ABSTRACT
PURPOSE: Bleeding risk evaluation of thrombocytopenic patients admitted in ICU has been poorly investigated. METHODS: A prospective observational study conducted in an 18-bed medical ICU. Consecutive patients with thrombocytopenia (<150 Giga/L) and no bleeding at admission were included. RESULTS: Over one year, 91 patients were included, mainly men (63%), with an age of 61 [46-68] years and a SOFA score of 6 [3-8]. Twenty-three patients (25%) had an hemorrhagic event during ICU stay, mainly digestive (n = 9; 39%) and urological (n = 6; 26%). The time between ICU admission and bleeding was 8 [2-19] days. Almost half of bleeding events required vasopressor infusion and a hemostatic procedure. At admission, two variables were significantly different between the Bleeding and No-Bleeding groups: plasma urea level was significantly higher in the Bleeding group (9 [5.1; 13] vs. 13 [8.9; 31] mmol/L; p < 0.001) and the presence of skin purpura was associated with a 3-fold higher risk for bleeding during ICU stay (HR: 3.4 [1.3-8.3]; p < 0.05). In contrast, admission platelet count was not significantly different between the 2 groups (90 [32; 128] vs 62 [36; 103] G/L; p = 0.26). CONCLUSION: Plasma urea levels and the presence of skin purpura are helpful in identifying thrombocytopenic patients at high-risk of bleeding during ICU stay.
Subject(s)
Purpura , Thrombocytopenia , Aged , Female , Humans , Male , Middle Aged , Hemorrhage/epidemiology , Intensive Care Units , Prognosis , Thrombocytopenia/complications , Thrombocytopenia/epidemiology , Urea , Prospective StudiesABSTRACT
Tumor-draining lymph node (TDLN) invasion by metastatic cells in breast cancer correlates with poor prognosis and is associated with local immunosuppression, which can be partly mediated by regulatory T cells (Tregs). Here, we study Tregs from matched tumor-invaded and non-invaded TDLNs, and breast tumors. We observe that Treg frequencies increase with nodal invasion, and that Tregs express higher levels of co-inhibitory/stimulatory receptors than effector cells. Also, while Tregs show conserved suppressive function in TDLN and tumor, conventional T cells (Tconvs) in TDLNs proliferate and produce Th1-inflammatory cytokines, but are dysfunctional in the tumor. We describe a common transcriptomic signature shared by Tregs from tumors and nodes, including CD80, which is significantly associated with poor patient survival. TCR RNA-sequencing analysis indicates trafficking between TDLNs and tumors and ongoing Tconv/Treg conversion. Overall, TDLN Tregs are functional and express a distinct pattern of druggable co-receptors, highlighting their potential as targets for cancer immunotherapy.
Subject(s)
Lymph Nodes/pathology , Lymphatic Metastasis/immunology , T-Lymphocytes, Regulatory/immunology , B7-1 Antigen/metabolism , Breast Neoplasms/pathology , Female , Humans , Immunosuppression Therapy , Lymph Nodes/cytology , Lymph Nodes/immunology , Lymphatic Metastasis/pathology , T-Lymphocytes, Regulatory/metabolismSubject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Blood Transfusion/ethics , Hematinics/administration & dosage , Jehovah's Witnesses , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Dose-Response Relationship, Drug , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Female , Humans , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Prednisone/administration & dosage , Prednisone/adverse effects , Treatment Outcome , Vincristine/administration & dosage , Vincristine/adverse effectsABSTRACT
Type 1 diabetes (T1D) is characterized by a chronic, progressive autoimmune attack against pancreas-specific antigens, effecting the destruction of insulin-producing ß-cells. Here we show interleukin-2 (IL-2) is a non-pancreatic autoimmune target in T1D. Anti-IL-2 autoantibodies, as well as T cells specific for a single orthologous epitope of IL-2, are present in the peripheral blood of non-obese diabetic (NOD) mice and patients with T1D. In NOD mice, the generation of anti-IL-2 autoantibodies is genetically determined and their titre increases with age and disease onset. In T1D patients, circulating IgG memory B cells specific for IL-2 or insulin are present at similar frequencies. Anti-IL-2 autoantibodies cloned from T1D patients demonstrate clonality, a high degree of somatic hypermutation and nanomolar affinities, indicating a germinal centre origin and underscoring the synergy between cognate autoreactive T and B cells leading to defective immune tolerance.
Subject(s)
Diabetes Mellitus, Type 1/immunology , Immune Tolerance , Interleukin-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Autoantibodies/immunology , Epitopes/immunology , Female , Humans , Immunoglobulin G/immunology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred NOD , Middle Aged , Pancreas/immunology , Peptides/immunology , T-Lymphocytes/cytology , Young AdultABSTRACT
Interleukin-2 (IL-2) is an old molecule with brand new functions. Indeed, IL-2 has been first described as a T-cell growth factor but recent data pointed out that its main function in vivo is the maintenance of immune tolerance. Mechanistically, IL-2 is essential for the development and function of CD4(+) Foxp3(+) regulatory T cells (Treg cells) that are essential players in the control of immune responded to self, tumors, microbes and grafts. Treg cells are exquisitely sensitive to IL-2 due to their constitutive expression of the high affinity IL-2 receptor (IL-2R) and the new paradigm suggests that low-doses of IL-2 could selectively boost Treg cells in vivo. Consequently, a growing body of clinical research is aiming at using IL-2 at low doses as a tolerogenic drug to boost endogenous Treg cells in patients suffering from autoimmune or inflammatory conditions. In this manuscript, we briefly review IL-2/IL-2R biology and the role of IL-2 in the development, maintenance, and function of Treg cells; and also its effects on other immune cell populations such as CD4(+) T helper cells and CD8(+) memory T cells. Then, focusing on type 1 diabetes, we review the preclinical studies and clinical trials supporting the use of low-doses IL-2 as a tolerogenic immunotherapy. Finally, we discuss the limitations and future directions for IL-2 based immunotherapy.
Subject(s)
Immune Tolerance , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Animals , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Autoimmune Diseases/therapy , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/therapy , Humans , Immunomodulation , Immunotherapy , Inflammation/immunology , Inflammation/metabolism , Inflammation/therapy , Interleukin-2/metabolism , Interleukin-2/therapeutic use , Mice , Receptors, Interleukin-2/metabolismABSTRACT
The tolerogenic anti-CD3ε monoclonal Abs (anti-CD3) are promising compounds for the treatment of type 1 diabetes. Anti-CD3 administration induces transient T cell depletion both in preclinical and in clinical studies. Notably, the said depletion mainly affects CD4(+) but not CD8(+) T cells. Moreover, type 1 diabetes reversal in preclinical models is accompanied by the selective expansion of CD4(+)Foxp3(+) T regulatory (Treg) cells, which are fundamental for the long-term maintenance of anti-CD3-mediated tolerance. The mechanisms that lead to this immune-shaping by affecting mainly CD4(+) T effector cells while sparing CD4(+)Foxp3(+) Treg cells have still to be fully elucidated. This study shows that CD3 expression levels differ from one T cell subset to another. CD4(+)Foxp3(-) T cells contain higher amounts of CD3 molecules than do CD4(+)Foxp3(+) and CD8(+) T cells in both mice and humans. The said differences correlate with the anti-CD3-mediated immune resetting that occurs in vivo after anti-CD3 administration in diabetic NOD mice. Additionally, transcriptome analysis demonstrates that CD4(+)Foxp3(+) Treg cells are significantly less responsive than are CD4(+)Foxp3(-) T cells to anti-CD3 treatment at a molecular level. Thus, heterogeneity in CD3 expression seems to confer to the various T cell subsets differing susceptibility to the in vivo tolerogenic anti-CD3-mediated modulation. These data shed new light on the molecular mechanism that underlies anti-CD3-mediated immune resetting and thus may open new opportunities to improve this promising treatment.
Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , CD3 Complex/immunology , Diabetes Mellitus, Type 1/drug therapy , Hypoglycemic Agents/pharmacology , Immunologic Factors/pharmacology , T-Lymphocyte Subsets/drug effects , Adolescent , Animals , Antibodies, Monoclonal, Humanized/immunology , CD3 Complex/genetics , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Child , Child, Preschool , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/pathology , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/immunology , Gene Expression Regulation , Genetic Heterogeneity , Humans , Hypoglycemic Agents/immunology , Immune Tolerance/drug effects , Lymphocyte Depletion , Male , Mice , Mice, Inbred NOD , Signal Transduction , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/pathology , Young AdultABSTRACT
We previously showed that Trypanosomacruzi infection in C57BL/6 mice results in a lethal infection linked to unbalanced pro- and anti-inflammatory mediators production. Here, we examined the dynamics of CD4(+)Foxp3(+) regulatory T (Treg) cells within this inflammatory and highly Th1-polarized environment. Treg cells showed a reduced proliferation rate and their frequency is progressively reduced along infection compared to effector T (Teff) cells. Also, a higher fraction of Treg cells showed a naïve phenotype, meanwhile Teff cells were mostly of the effector memory type. T. cruzi infection was associated with the production of pro- and anti-inflammatory cytokines, notably IL-27p28, and with the induction of T-bet and IFN-γ expression in Treg cells. Furthermore, endogenous glucocorticoids released in response to T. cruzi-driven immune activation were crucial to sustain the Treg/Teff cell balance. Notably, IL-2 plus dexamethasone combined treatment before infection was associated with increased Treg cell proliferation and expression of GATA-3, IL-4 and IL-10, and increased mice survival time. Overall, our results indicate that therapies aimed at specifically boosting Treg cells, which during T. cruzi infection are overwhelmed by the effector immune response, represent new opportunities for the treatment of Chagas disease, which is actually only based on parasite-targeted chemotherapy.
Subject(s)
Chagas Disease/immunology , T-Lymphocytes, Regulatory/immunology , Th1 Cells/immunology , Trypanosoma cruzi/immunology , Adrenalectomy , Animals , Chagas Cardiomyopathy/immunology , Chagas Cardiomyopathy/pathology , Chagas Disease/pathology , Corticosterone/blood , Dexamethasone/pharmacology , Disease Models, Animal , GATA3 Transcription Factor/drug effects , GATA3 Transcription Factor/immunology , Glucocorticoids/pharmacology , Interferon-gamma/drug effects , Interferon-gamma/immunology , Interleukin-10/immunology , Interleukin-2/pharmacology , Interleukin-4/immunology , Mice , Mice, Inbred C57BL , Muscle, Skeletal/pathology , Myocardium/pathology , Phenotype , T-Lymphocytes, Regulatory/drug effects , Th1 Cells/drug effectsABSTRACT
Low-dose IL-2 administration can control autoimmunity by specifically activating CD4(+) Foxp3(+) regulatory T cells (Tregs). Here, we studied IL-2-based immunotherapy in experimental graft-versus-host disease (GVHD). IL-2 administration to donor mice induced a dose-dependent expansion of Tregs in the graft but was insufficient to control GVHD. IL-2 administration to allogeneic-grafted recipient mice activated T-conventional cells (Tcons) and did not prevent GVHD. This loss of IL-2 selectivity toward Tregs was explained by an IL-2-induced increase in the IL-2 receptor α-chain expression on Tcons. Finally, in xeno-GVHD generated by human PBMCs transplanted into immunodeficient mice, low-dose IL-2 increased Treg frequencies but did neither control pro-inflammatory cytokine production by pathogenic Tcons, nor prevented GVHD. Furthermore, combination of low-dose IL-2 with rapamycin was ineffective in this model. Our results indicate that limitations on the use of IL-2 during acute GVHD are likely due to the massive activation of the allogeneic T cells unique to this setting.
Subject(s)
Antineoplastic Agents/pharmacology , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Interleukin-2/pharmacology , T-Lymphocytes, Regulatory/immunology , Acute Disease , Allografts , Animals , Disease Models, Animal , Graft vs Host Disease/drug therapy , Graft vs Host Disease/genetics , Graft vs Host Disease/immunology , Graft vs Host Disease/pathology , Heterografts , Humans , Immunosuppressive Agents/pharmacology , Interleukin-2 Receptor alpha Subunit/genetics , Mice , Mice, Transgenic , Sirolimus/pharmacology , T-Lymphocytes, Regulatory/pathologyABSTRACT
CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are essential players in the control of immune responses. Recently, accordingly to their origin, two main subsets of Tregs have been described: thymus-derived Tregs (tTregs) and peripherally derived Tregs (pTregs). Numerous signaling pathways including the IL-2/STAT5 or the TGF-ß/Smad3 pathways play a crucial role in segregating the two lineages. Here, we review some of the information existing on the distinct requirements of IL-2, TGF-ß, and TNF-α three major cytokines involved in tTreg and pTreg generation, homeostasis and function. Today it is clear that signaling via the IL-2Rß chain (CD122) common to IL-2 and IL-15 is required for proper differentiation of tTregs and for tTreg and pTreg survival in the periphery. This notion has led to the development of promising therapeutic strategies based on low-dose IL-2 administration to boost the patients' own Treg compartment and dampen autoimmunity and inflammation. Also, solid evidence points to TGF-ß as the master regulator of pTreg differentiation and homeostasis. However, therapeutic administration of TGF-ß is difficult to implement due to toxicity and safety issues. Knowledge on the role of TNF-α on the biology of Tregs is fragmentary and inconsistent between mice and humans. Moreover, emerging results from the clinical use of TNF-α inhibitors indicate that part of their anti-inflammatory effect may be dependent on their action on Tregs. Given the profusion of clinical trials testing cytokine administration or blocking to modulate inflammatory diseases, a better knowledge of the effects of cytokines on tTregs and pTregs biology is necessary to improve the efficiency of these immunotherapies.
ABSTRACT
Administration of low-dose interleukin-2 (IL-2) alone or combined with rapamycin (RAPA) prevents hyperglycemia in NOD mice. Also, low-dose IL-2 cures recent-onset type 1 diabetes (T1D) in NOD mice, partially by boosting pancreatic regulatory T cells (Treg cells). These approaches are currently being evaluated in humans. Our objective was to study the effect of higher IL-2 doses (250,000-500,000 IU daily) as well as low-dose IL-2 (25,000 IU daily) and RAPA (1 mg/kg daily) (RAPA/IL-2) combination. We show that, despite further boosting of Treg cells, high doses of IL-2 rapidly precipitated T1D in prediabetic female and male mice and increased myeloid cells in the pancreas. Also, we observed that RAPA counteracted IL-2 effects on Treg cells, failed to control IL-2-boosted NK cells, and broke IL-2-induced tolerance in a reversible way. Notably, the RAPA/IL-2 combination failure to cure T1D was associated with an unexpected deleterious effect on glucose homeostasis at multiple levels, including ß-cell division, glucose tolerance, and liver glucose metabolism. Our data help to understand the therapeutic limitations of IL-2 alone or RAPA/IL-2 combination and could lead to the design of improved therapies for T1D.