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1.
Curr Cardiol Rep ; 26(5): 339-347, 2024 May.
Article in English | MEDLINE | ID: mdl-38472629

ABSTRACT

PURPOSE OF REVIEW: Transcatheter aortic valve replacement (TAVR) has been a revolutionary therapy in the treatment of aortic valve stenosis. The risk of stroke associated with TAVR has decreased significantly since its introduction; however, it remains a devastating complication when it does occur. RECENT FINDINGS: Many of the strokes associated with TAVR occur peri-procedurally and are thought to be due to embolic debris entering the cerebrovascular circulation. A number of different cerebral embolic protection devices (CEPD) have been developed and are in various stages of testing and use. The results from clinical trials evaluating the role for CEPD to reduce the risk of stroke have been mixed. As a result, their uptake has been very heterogeneous. This review provides a summary of the diverse CEPD devices available for use and outlines the clinical evidence available to date.


Subject(s)
Aortic Valve Stenosis , Embolic Protection Devices , Intracranial Embolism , Transcatheter Aortic Valve Replacement , Humans , Transcatheter Aortic Valve Replacement/instrumentation , Transcatheter Aortic Valve Replacement/adverse effects , Aortic Valve Stenosis/surgery , Intracranial Embolism/prevention & control , Intracranial Embolism/etiology , Stroke/prevention & control , Stroke/etiology
6.
Sci China Life Sci ; 65(3): 451-465, 2022 03.
Article in English | MEDLINE | ID: mdl-35015247

ABSTRACT

Amblyopia resulting from early deprivation of vision or defocus in one eye reflects an imbalance of input from the eyes to the visual cortex. We tested the hypothesis that asynchronous stimulation of the two eyes might induce synaptic plasticity and rebalance input. Experiments on normal adults showed that repetitive brief exposure of grating stimuli, with the onset of each stimulus delayed by 8.3 ms in one eye, results in a shift in perceptual eye dominance. Clinical studies (Clinical trial registration number: ChiCTR2100049130), using popular 3D movies with similar asynchrony between the two eyes (amblyopic eye stimulated first) to treat anisometropic amblyopia, established that just 10.5 h of conditioning over <3 weeks produced improvement that met criteria for successful treatment. The benefits of asynchronous conditioning accumulate over 20-30 45 min sessions, and are maintained for at least 2 years. Finally, we demonstrate that asynchronous binocular treatment alone is more effective than patching only. This novel treatment is popular with children and is some 50 times more efficient than patching alone.


Subject(s)
Amblyopia/therapy , Neuronal Plasticity/physiology , Adult , Amblyopia/physiopathology , Child , Child, Preschool , Dominance, Ocular , Female , Humans , Male , Visual Acuity
9.
J Cardiothorac Vasc Anesth ; 33(6): 1620-1626, 2019 Jun.
Article in English | MEDLINE | ID: mdl-30713052

ABSTRACT

OBJECTIVE: To investigate whether pulse pressure (PP) in anesthetized patients undergoing cardiac surgery before and after cardiopulmonary bypass (CPB) is associated with higher postoperative acute kidney injury (AKI) stage. DESIGN: Retrospective cohort of 597 patients undergoing cardiac surgery. SETTING: Single academic health care center. PARTICIPANTS: Adult patients undergoing cardiac surgery requiring CPB (coronary artery bypass grafting, valve, aortic, or combined surgery). INTERVENTIONS: Pulse pressure was assessed during 3 time periods: pre- and post-CPB, and in the first postoperative hour in the intensive care unit. Pulse pressure, patient characteristics, and intraoperative variables were evaluated using univariable generalized estimating equation analysis for a relationship with AKI stage. Significant risk factors from the univariable analysis then were evaluated in a multivariable generalized estimating equation analysis. Acute kidney injury stage was defined using the Acute Kidney Injury Network criteria. PRIMARY OUTCOME: Stage of postoperative AKI. MEASUREMENTS AND MAIN RESULTS: Intraoperative prebypass PP was associated independently and significantly with postoperative AKI stage (odds ratio 1.0107; 95% Confidence Interval, 1.0046-1.0168; p = 0.0005). For every 1-mmHg increase in PP, the odds of a higher AKI stage increased 1.07%. The 2 other periods were not found to be significant predictors of AKI stage. CONCLUSION: During general anesthesia prior to initiation of CPB, elevated PP is significantly predictive of postoperative AKI stage. This finding merits further research.


Subject(s)
Acute Kidney Injury/etiology , Anesthesia, General/methods , Blood Pressure/physiology , Cardiopulmonary Bypass/adverse effects , Postoperative Complications/epidemiology , Acute Kidney Injury/diagnosis , Acute Kidney Injury/physiopathology , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Male , Middle Aged , Morbidity/trends , Preoperative Period , Prognosis , Retrospective Studies , Risk Factors , Survival Rate/trends , United States/epidemiology
10.
J Clin Pharmacol ; 58(1): 7-24, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29136276

ABSTRACT

Two pharmacologic approaches that are currently at the forefront of treating advanced cancer are those that center on disrupting critical growth/survival signaling pathways within tumor cells (commonly referred to as "targeted therapies") and those that center on enhancing the capacity of a patient's immune system to mount an antitumor response (immunotherapy). Maximizing responses to both of these approaches requires an understanding of the oncogenic events present in a given patient's tumor and the nature of the tumor-immune microenvironment. Although these 2 modalities were developed and initially used independently, combination regimens are now being tested in clinical trials, underscoring the need to understand how targeted therapies influence immunologic events. Translational studies and preclinical models have demonstrated that targeted therapies can influence immune cell trafficking, the production of and response to chemokines and cytokines, antigen presentation, and other processes relevant to antitumor immunity and immune homeostasis. Moreover, because these and other effects of targeted therapies occur in nonmalignant cells, targeted therapies are being evaluated for use in applications outside of oncology.


Subject(s)
Neoplasms/drug therapy , Neoplasms/immunology , Animals , Humans , Immunotherapy/methods , Medical Oncology/methods , Molecular Targeted Therapy/methods , Neoplasms/therapy
11.
Blood Adv ; 1(11): 628-643, 2017 Apr 25.
Article in English | MEDLINE | ID: mdl-28713871

ABSTRACT

Industrial-scale expansion of mesenchymal stromal cells (MSCs) is often used in clinical trials, and the effect of replicative senescence on MSC functionality is of mechanistic interest. Senescent MSCs exhibit cell-cycle arrest, cellular hypertrophy, and express the senescent marker ß-galactosidase. Although both fit and senescent MSCs display intact lung-homing properties in vivo, senescent MSCs acquire a significant defect in inhibiting T-cell proliferation and cytokine secretion in vitro. IFNγ does not upregulate HLA-DR on senescent MSCs, whereas its silencing did not reverse fit MSCs' immunosuppressive properties. Secretome analysis of MSC and activated peripheral blood mononuclear cell coculture demonstrate that senescent MSCs are significantly defective in up (vascular endothelial growth factor [VEGF], granulocyte colony-stimulating factor [GCSF], CXCL10, CCL2) or down (IL-1ra, IFNγ, IL-2r, CCL4, tumor necrosis factor-α, IL-5) regulating cytokines/chemokines. Unlike indoleamine 2,3 dioxygenase (IDO), silencing of CXCL9, CXCL10, CXCL11, GCSF, CCL2, and exogenous addition of VEGF, fibroblast growth factor-basic do not modulate MSCs' immunosuppressive properties. Kynurenine levels were downregulated in senescent MSC cocultures compared with fit MSC counterparts, and exogenous addition of kynurenine inhibits T-cell proliferation in the presence of senescent MSCs. IFNγ prelicensing activated several immunomodulatory genes including IDO in fit and senescent MSCs at comparable levels and significantly enhanced senescent MSCs' immunosuppressive effect on T-cell proliferation. Our results define immune functional defects acquired by senescent MSCs, which are reversible by IFNγ prelicensing.

12.
J Neurosci ; 36(50): 12598-12610, 2016 12 14.
Article in English | MEDLINE | ID: mdl-27821578

ABSTRACT

Although B cells are traditionally known for their role in propagating proinflammatory immune responses, their immunosuppressive effects have only recently begun to be appreciated. How these regulatory B cells (Bregs) suppress the immune response remains to be worked out in detail. In this article, we show that Bregs can induce the formation of conventional FoxP3+ regulatory T cells (Tregs), as well as a more recently described CD49b+CD223+ regulatory T-cell subset, known as type 1 regulatory T cells (Tr1s). When Bregs are transferred into mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, they home to the spleen and mesenteric lymph nodes, leading to an expansion of Tregs and Tr1 in vivo Tregs and Tr1s are also found in greater proportions in the CNS of mice with EAE treated with Bregs and are correlated with the remission of symptoms. The discovery that Bregs induce the formation of regulatory T-cell subsets in vivo may herald their use as immunosuppressive agents in adoptive cellular therapies for autoimmune pathologies. SIGNIFICANCE STATEMENT: Although B cells are traditionally known for their role in propagating proinflammatory immune responses, their immunosuppressive effects have only recently begun to be appreciated. How regulatory B cells (Bregs) suppress the immune response remains to be fully understood. In this article, we show that Bregs can induce the formation of conventional regulatory T cells (Tregs) as well as type 1 regulatory T cells (Tr1s). When Bregs are transferred into mice with experimental autoimmune encephalomyelitis (EAE), they home to secondary lymphoid organs, leading to an expansion of Tregs and Tr1s in vivo Tregs and Tr1s are also found in greater proportions in the CNS of mice with EAE treated with Bregs and are correlated with the remission of symptoms.


Subject(s)
B-Lymphocytes, Regulatory/physiology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Interleukin-10/biosynthesis , T-Lymphocytes/metabolism , Adoptive Transfer , Animals , CD4-Positive T-Lymphocytes/metabolism , Child, Preschool , Coculture Techniques , Forkhead Transcription Factors/metabolism , Humans , Leukocytes/pathology , Lymph Nodes/pathology , Mice , Mice, Inbred C57BL , Multiple Sclerosis/pathology , Spleen/pathology
13.
Cancer Res ; 76(19): 5683-5695, 2016 10 01.
Article in English | MEDLINE | ID: mdl-27488533

ABSTRACT

The clinical efficacy of immune cytokines used for cancer therapy is hampered by elements of the immunosuppressive tumor microenvironment such as TGFß. Here we demonstrate that FIST15, a recombinant chimeric protein composed of the T-cell-stimulatory cytokine IL15, the sushi domain of IL15Rα and a TGFß ligand trap, can overcome immunosuppressive TGFß to effectively stimulate the proliferation and activation of natural killer (NK) and CD8+ T cells with potent antitumor properties. FIST15-treated NK and CD8+ T cells produced more IFNγ and TNFα compared with treatment with IL15 and a commercially available TGFß receptor-Fc fusion protein (sTßRII) in the presence of TGFß. Murine B16 melanoma cells, which overproduce TGFß, were lysed by FIST15-treated NK cells in vitro at doses approximately 10-fold lower than NK cells treated with IL15 and sTßRII. Melanoma cells transduced to express FIST15 failed to establish tumors in vivo in immunocompetent murine hosts and could only form tumors in beige mice lacking NK cells. Mice injected with the same cells were also protected from subsequent challenge by unmodified B16 melanoma cells. Finally, mice with pre-established B16 melanoma tumors responded to FIST15 treatment more strongly compared with tumors treated with control cytokines. Taken together, our results offer a preclinical proof of concept for the use of FIST15 as a new class of biological therapeutics that can coordinately neutralize the effects of immunosuppressive TGFß in the tumor microenvironment while empowering tumor immunity. Cancer Res; 76(19); 5683-95. ©2016 AACR.


Subject(s)
Interleukin-15/pharmacology , Killer Cells, Natural/drug effects , Neoplasms/drug therapy , Recombinant Fusion Proteins/pharmacology , Transforming Growth Factor beta/pharmacology , Animals , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Humans , Killer Cells, Natural/immunology , Lymphocyte Activation/drug effects , Mice , Mice, Inbred C57BL , Neoplasms/immunology , Tumor Microenvironment
14.
J Transl Med ; 14(1): 106, 2016 04 27.
Article in English | MEDLINE | ID: mdl-27118475

ABSTRACT

BACKGROUND: Chronic lymphocytic leukemia (CLL) remains incurable with standard therapy, and is characterized by excessive expansion of monoclonal abnormal mature B cells and more regulatory immune properties of T cell compartment. Thus, developing novel strategies to enhance immune function merits further investigation as a possible therapy for CLL. METHODS: We generated a fusion cytokine (fusokine) arising from the combination of human GM-CSF and IL-4 (named GIFT4). Primary CLL cells were treated with GIFT4 or GM-CSG and IL-4 in vitro. GIFT4-triggered STAT5 signaling in CLL cells was examined by Western blot. The phenotype and secretome of GIFT4-treated CLL cells (GIFT4-CLL cells), and the immune stimulatory function of GIFT4-CLL cells on autologous T cells were analyzed by flow cytometry and luminex assay. RESULTS: GIFT4-CLL up-regulated the expression of co-stimulatory molecules CD40, CD80 and CD86 and adhesion molecule CD54. GIFT4-CLL cells secreted IL-1ß, IL-6, ICAM-1 and substantial IL-2 relative to unstimulated CLL cells. GIFT4 treatment led to JAK1, JAK2 and JAK3-mediated hyper-phosphorylation of STAT5 in primary CLL cells, which is essential for GIFT4-triggered conversion of CLL cells. GIFT4-CLL cells directly propelled the expansion of autologous IFN-γ-producing CD314(+) cytotoxic T cells in vitro, and that these could lyse autologous CLL cells. Furthermore, administration of GIFT4 protein promoted the expansion of human T cells in NOD-scid IL2Rγ(null) immune deficient mice adoptively pre-transferred with peripheral blood mononuclear cells from subjects with CLL. CONCLUSION: GIFT4 has potent capability to converts primary CLL cells into APC-like immune helper cells that initiate a T cell driven anti-CLL immune response.


Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Interleukin-4/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Recombinant Fusion Proteins/pharmacology , T-Lymphocytes, Helper-Inducer/immunology , Adult , Aged , Animals , Antigen-Presenting Cells/drug effects , Antigen-Presenting Cells/metabolism , Cell Proliferation/drug effects , Cross-Priming/drug effects , Cytotoxicity, Immunologic/drug effects , Female , Humans , Janus Kinases/metabolism , Male , Mice , Middle Aged , Phenotype , Proteome/metabolism , STAT5 Transcription Factor/metabolism , Signal Transduction/drug effects , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/drug effects
15.
Clin Transl Immunology ; 4(5): e37, 2015 May.
Article in English | MEDLINE | ID: mdl-26131365

ABSTRACT

The competence of cellular immunity depends on a diverse T-cell receptor (TCR) repertoire arising from thymic output. Normal thymopoiesis arises from marrow-derived CD3(-)CD4(-)CD8(-) triple-negative T-cell progenitors (TN), which develop into mature single-positive (SP) CD4 or CD8 T cells after expressing both CD4 and CD8 (double-positive, DP) transiently, leading to de novo T-cell production. Interleukin-7 (IL7) is a singularly important common γ-chain IL involved in normal thymic development. Our previous work has demonstrated that γc cytokines fused with granulocyte-macrophage colony stimulating factor (GMCSF) at the N-terminus acquire unheralded biological properties. Therefore, to enhance thymopoiesis, we developed a novel biopharmaceutical based on the fusion of GMCSF and IL7, hereafter GIFT7. Systemic administration of GIFT7 leads to cortical thymic hyperplasia including the specific expansion of CD44(int)CD25(-) double-negative 1 (DN1) thymic progenitors. During murine cytomegalovirus (mCMV) infection of aged animals, GIFT7-mediated neo-thymopoiesis led to increased absolute numbers of viral-specific CD8(+) T cell. Our work demonstrated that thymic precursors can be therapeutically repopulated and its reconstitution leads to meaningful central and peripheral T-cell neogenesis, correcting immune dysfunction arising from age-associated thymic atrophy.

16.
World J Gastroenterol ; 21(16): 4779-87, 2015 Apr 28.
Article in English | MEDLINE | ID: mdl-25944991

ABSTRACT

Utilization of mesenchymal stromal cells (MSCs) for the treatment of Crohn's disease and ulcerative colitis is of translational interest. Safety of MSC therapy has been well demonstrated in early phase clinical trials but efficacy in randomized clinical trials needs to be demonstrated. Understanding MSC mechanisms of action to reduce gut injury and inflammation is necessary to improve current ongoing and future clinical trials. However, two major hurdles impede the direct translation of data derived from animal experiments to the clinical situation: (1) limitations of the currently available animal models of colitis that reflect human inflammatory bowel diseases (IBD). The etiology and progression of human IBD are multifactorial and hence a challenge to mimic in animal models; and (2) Species specific differences in the functionality of MSCs derived from mice versus humans. MSCs derived from mice and humans are not identical in their mechanisms of action in suppressing inflammation. Thus, preclinical animal studies with murine derived MSCs cannot be considered as an exact replica of human MSC based clinical trials. In the present review, we discuss the therapeutic properties of MSCs in preclinical and clinical studies of IBD. We also discuss the challenges and approaches of using appropriate animal models of colitis, not only to study putative MSC therapeutic efficacy and their mechanisms of action, but also the suitability of translating findings derived from such studies to the clinic.


Subject(s)
Inflammatory Bowel Diseases/surgery , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Animals , Clinical Trials as Topic , Disease Models, Animal , Humans , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/physiopathology , Mesenchymal Stem Cells/immunology , Mesenchymal Stem Cells/metabolism , Mice , Phenotype , Species Specificity
17.
Mol Ther ; 23(7): 1248-1261, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25899824

ABSTRACT

Autologous bone marrow-derived mesenchymal stromal cells (MSCs) for adoptive cell therapy of luminal Crohn's disease (CD) are being tested in clinical trials. However, CD is associated with dysregulation of autophagy and its effect on MSC's immunobiology is unknown. Here, we demonstrate no quantitative difference in phenotype, in vitro growth kinetics and molecular signatures to IFNγ between MSCs derived from CD and healthy individuals. CD MSCs were indistinguishable from those derived from healthy controls at inhibiting T-cell proliferation through an indoleamine 2,3-dioxygenase (IDO)-dependent mechanism. Upon IFNγ prelicensing, both MSC populations inhibit T-cell effector functions. Neither a single-nucleotide polymorphism (SNP) rs7820268 in the IDO gene, nor a widely reported CD predisposing SNP ATG16L1rs2241880 modulated the suppressive function of MSCs carrying these haplotypes. IFNγ stimulation or coculture with activated T cells upregulated the expression of autophagy genes and/or vacuoles on MSCs. Pharmacological blockade of autophagy pathway did not reverse the immunosuppressive properties and IFNγ responsiveness of MSCs confirming the absence of a functional link between these two cell biochemical properties. We conclude that autophagy, but not IDO and IFNγ responsiveness, is dispensable for MSC's immunosuppressive properties. MSCs from CD subjects are functionally analogous to those of healthy individuals.


Subject(s)
Crohn Disease/immunology , Immunosuppression Therapy , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Interferon-gamma/genetics , Mesenchymal Stem Cells/immunology , Autophagy/immunology , Bone Marrow Cells , Cell Proliferation/genetics , Coculture Techniques , Crohn Disease/genetics , Crohn Disease/pathology , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/biosynthesis , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , Interferon-gamma/biosynthesis , Interferon-gamma/immunology , Lymphocyte Activation/immunology , Mesenchymal Stem Cells/pathology , T-Lymphocytes/immunology
18.
Stem Cells Transl Med ; 4(1): 66-73, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25391644

ABSTRACT

As our understanding of the basic precepts of immunobiology continue to advance at a rapid pace, translating such discoveries into meaningful therapies for patients has proved challenging. This is especially apparent in the use of cytokine-based immunotherapies for cancer. Unanticipated and serious side effects, as well as low objective response rates seen in clinical trials, have dealt setbacks to the field. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and common γ-chain (γ-c) interleukins are cytokines that have been used as stand-alone immunotherapies with moderate success. Our group has found that the fusion of GM-CSF to members of γ-c interleukins results in the generation of novel proteins with unique signaling properties and unheralded biological effects. These fusion proteins, termed GIFT (GM-CSF interleukin fusion transgenes) fusokines, are the result of combining GM-CSF and a γ-c interleukin into a single, bifunctional polypeptide. In our experience, GIFT fusokines often confer immune cells with a gain of function that cannot be explained by the mere sum of their constituent moieties. They act as bispecific ligands, coupling activated GM-CSF and interleukin receptors together to drive unique downstream signaling events. The synergy that arises from these fusions has shown great promise in its ability to modulate the immune response and overcome maladaptive biological processes that underlie diseases such as cancer and autoimmune conditions. In this review, we discuss the ways in which the GIFT fusokines are able to alter the immune response, particularly in disease states, with a special emphasis on how these novel molecules may be translated into effective therapies in the clinical setting.


Subject(s)
Autoimmune Diseases/therapy , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Immunotherapy/methods , Interleukins/therapeutic use , Neoplasms/therapy , Recombinant Fusion Proteins/therapeutic use , Animals , Humans
19.
Cancer Res ; 72(5): 1210-20, 2012 Mar 01.
Article in English | MEDLINE | ID: mdl-22241086

ABSTRACT

We have previously shown that interleukin (IL)-2 receptor-expressing lymphoid cells stimulated with a chimeric protein linking IL-2 to the ectodomain of TGF-ß receptor II (also known as FIST) become resistant to TGF-ß-mediated suppression and produce significant amounts of proinflammatory cytokines. In this study, we have characterized the antigen presentation properties of FIST-stimulated B cells (hereafter inducible B effector cells, iBEC). FIST converts naïve splenic B cells to B effector cells characterized by potent antigen presentation properties and production of TNFα and IFNγ. iBECs display hyperphosphorylation of STAT3 and STAT5 downstream of the IL-2 receptor and upregulation of T-bet expression. iBECs maintain B-cell identity based on the expression of PAX5 and CD19 and overexpress Smad7, which confers resistance to TGF-ß-mediated suppression of B-cell activation. iBEC antitumor immunity was determined by a mouse model of lymphoma-expressing ovalbumin (E.G7-OVA) as a specific tumor antigen. OVA-pulsed iBECs function as antigen-presenting cells (APC) in vitro by inducing the activation of OVA-specific CD4(+) and CD8(+) T cells, respectively, and in vivo by conferring complete protective immunity against E.G7-OVA tumor challenge. In addition, OVA-pulsed iBECs promote tumor regression in immunocompetent C57Bl/6 mice bearing E.G7-OVA tumors. In conclusion, iBECs represent an entirely novel B cell-derived APC for immune therapy of cancer.


Subject(s)
Antigen-Presenting Cells/immunology , B-Lymphocyte Subsets/immunology , Interleukin-2/immunology , Lymphocyte Activation , Neoplasms, Experimental/immunology , Animals , Cytotoxicity, Immunologic , Female , Gene Knockout Techniques , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Recombinant Fusion Proteins/immunology
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