• T-Lymphocytes, Regulatory/immunology
• Humans
• Arthritis/immunology
• Forkhead Transcription Factors/metabolism
• Forkhead Transcription Factors/immunology
• Animals
• Cell Differentiation/immunology
• Th17 Cells/immunology

• Foxp 3
• Tregs (regulatory T cells)
• acute rejection (AR)
• alloimmunity
• tolerance
• transplantation

• T32 HL007381 NHLBI NIH HHS

• Immunity regulation
• Oridonin
• Ovariectomized osteoporosis
• Wnt3a/β-catenin

• DAS28
• PF-06651600
• TCD4+
• cytokine release
• rheumatoid arthritis

For the last few decades, Calcineurin inhibitors (CNI)-based therapy has been the pillar of immunosuppression for prevention of organ transplant rejection. However, despite exerting effective control of acute rejection in the first year post-transplant, prolonged CNI use is associated with significant side effects and is not well suited for long term allograft survival. The implementation of Costimulation Blockade (CoB) therapies, based on the interruption of T cell costimulatory signals as strategy to control allo-responses, has proven potential for better management of transplant recipients compared to CNI-based therapies. The use of the biologic cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig is the most successful approach to date in this arena. Following evaluation of the BENEFIT trials, Belatacept, a high-affinity version of CTLA4-Ig, has been FDA approved for use in kidney transplant recipients. Despite its benefits, the use of CTLA4-Ig as a monotherapy has proved to be insufficient to induce long-term allograft acceptance in several settings. Multiple studies have demonstrated that events that induce an acute inflammatory response with the consequent release of proinflammatory cytokines, and an abundance of allograft-reactive memory cells in the recipient, can prevent the induction of or break established immunomodulation induced with CoB regimens. This review highlights advances in our understanding of the factors and mechanisms that limit CoB regimens efficacy. We also discuss recent successes in experimentally designing complementary therapies that favor CTLA4-Ig effect, affording a better control of transplant rejection and supporting their clinical applicability.

• Abatacept/pharmacology
• Abatacept/therapeutic use
• Biological Products/pharmacology
• CTLA-4 Antigen
• Calcineurin Inhibitors/pharmacology
• Cytokines/pharmacology
• Graft Rejection
• Graft Survival
• Humans
• Inflammation

• ALS
• JAK/STAT
• NK cells
• immune system
• tofacitinib

• Asthma
• JAK Inhibitor
• JAK/STAT pathway
• Janus kinase
• severe asthma

Regulatory T cells (Tregs) represent a distinct subpopulation of CD4⁺ T lymphocytes that promote immune tolerance and maintain immune system homeostasis. The dysfunction of Tregs is tightly associated with rheumatoid arthritis (RA). Although the complex pathogenic processes of RA remain unclear, studies on Tregs in RA have achieved substantial progress not only in fundamental research but also in clinical application. This review discusses the current knowledge of the characterizations, functions, and molecular mechanisms of Tregs in the pathogenesis of RA, and potential therapies for these disorders are also involved.

• Tregs
• dysfunctions
• molecular mechanisms
• rheumatoid arthritis
• therapeutic strategies

Psoriasis is a chronic inflammatory skin disease characterized by accelerated tumor necrosis factor-α/interleukin (IL)-23/IL-17 axis. Patients with psoriasis manifest functional defects in CD4⁺CD25⁺ forkhead box protein 3 (Foxp3)⁺ regulatory T cells (Tregs), which suppress the excess immune response and mediate homeostasis. Defects in Tregs contribute to the pathogenesis of psoriasis and may attribute to enhanced inhibition and/or impaired stimulation of Tregs. IL-23 induces the conversion of Tregs into type 17 helper T (Th17) cells. IL-17A reduces transforming growth factor (TGF)-β1 production, Foxp3 expression, and suppresses Treg activity. Short-chain fatty acids (SCFAs), butyrate, propionate, and acetate are microbiota-derived fermentation products that promote Treg development and function by inducing Foxp3 expression or inducing dendritic cells or intestinal epithelial cells to produce retinoic acids or TGF-β1, respectively. The gut microbiome of patients with psoriasis revealed reduced SCFA-producing bacteria, Bacteroidetes, and Faecallibacterium, which may contribute to the defect in Tregs. Therapeutic agents currently used, viz., anti-IL-23p19 or anti-IL-17A antibodies, retinoids, vitamin D3, dimethyl fumarate, narrow-band ultraviolet B, or those under development for psoriasis, viz., signal transducer and activator of transcription 3 inhibitors, butyrate, histone deacetylase inhibitors, and probiotics/prebiotics restore the defected Tregs. Thus, restoration of Tregs is a promising therapeutic target for psoriasis.

• butyrate
• dendritic cell
• forkhead box protein 3
• gut microbiome
• interleukin-17A
• interleukin-23
• psoriasis
• regulatory T cell
• short chain fatty acid

• basic (laboratory) research / science
• cytokines / cytokine receptors
• immunobiology
• immunosuppressant - fusion proteins and monoclonal antibodies: belatacept
• immunosuppression / immune modulation
• lymphocyte biology: activation
• signaling / signaling pathways: JAK / STAT
• tolerance: costimulation blockade

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is aberrantly activated in many malignancies. Inhibition of this pathway via JAK inhibitors (JAKinibs) is therefore an attractive therapeutic strategy underlined by Ruxolitinib (JAK1/2 inhibitor) being approved for the treatment of myeloproliferative neoplasms. As a consequence of the crucial role of the JAK-STAT pathway in the regulation of immune responses, inhibition of JAKs suppresses the immune system. This review article provides a thorough overview of the current knowledge on JAKinibs’ effects on immune cells in the context of hematological malignancies. We also discuss the potential use of JAKinibs for the treatment of diseases in which lymphocytes are the source of the malignancy.

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway propagates signals from a variety of cytokines, contributing to cellular responses in health and disease. Gain of function mutations in JAKs or STATs are associated with malignancies, with JAK2^V617F being the main driver mutation in myeloproliferative neoplasms (MPN). Therefore, inhibition of this pathway is an attractive therapeutic strategy for different types of cancer. Numerous JAK inhibitors (JAKinibs) have entered clinical trials, including the JAK1/2 inhibitor Ruxolitinib approved for the treatment of MPN. Importantly, loss of function mutations in JAK-STAT members are a cause of immune suppression or deficiencies. MPN patients undergoing Ruxolitinib treatment are more susceptible to infections and secondary malignancies. This highlights the suppressive effects of JAKinibs on immune responses, which renders them successful in the treatment of autoimmune diseases but potentially detrimental for cancer patients. Here, we review the current knowledge on the effects of JAKinibs on immune cells in the context of hematological malignancies. Furthermore, we discuss the potential use of JAKinibs for the treatment of diseases in which lymphocytes are the source of malignancies. In summary, this review underlines the necessity of a robust immune profiling to provide the best benefit for JAKinib-treated patients.

• JAK
• JAK inhibitor
• NK cells
• STAT
• T cells
• leukemia

In an earlier publication a binary model for chronic diseases classification has been proposed. According to the model, chronic diseases were classified as “high Treg” or “low Treg” diseases, depending on whether the immune response is anti- or pro-inflammatory and assuming that regulatory T cells are major determinants of the response. It turned out that most cancers are “high Treg” diseases, while autoimmune diseases are “low Treg”. This paper proposes a molecular cause for this binary response. The mechanism proposed depends on the effect of protein kinases on the immune system. Thus, protein kinases are classified as anti- or pro-inflammatory kinases depending on whether they drive “high Treg” or “low Treg” diseases. Observations reported in the earlier publication can be described in terms of anti-inflammatory kinase (AIK) or pro-inflammatory kinase (PIK) activity. Analysis of literature data reveals that the two classes of kinases display distinctive properties relating to their interactions with pathogens and environmental factors. Pathogens that promote Treg activity (“high Treg” pathogens) activate AIKs, while pathogens that suppress Treg activity (“low Treg” pathogens) activate PIKs. Diseases driven by AIKs are associated with “high Treg” pathogens while those diseases driven by PIKs are associated with “low Treg” pathogens. By promoting the activity of AIKs, alcohol consumption increases the risk of “high Treg” cancers but decreases the risk of some “low Treg” autoimmune diseases. JAK1 gain-of-function mutations are observed at high frequencies in autoimmune diseases while JAK1 loss-of-function mutations are observed at high frequencies in cancers with high tumor-infiltrating Tregs. It should also be noted that the corresponding two classes of protein kinase inhibitors are mutually exclusive in terms of their approved therapeutic indications. There is no protein kinase inhibitor that is approved for the treatment of both autoimmune diseases and “high Treg” cancers. Although there are exceptions to the conclusions presented above, these conclusions are supported by the great bulk of published data. It therefore seems that the binary division of protein kinases is a useful tool for elucidating (at the molecular level) many distinctive properties of cancers and autoimmune diseases.

• autoimmunity
• cancer
• inflammation
• protein kinases
• regulatory T cells

• Foxp3
• HCC
• IL-10
• STAT5
• iTregs

• Immune rejection
• Immunosuppressant
• Islet xenotransplantation
• Porcine islet

• Animals
• CD40 Ligand
• Graft Rejection/prevention & control
• Graft Survival
• Humans
• Immunomodulation
• Immunosuppressive Agents/therapeutic use
• Islets of Langerhans Transplantation
• Swine
• Transplantation, Heterologous

Regulatory T cells (Tregs) have a prominent role in the control of immune homeostasis. Pharmacological impact on their activity or balance with effector T cells could contribute to (impaired) clinical responses or adverse events. Monitoring treatment-related effects on T cell subsets may therefore be part of (pre-)clinical studies for medicinal products. However, the extent of immune monitoring performed in studies for marketing authorisation and the degree of correspondence with data available in the public domain is not known. We evaluated the presence of T cell immunomonitoring in 46 registration dossiers of monoclonal antibodies indicated for immune-related disorders and published scientific papers. We found that the depth of Treg analysis in registration dossiers was rather small. Nevertheless, data on treatment-related Treg effects are available in public academia-driven studies (post-registration) and suggest that Tregs may act as a biomarker for clinical responses. However, public data are fragmented and obtained with heterogeneity of experimental approaches from a diversity of species and tissues. To reveal the potential added value of T cell (and particular Treg) evaluation in (pre-)clinical studies, more cell-specific data should be acquired, at least for medicinal products with an immunomodulatory mechanism. Therefore, extensive analysis of T cell subset contribution to clinical responses and the relevance of treatment-induced changes in their levels is needed. Preferably, industry and academia should work together to obtain these data in a standardised manner and to enrich our knowledge about T cell activity in disease pathogenesis and therapies. This will ultimately elucidate the necessity of T cell subset monitoring in the therapeutic benefit-risk assessment.

• (pre-)clinical study recommendations
• JAK inhibitors
• biomarkers
• immunomonitoring
• monoclonal antibodies
• registration dossiers
• regulatory T cells

Maintenance of regulatory T cells CD4⁺CD25^highFOXP3⁺ (Treg) stability is vital for proper Treg function and controlling the immune equilibrium. Treg cells are heterogeneous and can reveal plasticity, exemplified by their potential to express IL-17A. TNFα-TNFR2 signaling controls IL-17A expression in conventional T cells via the anti-inflammatory ubiquitin-editing and kinase activity regulating enzyme TNFAIP3/A20 (tumor necrosis factor-alpha-induced protein 3). To obtain a molecular understanding of TNFα signaling on IL-17 expression in the human effector (_effTreg, CD25^highCD45RA⁻) Treg subset, we here studied the kinome activity regulation by TNFα signaling. Using FACS-sorted naïve (_naïveTreg, CD25^highCD45RA⁺) and _effTreg subsets, we demonstrated a reciprocal relationship between TNFα and IL-17A expression; _effTreg (TNFα^low/IL-17A^high) and _naïveTreg (TNFα^high/IL-17A^low). In _effTreg, TNFα-TNFR2 signaling prevented IL-17A expression, whereas inhibition of TNFα signaling by clinically applied anti-TNF antibodies led to increased IL-17A expression. Inhibition of TNFα signaling led to reduced TNFAIP3 expression, which, by using siRNA inhibition of TNFAIP3, appeared causally linked to increased IL-17A expression in _effTreg. Kinome activity screening of CD3/CD28-activated _effTreg revealed that anti-TNF-mediated neutralization led to increased kinase activity. STRING association analysis revealed that the TNF suppression _effTreg kinase activity network was strongly associated with kinases involved in TCR, JAK, MAPK, and PKC pathway signaling. Small-molecule-based inhibition of TCR and JAK pathways prevented the IL-17 expression in _effTreg. Together, these findings stress the importance of TNF-TNFR2 in regulating the kinase architecture of antigen-activated _effTreg and controlling IL-17 expression of the human Treg. These findings might be relevant for optimizing anti-TNF-based therapy and may aid in preventing Treg plasticity in case of Treg-based cell therapy.

• FOXP3
• IL-17A
• JAK
• TCR
• TNF
• Treg
• anti-TNF

• Cancer
• Cytokine
• JAK-STAT
• Kinase inhibitor

• National Research Foundation of Korea

Allergen-specific immunotherapy (AIT) is the only curative treatment for type-1 allergies, but sometimes shows limited therapeutic response as well as local and systemic side effects. Limited control of local inflammation and patient symptoms hampers its widespread use in severe allergic asthma.

Our aim was to evaluate whether AIT is more effective in suppression of local inflammation if performed under the umbrella of short-term non-specific immunomodulation using a small molecule inhibitor of JAK pathways.

In C57BL/6J mice, a model of ovalbumin (OVA)-induced allergic airway inflammation and allergen-specific immunotherapy was combined with the administration of Tofacitinib (TOFA, a FDA-approved JAK inhibitor) from 48 hours prior to 48 hours after therapeutic OVA-injection. The effect of TOFA on human FOXP3⁺CD4⁺ T cells was studied in vitro.

AIT combined with short-term TOFA administration was significantly more effective in suppressing total cell and eosinophil infiltration into the lung, local cytokine production including IL-1β and CXCL1 and showed a trend for the reduction of IL-4, IL-13, TNF-α and IL-6 compared to AIT alone. Furthermore, TOFA co-administration significantly reduced systemic IL-6, IL-1β and OVA-specific IgE levels and induced IgG1 to the same extent as AIT alone. Additionally, TOFA enhanced the induction of human FOXP3⁺CD4⁺ T cells.

This proof of concept study shows that JAK inhibition did not inhibit tolerance induction, but improved experimental AIT at the level of local inflammation. The improved control of local inflammation might extend the use of AIT in more severe conditions such as polyallergy, asthma and high-risk patients suffering from mastocytosis or anaphylaxis.

• Animals
• Antigens, CD/immunology
• Antigens, Neoplasm/immunology
• CD52 Antigen
• Calcineurin Inhibitors/pharmacology
• Glycoproteins/immunology
• Homeostasis
• Humans
• Immunosuppressive Agents/pharmacology
• Interleukin-2/pharmacology
• Interleukin-2 Receptor alpha Subunit/immunology
• Receptors, Interleukin-6/immunology
• T-Lymphocytes, Regulatory/drug effects
• T-Lymphocytes, Regulatory/immunology
• TOR Serine-Threonine Kinases/antagonists & inhibitors
• Vitamin D/metabolism

• T32 AI125222 NIAID NIH HHS
• U01 AI104347 NIAID NIH HHS
• U01 AI110658 NIAID NIH HHS
• U01 AI113362 NIAID NIH HHS

• Adjuvant-induced arthritis
• JAK inhibitor
• Memory B cells
• STAT3
• Th17
• Treg

• arthritis
• jak
• syk
• small molecule inhibitors
• anti-tnf therapy
• fibroblast-like synoviocytes
• osteoclasts
• memory cells

• Animals
• Antirheumatic Agents/administration & dosage
• Arthritis, Experimental/immunology
• Arthritis, Experimental/pathology
• Arthritis, Rheumatoid/immunology
• Arthritis, Rheumatoid/pathology
• Cyclohexylamines/administration & dosage
• Disease Models, Animal
• Drug Therapy, Combination/methods
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Immunophenotyping
• Intracellular Signaling Peptides and Proteins/antagonists & inhibitors
• Janus Kinases/antagonists & inhibitors
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred DBA
• Piperidines/administration & dosage
• Protein Kinase Inhibitors/administration & dosage
• Protein-Tyrosine Kinases/antagonists & inhibitors
• Pyrimidines/administration & dosage
• Pyrroles/administration & dosage
• Syk Kinase

• Seventh Framework Programme (BE)
• Innovative Medicines Initiative

In recent years, the incidence of inflammatory bowel disease (IBD) has been on the rise, extending to countries where it was infrequent in the past. As a result, the gap between high and low incidence countries is decreasing. The disease, therefore, has an important economic impact on the healthcare system. Advances in recent years in pharmacogenetics and clinical pharmacology have allowed for the development of treatment strategies adjusted to the patient profile. Concurrently, new drugs aimed at inflammatory targets have been developed that may expand future treatment options. This review examines advances in the optimization of existing drug treatments and the development of novel treatment options for IBD.

• Inflammatory bowel disease
• Future directions
• Pharmacogenetic
• Pharmacokinetics
• New drugs

• Animals
• Anti-Inflammatory Agents/pharmacokinetics
• Anti-Inflammatory Agents/therapeutic use
• Drug Discovery/trends
• Forecasting
• Gastrointestinal Agents/pharmacokinetics
• Gastrointestinal Agents/therapeutic use
• Humans
• Incidence
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/epidemiology
• Molecular Targeted Therapy/trends
• Pharmacogenetics/trends

• ALPS
• Autoimmunity
• SLE
• lymphoproliferation
• tofacitinib

• Host-directed therapy
• Tofacitinib
• Tuberculosis

Tofacitinib, a novel, oral Janus kinase inhibitor, demonstrated a dose-dependent efficacy for induction of clinical response and remission in patients with active ulcerative colitis (UC). The objective of the current study was to determine the effect of tofacitinib on patient-reported outcomes (PROs).

Eligible patients (≥18 years of age) with a diagnosis of active UC (total Mayo score of 6-12 points and moderately-to-severely active disease on sigmoidoscopy) were randomized in a 2:2:2:3:3 ratio to receive oral tofacitinib 0.5 mg, 3 mg, 10 mg, or 15 mg, or placebo twice daily (BID) for 8 weeks. PROs were assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Inflammatory Bowel Disease Patient-Reported Treatment Impact (IBD PRTI) survey.

At Week 8, mean IBDQ total scores had improved relative to baseline across all five treatment groups (baseline range 123.2-134.5; Week 8 range 149.6-175.4). Improvement from baseline was significantly greater (P = 0.001) for tofacitinib 15 mg BID versus placebo. For tofacitinib 15 mg BID, most patients reported satisfaction or extreme satisfaction, definite preference for tofacitinib, and definite willingness to use tofacitinib again on the IBD PRTI at week 8. Patients achieving endoscopic remission (Mayo endoscopy score of 0) had significantly higher IBDQ scores and favorable PRTI scores than those not achieving endoscopic remission.

Short-term treatment with tofacitinib BID was associated with dose-dependent improvement in health-related quality of life and patient preferences for tofacitinib. The results complement previously reported efficacy and safety data for the Phase II study. (NCT 00787202, November 6, 2008).

The online version of this article (doi:10.1186/s12876-015-0239-9) contains supplementary material, which is available to authorized users.

• autoimmunity
• kidney transplantation
• regulatory T cells
• sotrastaurin

JAK3 inhibition with the CP-690,550 compound has an immunosuppressive potency in murine models, nonhuman primates and humans. This drug blocks STAT5 activation in most T-cell subpopulations but less effectively in T-regulator cells. In low to moderate risk human kidney transplant recipients, combined with mycophenolate mofetil, steroids and an induction with basiliximab, CP-690,550 proved as effective as calcineurin inhibitors with regard to prevention of acute rejection but better than calcineurin inhibitors with regard to preservation of kidney function and histology. However, at the same time, an increased incidence of overimmunosuppression consequences (cytomegalovirus, BK virus and lymphoproliferation) was observed and led to discontinuation of this specific drug development in kidney transplantation.

• End Stage Liver Disease/surgery
• Humans
• Immune Tolerance/immunology
• Immunosuppression Therapy
• Liver Transplantation/immunology
• Liver Transplantation/trends
• Transplantation Chimera/immunology
• Transplantation Tolerance/immunology

• Administration, Oral
• Adult
• Colitis, Ulcerative/drug therapy
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Humans
• Janus Kinases/antagonists & inhibitors
• Lipoproteins, HDL/blood
• Lipoproteins, LDL/blood
• Male
• Middle Aged
• Piperidines
• Protein Kinase Inhibitors/administration & dosage
• Protein Kinase Inhibitors/adverse effects
• Protein Kinase Inhibitors/therapeutic use
• Pyrimidines/administration & dosage
• Pyrimidines/adverse effects
• Pyrimidines/therapeutic use
• Pyrroles/administration & dosage
• Pyrroles/adverse effects
• Pyrroles/therapeutic use
• Remission Induction

• Adalimumab
• Adult
• Antibodies, Monoclonal, Humanized/administration & dosage
• Antibodies, Monoclonal, Humanized/adverse effects
• Antibodies, Monoclonal, Humanized/therapeutic use
• Antirheumatic Agents/administration & dosage
• Antirheumatic Agents/adverse effects
• Antirheumatic Agents/therapeutic use
• Arthritis, Rheumatoid/drug therapy
• Arthritis, Rheumatoid/immunology
• Cholesterol/blood
• Double-Blind Method
• Drug Therapy, Combination
• Enzyme Inhibitors/adverse effects
• Enzyme Inhibitors/therapeutic use
• Female
• Humans
• Janus Kinase 3/antagonists & inhibitors
• Least-Squares Analysis
• Leukocyte Count
• Lipoproteins/blood
• Male
• Methotrexate/therapeutic use
• Middle Aged
• Neutrophils
• Piperidines
• Pyrimidines/administration & dosage
• Pyrimidines/adverse effects
• Pyrimidines/therapeutic use
• Pyrroles/administration & dosage
• Pyrroles/adverse effects
• Pyrroles/therapeutic use
• Treatment Outcome

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Autoimmune Diseases/drug therapy
• Autoimmune Diseases/immunology
• Graft Rejection/drug therapy
• Graft Rejection/immunology
• Humans
• Janus Kinases/antagonists & inhibitors
• Janus Kinases/immunology
• Myeloproliferative Disorders/drug therapy
• Myeloproliferative Disorders/immunology
• Neoplasms/drug therapy
• Neoplasms/immunology
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Receptors, Cytokine/immunology
• Signal Transduction

• ZIA AR041106 Intramural NIH HHS
• ZIA AR041106-17 Intramural NIH HHS

• Animals
• Antirheumatic Agents/pharmacology
• Arthritis, Rheumatoid/metabolism
• Arthritis, Rheumatoid/pathology
• Autocrine Communication/drug effects
• Cells, Cultured
• Chemokines/biosynthesis
• Drug Evaluation, Preclinical/methods
• Fibroblasts/drug effects
• Humans
• Interferon Type I/physiology
• Interleukin-6/antagonists & inhibitors
• Interleukin-6/pharmacology
• Janus Kinase 3/antagonists & inhibitors
• Mice
• Phosphorylation/drug effects
• Piperidines
• Pyrimidines/pharmacology
• Pyrroles/pharmacology
• STAT1 Transcription Factor/antagonists & inhibitors
• STAT1 Transcription Factor/metabolism
• STAT3 Transcription Factor/antagonists & inhibitors
• STAT3 Transcription Factor/metabolism
• Synovial Membrane/drug effects
• Synovial Membrane/pathology
• Tumor Necrosis Factor-alpha/antagonists & inhibitors
• Tumor Necrosis Factor-alpha/pharmacology