.
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Myeloid regulatory cell-based therapy has been shown to be a promising cell-based medicinal approach in organ transplantation and for the treatment of autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, Crohn’s disease and multiple sclerosis. Dendritic cells (DCs) are the most efficient antigen-presenting cells and can naturally acquire tolerogenic properties through a variety of differentiation signals and stimuli. Several subtypes of DCs have been generated using additional agents, including vitamin D3, rapamycin and dexamethasone, or immunosuppressive cytokines, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). These cells have been extensively studied in animals and humans to develop clinical-grade tolerogenic (tol)DCs. Regulatory macrophages (Mregs) are another type of protective myeloid cell that provide a tolerogenic environment, and have mainly been studied within the context of research on organ transplantation. This review aims to thoroughly describe the ex vivo generation of tolDCs and Mregs, their mechanism of action, as well as their therapeutic application and assessment in human clinical trials.
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Kildyushevsky, A. V., Ya G. Moysyuk, A. V. Molochkov, T. A. Mitina, and A. P. Faenko. "Extracorporeal photopheresis in solid organ transplantation." Almanac of Clinical Medicine 48, no. 3 (October 5, 2020): 207–24. http://dx.doi.org/10.18786/2072-0505-2020-48-046.
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Despite the use of up-to-date immunosuppressive agents, graft rejection episodes are quite common and pose a serious threat to thousands of solid organ recipients. Continuous use of various combinations of immunosuppressants cause serious complications, such as arterial hypertension, post-transplant diabetes mellitus, renal failure, increased risk of infections, malignant neoplasms, etc. The attempts to achieve the desired or forced minimization of the graft immunosuppression are associated with the threat of its rejection, which makes it necessary to search for less toxic, non-medical, immunological, including cellular, management methods. One of the promising methods based on cell technology is extracorporeal photopheresis (ECP). ECP is a well-established second line therapy recommended for the prevention and treatment of refractory rejection of a heart transplant. ECP improves the pulmonary allograft functioning in patients with treatment resistant obliterating bronchiolitis syndrome. However, its value as a preventive method has not yet been established. ECP effectiveness for induction, maintenance, or anti-crisis therapy in transplantation of kidney, liver or other solid organs has been rather convincing, but the lack of randomized multicenter studies limits its use. The optimal ECP strategy has not been yet established. Nevertheless, current understanding of the pathophysiological and immunological aspects of ECP is sufficient to develop a standard methodology and technology for the procedure, as well as for a quality control system for ECP in kidney and liver transplant recipients. The review discusses possible mechanisms of the immunomodulating effect of ECP. ECP is being increasingly studied in prospective randomized trials with larger samples. This allows for an extension of its clinical indications with clear criteria, as well as for studying its multifactorial underlying immunomodulating mechanism of action. Further research is needed to identify biomarkers that could predict ECP effectiveness in solid organ transplantation.
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Routy, B., T. Huynh, R. Fraser, and C. Séguin. "Vascular Endothelial Cell Function in Catastrophic Antiphospholipid Syndrome: A Case Report and Review of the Literature." Case Reports in Hematology 2013 (2013): 1–4. http://dx.doi.org/10.1155/2013/710365.
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Catastrophic antiphospholipid syndrome (CAPS) is a rare autoimmune condition, which has been associated with a high mortality rate. However, with current management that includes a combination of anticoagulation, glucocorticoid administration, and plasma exchange, mortality rate has declined. Despite survival improvement with new generation immunosuppressive agents, their mechanisms of action are poorly defined, and CAPS is still considered a high-risk complication in patients known with antiphospholipid antibody syndrome. Herein, we present a case of a 79-year-old male who presented with a myocardial infarct and renal failure secondary to CAPS following a splenectomy for immune thrombocytopenia. Regardless of rapid combination of first-line treatment and rituximab therapy, the patient developed lethal cardiogenic shock secondary to mitral valve papillary muscle necrosis. Discussion of the pathophysiology and avenues of future therapies in CAPS are reported.
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Bai, Fanqi, JianXiang Zou, Jun Yang, Edna Ku, Sheng Wei, Thomas P. Loughran, and P. K. Epling-Burnette. "Complex Immunosuppressive Action of Farnesyltransferase Inhibitor (FTI) R115777 (Tipifarnib, Zarnestra®) with Induction of Apoptosis in T Cells from Patients with Large Granular Lymphocyte (LGL) Leukemia." Blood 108, no. 11 (November 16, 2006): 4960. http://dx.doi.org/10.1182/blood.v108.11.4960.4960.
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Abstract BACKGROUND: Large Granular Lymphocyte (LGL) leukemia is an indolent clonal disorder arising from either CD3+ or CD3− immunophenotypes characterized as T-cell and Natural-Killer (NK)-cell malignancies, respectively. Due to a rare incidence, all therapeutic investigations in LGL leukemia are generated from single institution experiences, which consist primarily of retrospective cohort analyses. Pathogenesis may relate to an underlying autoimmune mechanism with low-dose methotrexate (10mg/m2 weekly), cyclophosphamide (50–100mg daily), and cyclosporine A (5–10mg/kg daily) used as first-line agents for the treatment of associated cytopenias. The mechanism(s) controlling survival of leukemic LGL are not fully characterized. We hypothesize that agents that target survival signaling will serve as effective therapeutics. Using pharmacologic inhibitors of the Mitogen Activated Protein Kinase (MAPK/ERK) signaling cascase, we found that ERK/Ras drives NK leukemia survival (Epling-Burnette, et al. Oncogene, 23:9220, 2004). The goal of this study was to investigate the in vitro actions of the farnysltransferase-inhibitor R115777 (tipifarnib, Zarnestra®, Johnson and Johnson) on survival and immune response leukemic T cells. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from patients with T LGL leukemia. All patients had increased numbers of CD3+ αβ T lymphocytes and evidence of clonality. Western blot analysis was used to examine the protein levels of phosphorylated (active) ERK1 and ERK2 (MAPK), Bcl-2, and total MAPK. Apoptosis assays were performed by staining with annexin-V-FITC and 7-aminoactinomycin (7-AAD) and flow cytometry analysis. Anti-CD3 plus anti-CD28 was used to stimulate T cells in the presence of brefelden A and IL-2, IFN-γ, TNF-α, IL-4, and IL-10 were determined in distinct T cell subpopulations by intracellular staining. T cell proliferation was assessed by Brdu incorporation in CD4+ and CD8+ T cells. RESULTS: PBMCs from patients with T LGL displayed constitutively-active MAPK/ERK expression as determined by Western blot analysis (n=5). Using MEK pharmacological inhibitors, we found that blockade of the active MEK/ERK signaling pathway induced apoptosis in leukemic T LGL. Bcl-2 was expressed in 80% of patients and when MEK/ERK was inhibited there was a corresponding reduction in expression. Targeted disruption of farnesyl-transferase with two different inhibitors (FTI2153 and R115777, n=9) led to a dose-dependent increase in apoptosis with an apoptotic index that was significantly greater than normal T cells. In addition to apoptosis, we found that antigen-induced proliferation of CD4+ and CD8+ T cells was impaired by R115777 (11% ± 7 vs. 3% ±1.7 and 11% ± 9 vs. 3% ± 1.6, respectively). Furthermore, R115777 biased antigen-dependent cytokine response to a Th2 type with increased expressionof IL-4 and IL-10 after drug treatment (average increase 100% and 43%, respectively). CONCLUSIONS: These findings suggest that FTIs regulate immune response and lead to apoptosis of leukemic T LGL cells. A pilot trial of R115777 (tipifarnib, Zarnestra®) is ongoing for the treatment of LGL leukemia.
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Wolf, Andrew, and Enrique Alvarez. "COVID-19 Vaccination in Patients With Multiple Sclerosis on Disease-Modifying Therapy." Neurology: Clinical Practice 11, no. 4 (April 14, 2021): 358–61. http://dx.doi.org/10.1212/cpj.0000000000001088.
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The COVID-19 pandemic has resulted in challenges for the practice of neurology. One major concern is how to best manage patients with multiple sclerosis (MS) who are on disease-modifying therapies (DMTs). DMTs frequently have immunosuppressive properties that both increase the risk for COVID-19 and potentially reduce the immunologic response to vaccination in a group already vulnerable to infection due to neurologic deficits. Here, we review early data on COVID-19 outcomes in patients with MS and discuss what is known about vaccine effectiveness in those on anti-CD20 and sphingosine-1-phosphate receptor agents, which are proposed to have attenuating effects based on their mechanisms of action. In addition, we provide recommendations to best use novel COVID-19 vaccines in this population and highlight what information may better inform vaccine strategies in the future.
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Marciani, Dante J. "Sole Anti-inflammatory Immunomodulators: Innovative Drugs to Prevent and Treat Autoimmune Diseases and Proteopathies." Current Chinese Science 1, no. 2 (April 19, 2021): 273–85. http://dx.doi.org/10.2174/2210298101666210108110556.
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Objective: To review the available sole anti-inflammatory immunomodulators or adjuvants, different from pro-inflammatory ones, which elicit a Th2 immunity while inhibiting but without abrogating Th1/Th17 immunities. Adjuvants that are useful to develop vaccines for T-cell mediated autoimmune conditions. Methods: A literature search using PubMed and Google Scholar databases was made to identify reports regarding adjuvants, mechanisms of action, pro-inflammatory autoimmunity and vaccines to treat it, immunosuppressive agents, dendritic cells, helminths, immunotolerance, and infectious diseases causing autoimmunity. Results: Some anti-inflammatory drugs to treat autoimmune diseases inhibit DNA or protein synthesis causing global immunosuppression, which is reduced by using biologics to block key steps in the inflammatory cascade. Fucosylated glycans from helminths, which are anti-inflammatory but not immune-suppressive, offer an avenue to develop better drugs. Fucosylated glycans bind to DC-SIGN, a receptor on dendritic cells, entering the cells via receptor-mediated endocytosis, biasing their immunoresponse to a sole Th2 anti-inflammatory immunity, while inhibiting the proinflammatory Th1/Th17 immunities. New anti-inflammatory drugs are particular plant-derived fucosylated glycosides with immunological properties like those of helminth-derived glycans. Another class of anti-inflammatory immunomodulators is ligands of the aromatic-hydrocarbon receptor, which by activating this intracellular receptor, boosts the differentiation of regulatory Tcells, inducing an anti-inflammatory immunity. However, aromatic ligands can also stimulate a pro-inflammatory response. Exogenous aromatic ligands are usually delivered intracellularly using carriers like nanoparticles, which upon translocation to the nucleus, activate this receptor. Conclusions: Autoimmune conditions and some infectious diseases, characterized by organ damage due to pro-inflammatory autoimmune immunoresponses, could benefit from nonimmunosuppressive agents to modulate immunity; this way, averting a damaging inflammation.
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Cuker, Adam, and Cindy E. Neunert. "How I treat refractory immune thrombocytopenia." Blood 128, no. 12 (September 22, 2016): 1547–54. http://dx.doi.org/10.1182/blood-2016-03-603365.
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Abstract This article summarizes our approach to the management of children and adults with primary immune thrombocytopenia (ITP) who do not respond to, cannot tolerate, or are unwilling to undergo splenectomy. We begin with a critical reassessment of the diagnosis and a deliberate attempt to exclude nonautoimmune causes of thrombocytopenia and secondary ITP. For patients in whom the diagnosis is affirmed, we consider observation without treatment. Observation is appropriate for most asymptomatic patients with a platelet count of 20 to 30 × 109/L or higher. We use a tiered approach to treat patients who require therapy to increase the platelet count. Tier 1 options (rituximab, thrombopoietin receptor agonists, low-dose corticosteroids) have a relatively favorable therapeutic index. We exhaust all Tier 1 options before proceeding to Tier 2, which comprises a host of immunosuppressive agents with relatively lower response rates and/or greater toxicity. We often prescribe Tier 2 drugs not alone but in combination with a Tier 1 or a second Tier 2 drug with a different mechanism of action. We reserve Tier 3 strategies, which are of uncertain benefit and/or high toxicity with little supporting evidence, for the rare patient with serious bleeding who does not respond to Tier 1 and Tier 2 therapies.
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Alberti, C., M. Mediago, G. Chiapello, D. Bernardi, and G. Arena. "Retroperitoneal Fibrosis, Today: An Updating of Knowledges on this Subjet." Urologia Journal 73, no. 2 (April 2006): 205–16. http://dx.doi.org/10.1177/039156030607300201.
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Retroperitoneal fibrosis (RPF) is characterized, at first, by a replacement of the normal retroperitoneal tissue by an active granulomatosis inflammation (cellular phase), and at a later stage by a fibrous scar tissue (established fibrotic phase). The aetiology of secondary RPFs includes several drugs (notably methysergide, ergotamine, pergolide, hydralazine), both chronic atherosclerotic aortitis-periaortitis and inflammatory aortic aneurisms, autoimmune diseases such as different forms of systemic vasculitis and collagen diseases, histiocytosis such as Erdheim-Chester syndrome, desmoplastic reactions to retroperitoneal malignancy carcinoid syndrome, retroperitoneal accidentally and surgically occurred traumas, abdominal radiation therapy. On the contrary, the causes of idiopathic RPF remain uncertain; its pathogenesis is associated to immuno-mediated mechanisms. The inflammatory process can involve retroperitoneal vessels, ureters, peri- and pararenal spaces, mesenteric small intestine, duodenum, psoas muscles, and can spread to mediastinal space. Diagnosis and characterization of the polyphase inflammatory evolution require integrated approaches including laboratory tests, morpho-functional imaging and, sometimes, histopathologic assessment. In the early stages, the management of RPF ranges from the removal of identifiable etiologic agents to the interfering with the inflammatory immuno-mediated process by means of several drugs. Unfortunately, many effective immunosuppressive drugs induce adverse reactions unrelated to their specific immunosuppressive action; this is the reason why the biopharmacology research today is struggling towards the identification of molecular targets having their expression restricted to immune cells and/or cytokines. Moreover, the progression of atheromatous aortitis to RPF could be prevented by statins which are able to interfere with the inflammatory pathway as well as to induce the well-known reduction in the levels of atherogenic lipoproteins. In the late established fibrotic stage, either open surgery or endourologic, laparoscopic procedures are performed; nevertheless neoadiuvant and adiuvant corticosteroid-immunosuppressive treatments are mandatory in order to avoid any relapse of the disease.
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Andronova, V. L. "MODERN ETHIOTROPIC CHEMOTHERAPY OF HUMAN CYTOMEGALOVIRUS INFECTION: CLINICAL EFFECTIVENESS, MOLECULAR MECHANISM OF ACTION, DRUG RESISTANCE, NEW TRENDS AND PROSPECTS. PART 1." Problems of Virology, Russian journal 63, no. 5 (October 20, 2018): 202–11. http://dx.doi.org/10.18821/0507-4088-2018-63-5-202-211.
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Modern chemotherapy of cytomegalovirus (CMV) infections has a very limited arsenal of first-line drugs. These are preparations of ganciclovir (GCV) belonging to the class of modified nucleosides and its metabolic precursor ganciclovir valine ester. After three-step phosphorylation, GCV, as a structural analogue of the natural nucleotide, competes with it for binding to DNA polymerase and, due to its structural features, inhibits its activity. However, with prolonged use of GCV, mainly under conditions of immunosuppression, the virus develops drug resistance associated in most cases with changes in pUL97 catalyzing the first stage of GCV phosphorylation, as well as in the catalytic subunit of DNA polymerase. When variants of viruses resistant to GCV appear, second-line drugs are used: pyrophosphate analog of foscarnet and nucleotide cidofovir. Resistance to second-line drugs is due to mutations in the pol-gene and in a number of cases leads to multiresistance, which makes it impossible to use traditional anti-CMV drugs. In addition, the use of all of the above drugs is accompanied by the development of severe side effects. All of the above determines the need to search for new compounds that can effectively inhibit the reproduction of the virus, harmless to the macroorganism, convenient to use, overcoming the drug resistance barrier in viruses. As a result of the search in international databases (PubMed, MedLine, eLIBRARY.RU, ClinicalTrials.gov, etc.), the main trends in the search for new anti-CMV agents were identified. In the first part of the review, we concentrated on compounds that are modifications of known antiviral agents currently used in clinical practice, the most promising for the development of drug anti-CMV drugs.
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Karateev, D. E., and E. L. Luchikhina. "Immunomodulatory drug therapy for the disease caused by SARS-CoV-2 infection (COVID-19)." Almanac of Clinical Medicine 48 (September 19, 2020): 51–67. http://dx.doi.org/10.18786/2072-0505-2020-48-036.
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This systematic review focuses on the state-of-the-art pharmacotherapy of immune disorders in the novel coronavirus infection (COVID-19), leading to a cytokine storm and uncontrolled inflammatory response that causes severe tissue damage and multiple organ failure. A lot of theoretical, experimental and clinical data support the need for immunomodulatory (immunosuppressive) therapy for this disease. It should be emphasized that all immunomodulatory drugs for COVID-19 are prescribed off label, and the evidence base of the results of randomized trials is just being accumulated. We review the immunomodulatory therapy for COVID-19 with the following agents: glucocorticoids, hydroxychloroquine and chloro-quine, type 1 interferons, interleukin-6 antagonists (tocilizumab, sarilumab, olokizumab), interleukin-1 p inhibitor canakinumab, tumour necrosis factor inhibitors (infliximab), Janus kinase (JAK) inhibitors (tofacitinib, baricitinib, ruxolitinib), as well as drugs with other mechanisms of action (abatacept, nivolumab, tacrolimus, sirolimus, fingolimod, melphalan, cyclosporine, methotrexate). At the moment, the most reasonable is the use of interleukin-6 receptor inhibitors, intermediate and high dose glucocorticoids, and JAK inhibitors. Based on the latest data from clinical studies, especially the "Solidarity” trial, the use of hydroxychloroquine and chloroquine seems to have insufficient evidence. There are significant pathophysiological overlaps in the development of immunopathology in COVID-19 and in rheumatic diseases, and the strategy of early aggressive immunosuppressive therapy proposed by a number of researchers almost completely coincides with the current strategies for rheumatoid arthritis.
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Pritulo, O. A., A. A. Petrov, and A. V. Petrov. "Evolution of immunotherapy methods for psoriasis and psoriatic arthritis: from total immunosuppression to selective treatment of therapeutic targets." Medical alphabet, no. 15 (2020) (September 12, 2020): 15–21. http://dx.doi.org/10.33667/2078-5631-2020-15-15-21.
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The literature review presents data on existing treatments for psoriasis (P) and psoriatic arthritis (PsA). The relevance of the work is rationale with the difficulties of choosing a particular therapeutic agent by a specialist, depending on the peculiarities of the course of the skin pathological process, damage to the musculoskeletal system, spine and related diseases. Synthetic and targeted drugs are described in a chronological consequences, the review provides accumulated information about their effectiveness in relation to various manifestations of P and PsA, and the safety of their use. In conclusion, current recommendations on the differentiated use of various agents for target therapy based on a comprehensive assessment of the clinical characteristics of patients as well as mechanism of action and side effects of the drugs, are discussed.
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Gediz, Fusun, and Senol Kobak. "Immune Checkpoint Inhibitors-related Rheumatic Diseases: What Rheumatologist Should Know?" Current Rheumatology Reviews 15, no. 3 (July 31, 2019): 201–8. http://dx.doi.org/10.2174/1573397115666190119094736.
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: Immune checkpoint inhibitors are revolutionized drugs for cancer immunotherapy in the last years. The mechanism of action of CPIs including the limitation of the activation of Tcells, and thus enhancing the self-immune response against tumour cells. Checkpointinhibitors( CPIs) may dysregulate the immune system, resulting in some toxicities. These toxicities or side effects are called Immune-related Adverse Events (IRAEs) that can potentially affect any organ and tissue. Rheumatic diseases due to checkpoint inhibitors are also reported in the literature. The spectrum of rheumatic manifestations are quite wide; the most common are arthralgia/arthritis, myalgia/myositis, polimyalgia rheumatica, lupus, rheumatoid arthritis, Sjögren’s syndrome. At the same time, these drugs can also cause an exacerbation of known rheumatologic disease. Treatment approaches for developing rheumatic findings due to checkpoint inhibitors should be multidisciplinary. There should be a close relationship between oncologists who follow-up these patients and rheumatologists. The rheumatic manifestations should be defined and treated early. In general, the musculoskeletal side effects are transient and may regress after stopping CPIs. The most commonly used medications are corticosteroids. Immunosuppressive drugs (HQ, MTX, anti-TNF-alpha, anti-IL-6) should be preferred when treatment is unresponsive or as steroid-sparing agents. : The aim of this review was to evaluate the checkpoint inhibitors-related rheumatologic findings and therapeutic strategies in light of recent literature data.
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Skolarczyk, Justyna, Joanna Pekar, and Barbara Nieradko-Iwanicka. "Immune disorders induced by exposure to pyrethroid insecticides." Postępy Higieny i Medycyny Doświadczalnej 71, no. 1 (June 8, 2017): 0. http://dx.doi.org/10.5604/01.3001.0010.3827.
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Pyrethroids are biocides, which belong to the third generation of insecticides. They are used as biocides, insecticides and medicines. These agents react selectively, because they are less harmful to birds and mammals (due to poor intestinal absorption and rapid detoxification in the body of homeothermic organisms) and they are poisonous for fish and insects.The aim of the article is to present the current state of knowledge on the effects of pyrethroids on the immune system based on the latest scientific research.The mechanism of action of pyrethroids include the delaying closure of voltage- sensitive sodium and chloride channels (including GABA- dependent channels). These compounds are neurotoxic.Studies have shown that they cause numerous immune disorders contributing to lowering of immunity in humans and animals. Exposure to pyrethroids can cause inhibition of proliferation of peripheral blood leukocytes and reducing the concentration of IgG immunolgobulines. They also cause reduced macrophages and decrease in interleukin 2 (IL-2), interleukin 8 (IL-8), interleukin 12p70 (IL-12p70), and interferon γ (IFN-γ). Some of these compounds cause increase of liver weight and increase of bone marrow cellularity, and may induce apoptosis of the thymus. Pyrethroids can cause allergies and asthma. Their immunosuppressive effects can impair host resistance against infections. Exposure to these compounds can also contribute to induction of the cancer, especially in patients with impaired immune function.
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Zang, Yimei. "Pharmacological Activities of Coumarin Compounds in Licorice: A Review." Natural Product Communications 15, no. 9 (September 2020): 1934578X2095395. http://dx.doi.org/10.1177/1934578x20953954.
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Licorice is a traditional medicine commonly used in China and many other countries. Over the last 50 years, the structure and pharmacological effects of coumarin compounds in licorice have been investigated. However, a comprehensive review of the literature summarizing current trends is currently lacking. Thus, the aim of the present review is to provide an up-to-date summary of the scientific literature regarding the pharmacological effects of coumarin compounds in licorice, thereby laying the foundation for further research and optimal utilization of licorice. We retrieved 111 articles on the coumarin components of licorice and their potential pharmacological effects, based on titles, keywords, and abstracts from databases (including PubMed and Web of Science). Glycycoumarin, isoglycycoumarin, licoarylcoumarin, licopyranocoumarin, glycyrin, isotrifoliol, glycyrol, and glycyrurol have been investigated for their anticancer, hepatoprotective, antispasmodic, immunosuppressive, anti-inflammatory, and antibacterial properties, and use as therapeutic agents in metabolic syndrome, thereby demonstrating their potential for clinical applications. Future research should further explore the pharmacological mechanisms of action of coumarin compounds, including their antibacterial activities. Investigations into the pharmacological activities of different glycycoumarin isomers might open new research frontiers.
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Johnson, Theodore S., Catherine E. Terrell, and Michael B. Jordan. "Defining the Mechanism of Etoposide Activity in Hemophagocytic Lymphohistiocytosis Using a Murine Disease Model." Blood 114, no. 22 (November 20, 2009): 714. http://dx.doi.org/10.1182/blood.v114.22.714.714.
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Abstract Abstract 714 Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystem hyperinflammatory syndrome associated with immune dysregulation due to genetic or acquired defects in cytotoxic natural killer cell and CD8 T cell function. Although the mechanism of activity is currently unknown, etoposide has been the mainstay of HLH therapy during the past two decades, since its initial empiric use. Jordan, et al (Blood 2004;104(3):735-43) demonstrated that the clinical and laboratory manifestations of HLH are recapitulated in perforin-deficient (prf−/−) mice infected with lymphocytic choriomeningitis virus (LCMV). In this animal model, ineffective cytotoxic T effector cells fail to down-modulate stimulatory signals provided by antigen presenting cells (APCs). Excessive T cell stimulation leads to massive cytokine production which drives systemic macrophage activation resulting in HLH-like disease pathology. Thus, at least three critical events occur in the pathogenesis of HLH: 1) Abnormal increase in antigen presentation, 2) Abnormal increase in CD8 T cell activation and cytokine secretion, and 3) Pathological macrophage activation and hemophagocytosis. We hypothesize that our unique animal model of HLH can be used to test the activity and mechanisms of action of current and novel therapeutic approaches for this disease. Methods: Five days after perforin-deficient (prf−/−) or wild-type (WT) mice were infected with LCMV, they were given intraperitoneal (IP) injections of either: etoposide (VP16), dexamethasone (DEX), other chemotherapeutic agents, or irrelevant carrier controls. Outcome measures included: serial measurements of disease severity using a clinical scoring system, post-infection survival, serial measurements of serum interferon-gamma (IFNγ), determination of hemoglobin levels 15 days post-infection, and flow cytometric analyses of whole spleen 8 days post-infection to assess total cellularity, T cell activation, and macrophage infiltration. Effectiveness of antigen presentation by APCs from LCMV-infected drug-treated mice was assessed by ex vivo IFNγ production using effector T cells previously generated in vitro. Osmotic pumps were used to deliver exogenous IFNγ to WT mice to assess the effect of drug therapy on IFNγ-mediated macrophage activation in the absence of viral infection. Results: VP16 was an effective single agent, whereas DEX was not, in our murine model of HLH leading to significant improvements in: disease severity (p<0.03 after day 22 post-infection, VP16 v. control), survival (p<0.02), peak serum IFNγ levels (p<0.009), and hemoglobin levels (p<0.002). Flow cytometric analyses of whole spleen from animals treated with VP16 showed decreases in total cellularity (p<0.0002, VP16 v. control) as well as absolute numbers of CD8 T cells (p<0.002), virus-specific CD8 T cells (p<0.002), and macrophages (p<0.0007). The decrease in T cell numbers was not caused by a direct effect of these drugs on antigen presentation by APCs, and there was no effect of drug treatment on IFNγ-mediated macrophage dependent pathology in the absence of viral infection. Conclusions: We present data using an animal model to test treatments for HLH by examining their effects on different aspects of HLH pathology. Our studies indicate that VP16 acts primarily via cytolytic effects on dividing T cells. This leads to a diminished pool of activated but ineffective responding T cells and attenuation of hypercytokinemia. Normalization of peak serum IFNγ levels results in decreased tissue infiltration of activated macrophages with less hemophagocytosis. Thus, improvement in HLH-like disease severity and survivability after treatment with VP16 is a direct effect of deleting activated IFNγ-producing T cells. Furthermore, this data serves to validate the use of this murine model of HLH pathogenesis to define the mechanism(s) of current and novel anti-HLH therapeutic agents. We envision using this model in the future to design rational anti-HLH therapy by combining cytolytic, immunosuppressive, and/or selective biological agents that have complementary modes of action. Disclosures: No relevant conflicts of interest to declare.
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Wangchuk, Phurpa, Simon Apte, Michael Smout, Penny Groves, Alex Loukas, and Denise Doolan. "Defined Small Molecules Produced by Himalayan Medicinal Plants Display Immunomodulatory Properties." International Journal of Molecular Sciences 19, no. 11 (November 6, 2018): 3490. http://dx.doi.org/10.3390/ijms19113490.
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Plant-derived compounds that modulate the immune responses are emerging as frontline treatment agents for cancer, infectious diseases and autoimmunity. Herein we have isolated 40 phytochemicals from five Bhutanese Sowa Rigpa medicinal plants—Aconitum laciniatum, Ajania nubegina, Corydalis crispa, Corydalis dubia and Pleurospermum amabile—and tested 14 purified compounds for their immunomodulatory properties using a murine dendritic cell (DC) line, and cytotoxicity against a human cholangiocyte cell line using xCELLigence real time cell monitoring. These compounds were: pseudaconitine, 14-veratryolpseudaconitine, 14-O-acetylneoline, linalool oxide acetate, (E)-spiroether, luteolin, luteolin-7-O-β-d-glucopyranoside, protopine, ochrobirine, scoulerine, capnoidine, isomyristicin, bergapten, and isoimperatorin. Of the 14 compounds tested here, scoulerine had adjuvant-like properties and strongly upregulated MHC-I gene and protein expression whereas bergapten displayed immunosuppressive properties and strongly down-regulated gene and protein expression of MHC-I and other co-stimulatory molecules. Both scoulerine and bergapten showed low cytotoxicity against normal healthy cells that were consistent with their immunoregulatory properties. These findings highlight the breadth of immunomodulatory properties of defined compounds from Bhutanese medicinal plants and show that some of these compounds exert their mechanisms of action by modulating DC activity.
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Silva, Marcos V., Juliana R. Machado, Laura P. Rocha, Lúcio R. Castellano, Marlene A. Reis, and Rosana R. M. Corrêa. "CD28 Family and Chronic Rejection: “To Belatacept...and Beyond!”." Journal of Transplantation 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/203780.
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Kidneys are one of the most frequently transplanted human organs. Immunosuppressive agents may prevent or reverse most acute rejection episodes; however, the graft may still succumb to chronic rejection. The immunological response involved in the chronic rejection process depends on both innate and adaptive immune response. T lymphocytes have a pivotal role in chronic rejection in adaptive immune response. Meanwhile, we aim to present a general overview on the state-of-the-art knowledge of the strategies used for manipulating the lymphocyte activation mechanisms involved in allografts, with emphasis on T-lymphocyte costimulatory and coinhibitory molecules of the B7-CD28 superfamily. A deeper understanding of the structure and function of these molecules improves both the knowledge of the immune system itself and their potential action as rejection inducers or tolerance promoters. In this context, the central role played by CD28 family, especially the relationship between CD28 and CTLA-4, becomes an interesting target for the development of immune-based therapies aiming to increase the survival rate of allografts and to decrease autoimmune phenomena. Good results obtained by the recent development of abatacept and belatacept with potential clinical use aroused better expectations concerning the outcome of transplanted patients.
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Blaess, J., J. Walther, J. E. Gottenberg, J. Sibilia, L. Arnaud, and R. Felten. "AB0332 IMMUNOSUPPRESSIVE AND IMMONOMODULATING AGENTS IN RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW OF CLINICAL TRIALS AND THEIR CURRENT DEVELOPMENT STAGE." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1464.1–1465. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1124.
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Background:Rheumatoid arthritis (RA) is the most frequent chronic inflammatory diseases with an incidence of 0.5% to 1%. Therapeutic arsenal of RA has continuously expanded in recent years with the recent therapeutic progress with the arrival of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biological (bDMARDs) and targeted synthetic (tsDMARDs), JAK inhibitors. However, there are still some unmet needs for patients who do not achieve remission and who continue to worsen despite treatments. Of note, only approximately 40% of patients are ACR70 responders, in most randomized controlled trials. For these patients, finding new therapeutic avenues is challenging.Objectives:The objective of our study was to analyze the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development.Methods:We conducted a systematic review of all drug therapies in clinical development in RA in 17 databases of international clinical trials. Inclusion criterion: study from one of the databases using the keywords “Rheumatoid arthritis” (search date: June 1, 2019). Exclusion criteria: non-drug trials, trials not related to RA or duplicates. We also excluded dietary regimen or supplementations, cellular therapies, NSAIDs, glucorticoids or their derivatives and non-immunosuppressive or non-immunomodulating drugs. For each csDMARD, bDMARD and tsDMARD, we considered the study at the most advanced stage. For bDMARDs, we did not take into account biosimilars.Results:The research identified 4652 trials, of which 242 for 243 molecules met the inclusion and exclusion criteria. The developed molecules belong to csDMARDs (n=21), bDMARDs (n=117), tsDMARDs (n=105).Among the 21 csDMARDs molecules: 8 (38%) has been withdrawn, 4 (19%) are already labelled in RA (hydroxychloroquine, leflunomide, methotrexate and sulfasalazine) and 9 (43%) are in development: 1 (11%) is in phase I/II, 5 (56%) in phase II, 3 (33%) in phase IV.Among the 117 bDMARDs molecules: 69 (59%) has been withdrawn, 9 (8%) are labeled in RA (abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab) and 39 (33%) are in development: 9 (23%) in phase I, 3 (8%) in phase I/II, 21 (54%) in phase II, 5 (12%) are in phase III, 1 (3%) in phase IV. bDMARDs currently under development target B cells (n=4), T cells (n=2), T/B cells costimulation (n=2),TNF alpha (n=2), Interleukine 1 or his receptor (n=3), Interleukine 6 or his receptor (n=7), Interleukine 17 (n=4), Interleukine 23 (n=1), GM-CSF (n=1), other cytokines or chemokines (n=5), integrins or adhesion proteins (n=3), interferon receptor (n=1) and various other targets (n=4).Among the 105 tsDMARDs molecules: 64 (61%) has been withdrawn, 6 (6%) JAK inhibitors, have just been or will probably soon be labelled (baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib), 35 (33%) are in development: 8 (24%) in phase I, 26 (74%) in phase II, 1 (3%) in phase III and. tsDMARDs currently under development target tyrosine kinase (n=12), janus kinase (JAK) (n=3), sphingosine phostate (n=3), PI3K pathway (n=1), phosphodiesterase-4 (n=3) B cells signaling pathways (n=3) and various other targets (n=10).Conclusion:A total of 242 therapeutic trials involving 243 molecules have been or are being evaluated in RA. This development does not always lead to new treatments since 141 (58%) have already been withdrawn. Hopefully, some of the currently evaluated drugs will contribute to improve the therapeutic management of RA patients, requiring a greater personalization of therapeutic strategies, both in the choice of molecules and their place in therapeutic sequences.Disclosure of Interests:Julien Blaess: None declared, Julia Walther: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Jean Sibilia: None declared, Laurent Arnaud: None declared, Renaud FELTEN: None declared
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Khanna, Reena, Mahmoud H. Mosli, and Brian G. Feagan. "Anti-Integrins in Ulcerative Colitis and Crohn's Disease: What Is Their Place?" Digestive Diseases 34, no. 1-2 (2016): 153–59. http://dx.doi.org/10.1159/000443132.
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Background: Inflammatory bowel diseases (IBD) are a group of heterogeneous conditions, characterized by immune-mediated inflammation of the gastrointestinal tract. Traditionally, medical management of these disorders has been based on use of systemic immunosuppressives. The development of new drugs that selectively inhibit leukocyte trafficking to the gut has the potential to reduce inflammation and minimize systemic toxicities. Key Messages: In this article, we review the immunology of the gut and the mechanism of action these emerging therapies for IBD. Natalizumab, a monoclonal antibody to the α4 integrin, was approved for the treatment of multiple sclerosis and showed promise in Crohn's disease (CD), however it is encumbered by the risk of progressive multifocal leukoencephalopathy. Vedolizumab inhibits the α4β7 integrin to induce clinical remission in patients with both ulcerative colitis and CD. Long-term safety data on this agent is not yet available. We also review agents in the pipeline. Finally, we discuss the positioning of therapies and potential alterations to therapeutic algorithms as new medications emerge. Conclusions: New therapies are emerging for IBD; however, long-term data are pending. The positioning of these agents in algorithms will evolve.
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Smith, Melody M., William Powers, Cindy R. Giver, Ned Waller, and Christopher Flowers. "Mechanism for the Immuno-Suppresion Activity of Pentostatin: Selective Apoptosis of Naive T Cell Subsets." Blood 108, no. 11 (November 16, 2006): 5160. http://dx.doi.org/10.1182/blood.v108.11.5160.5160.
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Abstract Background: Nucleoside analogs have potent anti-tumor activity, especially against lymphoid malignancies, with immuno-suppression being a significant toxicity. We have previously described the immunosuppressive effects of fludarabine on murine T-cells, and found selective cytotoxicity against naïve subsets that reduced their allo-reactivity in a GvHD model of murine BMT (Giver et al 2003 BBMT 9:616). In this study we tested the cytotoxicity of fludarabine and pentostatin against human and murine T-cell subsets to determine their immune-suppressive activity, mechanism of action, and their potential utility as agents to decrease the allo-reactivity of allogeneic donor lymphocyte infusions. Methods: Peripheral blood mononuclear cell samples from normal donors were incubated ex vivo ex vivo treatment with Flu at doses of 5, 50, and 250 mcg/ml or pentostatin at doses of 1, 10, and 100 mcg/ml at 0, 4, 24, and 48-hour time points following 1 or 24 hour drug exposure. All samples that obtained dCF also received 25 mcg/ml of deoxyadenosine (dAdo), which enables dCF to mediate cytotoxicity against lymphocytes. Control samples for fludarabine and pentostatin treatment were untreated or treated with dAdo only, respectively. The total number of viable cells and the fractions of the CD4 and CD8 memory and naive T cell subsets that survived nucleoside exposure were determined by multi-parameter flow cytometry following staining with antibodies to CD3, CD4, CD8, CD45RA, CD6L, Annexin, and 7-AAD. Results: The decrease in the viability of the human naïve CD4 T cells, whether treated with fludarabine or pentostatin, was rapid and most notably observed after the 24-hour time point. On the other hand, the human memory CD4 T cells displayed a more gradual decline in percent viability in both treatment with fludarabine and pentostatin. Furthermore, the potency of pentostatin was exhibited in that it achieved a comparable effect to fludarabine while at substantially lower doses. Data obtained from the murine model also demonstrated a relative a relative sensitivity of the CD4 naïve T cells as oppesed to the CD4 memory to purine analog exposure. Conclusions: Future work will determine the optimal dosage and period of incubation for pentostatin and fludarabine that can utilized to induce immunosuppresion ex vivo in donor lymphocytes. SELECTIVE DEPLETION OF NAÏVE CD4+ T-CELLS FOLLOWING IN VITRO EXPOSURE TO PURINE ANALOGS SELECTIVE DEPLETION OF NAÏVE CD4+ T-CELLS FOLLOWING IN VITRO EXPOSURE TO PURINE ANALOGS
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Ushkalova, E. A., S. K. Zyryanov, and K. E. Zatolochina. "Muramyldipeptide - based compounds in current medicine: focus on glucosaminylmuramyl dipeptide." Terapevticheskii arkhiv 91, no. 12 (December 15, 2019): 122–27. http://dx.doi.org/10.26442/00403660.2019.12.000471.
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The role of immune mechanisms in the pathogenesis of almost all human diseases shown in recent decades, increase in antibiotic resistance and secondary immunodeficiency, aging of the population and widespread use of immunosuppressive drugs and procedures suggest a wider use of immunomodulators in current clinical practice, but the use of most of them limits the lack of knowledge. The most promising compounds for the development as immunomodulating agents and adjuvants for a wide range of vaccines are low molecular weight fragments of peptidoglycan - muramylpeptides. The article describes the mechanisms of action of muramylpeptides, their biological effects and properties of medicines developed on their basis. Special emphasis is placed to glucosaminylmuramyl dipeptide registered in the Russian Federation under the trade name Likopid, which is currently the best - studied drug in its group. The results of Likopid studies when used as a prophylactic and therapeutic agent for infections of various localization in adults and children, for oncological diseases and complications of chemotherapy and radiation therapy, psoriasis, atopic and other diseases are presented. It is emphasized that in diseases associated with human papillomavirus and plaque psoriasis, according to current criteria of evidence - based medicine, Likopid should be classified as drug with level A efficacy (high efficiency in 80-100% of patients). High safety of Likopid in adults and children, including newborns, is noted.
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Dunđerski, Jadranka, and Gordana Matić. "Glucocorticoid Receptor in Health and Disease." Journal of Medical Biochemistry 28, no. 4 (October 1, 2009): 248–61. http://dx.doi.org/10.2478/v10011-009-0022-y.
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Glucocorticoid Receptor in Health and DiseaseGlucocorticoid hormones are essential for life, have a vital place in the treatment of inflammatory and autoimmune diseases and are increasingly implicated in the pathogenesis of a number of common disorders. Their action is mediated by an intracellular receptor protein, the glucocorticoid receptor (GR), functioning as a ligand-inducible transcription factor. Multiple synthetic glucocorticoids are used as potent antiinflammatory and immunosuppressive agents, but their therapeutic usefulness is limited by a wide range and severity of side-effects. One of the most important pharmaceutical goals has been to design steroidal and non-steroidal GR ligands with profound therapeutic efficacy and reduced unwanted effects. The therapeutic benefit of glucocorticoid agonists is frequently compromised by resistance to glucocorticoids, which may depend on: access of the hormones to target cells, steroid metabolism, expression level and isoform composition of the GR protein, mutations and polymorphisms in the GR gene and association of the receptor with chaperone proteins. The major breakthrough into the critical role of glucocorticoid signaling in the maintenance of homeostasis and pathogenesis of diseases, as well as into the molecular mechanisms underlying the therapeutic usefulness of antiinflammatory drugs acting through the GR is expected to result from the current progress in large-scale gene expression profiling technologies and computational biology.
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Kelly, William James, Amber Jin Giles, and Mark Gilbert. "T lymphocyte-targeted immune checkpoint modulation in glioma." Journal for ImmunoTherapy of Cancer 8, no. 1 (February 2020): e000379. http://dx.doi.org/10.1136/jitc-2019-000379.
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Immunomodulatory therapies targeting inhibitory checkpoint molecules have revolutionized the treatment of solid tumor malignancies. Concerns about whether systemic administration of an immune checkpoint inhibitor could impact primary brain tumors were answered with the observation of definitive responses in pediatric patients harboring hypermutated gliomas. Although initial clinical results in patients with glioblastoma (GBM) were disappointing, recently published results have demonstrated a potential survival benefit in patients with recurrent GBM treated with neoadjuvant programmed cell death protein 1 blockade. While these findings necessitate verification in subsequent studies, they support the possibility of achieving clinical meaningful immune responses in malignant primary brain tumors including GBM, a disease in dire need of additional therapeutic options. There are several challenges involved in treating glioma with immune checkpoint modulators including the immunosuppressive nature of GBM itself with high inhibitory checkpoint expression, the immunoselective blood brain barrier impairing the ability for peripheral lymphocytes to traffic to the tumor microenvironment and the high prevalence of corticosteroid use which suppress lymphocyte activation. However, by simultaneously targeting multiple costimulatory and inhibitory pathways, it may be possible to achieve an effective antitumoral immune response. To this end, there are now several novel agents targeting more recently uncovered “second generation” checkpoint molecules. Given the multiplicity of drugs being considered for combination regimens, an increased understanding of the mechanisms of action and resistance combined with more robust preclinical and early clinical testing will be needed to be able to adequately test these agents. This review summarizes our current understanding of T lymphocyte-modulating checkpoint molecules as it pertains to glioma with the hope for a renewed focus on the most promising therapeutic strategies.
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Dmitriev, S. E., D. O. Vladimirov, and K. A. Lashkevich. "A Quick Guide to Small-Molecule Inhibitors of Eukaryotic Protein Synthesis." Biochemistry (Moscow) 85, no. 11 (November 2020): 1389–421. http://dx.doi.org/10.1134/s0006297920110097.
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Abstract Eukaryotic ribosome and cap-dependent translation are attractive targets in the antitumor, antiviral, anti-inflammatory, and antiparasitic therapies. Currently, a broad array of small-molecule drugs is known that specifically inhibit protein synthesis in eukaryotic cells. Many of them are well-studied ribosome-targeting antibiotics that block translocation, the peptidyl transferase center or the polypeptide exit tunnel, modulate the binding of translation machinery components to the ribosome, and induce miscoding, premature termination or stop codon readthrough. Such inhibitors are widely used as anticancer, anthelmintic and antifungal agents in medicine, as well as fungicides in agriculture. Chemicals that affect the accuracy of stop codon recognition are promising drugs for the nonsense suppression therapy of hereditary diseases and restoration of tumor suppressor function in cancer cells. Other compounds inhibit aminoacyl-tRNA synthetases, translation factors, and components of translation-associated signaling pathways, including mTOR kinase. Some of them have antidepressant, immunosuppressive and geroprotective properties. Translation inhibitors are also used in research for gene expression analysis by ribosome profiling, as well as in cell culture techniques. In this article, we review well-studied and less known inhibitors of eukaryotic protein synthesis (with the exception of mitochondrial and plastid translation) classified by their targets and briefly describe the action mechanisms of these compounds. We also present a continuously updated database (http://eupsic.belozersky.msu.ru/) that currently contains information on 370 inhibitors of eukaryotic protein synthesis.