scholarly journals Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Christina Gavegnano ◽  
Woldeab B. Haile ◽  
Selwyn Hurwitz ◽  
Sijia Tao ◽  
Yong Jiang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Neurocognitive Disorders ◽  
Lymphoid Cells ◽  
High Dose ◽  
Jak Inhibitors ◽  
Hiv Encephalitis ◽  
Cns Inflammation ◽  
Human Macrophages ◽  
Hiv Associated Neurocognitive Disorders

Abstract Background Since HIV-associated neurocognitive disorders (HANDs) occur in up to half of HIV-positive individuals, even with combined antiretroviral therapy (cART), adjunctive therapies are needed. Chronic CNS inflammation contributes to HAND and HIV encephalitis (HIVE). Baricitinib is a JAK 1/2 inhibitor approved in the USA, EU, and Japan for rheumatoid arthritis, demonstrating potent inhibition of IL-6, D-dimer, CRP, TNF-α, IFN-α/β, and other pro-inflammatory cytokines. Methods Our modified murine HAND model was used to evaluate the ability of baricitinib to cross the blood-brain barrier (BBB) and modulate monocyte/macrophage-driven HAND. Severity of HAND was measured by assessing cognitive performance of low- and high-dose baricitinib treated versus untreated HAND mice. The severity of brain neuroinflammation was evaluated in these mouse groups after flow cytometric analyses. We also assessed the ability of baricitinib to block events in myeloid and lymphoid cells in vitro that may undergird the persistence of HIV in the central nervous system (CNS) in primary human macrophages (Mϕ) and lymphocytes including HIV replication, HIV-induced activation, reservoir expansion, and reservoir maintenance. Results In vivo, both doses of 10 and 50 mg/kg qd baricitinib crossed the BBB and reversed behavioral abnormalities conferred by HIV infection. Moreover, baricitinib significantly reduced HIV-induced neuroinflammation marked by glial activation: activated microglia (MHCII+/CD45+) and astrogliosis (GFAP). Baricitinib also significantly reduced the percentage of p24+ human macrophages in mouse brains (p < 0.05 versus HAND mice; t test). In vitro, baricitinib significantly reduced markers of persistence, reservoir size, and reseeding in Mϕ. Conclusion These results show that blocking the JAK/STAT pathway reverses cognitive deficits and curtails inflammatory markers in HAND in mice. Our group recently reported safety and tolerability of ruxolitinib in HIV-infected individuals (Marconi et al., Safety, tolerability and immunologic activity of ruxolitinib added to suppressive ART, 2019), underscoring potential safety and utility of JAK inhibitors for additional human trials. The data reported herein coupled with our recent human trial with JAK inhibitors provide compelling preclinical data and impetus for considering a trial of baricitinib in HAND individuals treated with cART to reverse cognitive deficits and key events driving viral persistence.

High-Dose IgG Alters the Relative Expression of Fcgamma RIIA and Fcgamma RIIB On Human Macrophages: A Mechanism for IVIG Therapy in Human Immune Thrombocytopenia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 683-683 ◽  
Author(s):  
Salley Pels ◽  
Caroline Tang ◽  
Mehmet Ertem ◽  
Diana S. Beardsley
Keyword(s):  
Board Of Directors ◽  
Immune Thrombocytopenia ◽  
Ivig Therapy ◽  
High Dose ◽  
Igg Antibody ◽  
Platelet Destruction ◽  
Advisory Committees ◽  
Human Macrophages ◽  
Human Immune

Abstract Abstract 683 The pathogenic mechanism of immune thrombocytopenia involves antibody mediated destruction of platelets in the reticuloendothelial system. Infection often triggers an exacerbation of thrombocytopenia in patients with ITP that may be treated with intravenous immunoglobulin (IVIG). However, the precise mechanism of action of IVIG has not been clearly elucidated. Studies by McKenzie et al. (Journal of Immunology, 1999) in an animal model for immune thrombocytopenia (ITP) using a mouse transgenic for human activating receptor FcgammaRIIA and lacking murine activating receptors FcgammaRI and FcgammaRIII revealed that human FcgammaRIIA is necessary for antibody mediated platelet destruction. (Murine macrophages lack an analogous activating FcgammaRII.) In another animal model of ITP, Samuelsson et al. (Science, 2001) showed that decreased expression of the murine inhibiting FcgammaRIIb was associated with increased platelet destruction that was not responsive to IVIG. The present studies were undertaken to test the hypothesis that human antibody mediated platelet phagocytosis depends upon the balance between the activating (FcgammaRIIA) and inhibiting (FcgammaRIIB) receptors on human macrophages and that IVIG alters this balance by increasing the expression of the inhibiting receptor. We additionally hypothesized that infection results in decreased FcgammaRIIB expression and enhanced phagocytosis that may be abrogated by IVIG. Methods: Antibody-mediated phagocytosis of platelets by THP-1 (human macrophage) cells in culture was assayed by co-incubation of THP-1 cells with anti-platelet antibody as a model for human immune mediated platelet destruction. Platelets were labeled with 5-(and 6-) carboxyfluorescein diacetate mixed isomers (CFDA) in the presence of human serum containing anti-HPA 1a IgG antibody. Macrophages that had ingested human platelets were identified by flow cytometry as previously reported. To study the mechanism of action of IVIG therapy for immune thrombocytopenia, in vitro phagocytosis was assayed after the addition of purified IgG (100mg/ml) to the THP-1 cells 30 minutes prior to exposure of the labeled platelets to anti-HPA 1a IgG antibody. The effect of LPS on platelet phagocytosis was studied as a model for infection which can exacerbate immune platelet destruction. Phagocytosis was assayed before and after incubation with LPS (1ug/ml) for 2 hours at 37 degrees Celsius. For each experiment, total FcgammaRIIA (CD32A) and FcgammaRIIB (CD32B) were determined by immunoprecipitation and immunoblotting. Results: Pretreatment with IVIG had no effect on FcgammaRIIA (n=3) expression; however, FcgammaRIIB expression increased an average of 5 fold (n=6). Addition of LPS alone resulted in marked decrease in expression of FcgammaRIIB for up to 60 minutes; however, FcgammaRIIA did not change. Experiments performed with addition of both IVIG and LPS showed that FcgammaRIIB expression remained elevated 3 fold (n=3). Following increased expression of FcgammaRIIB, IgG exposure resulted in decreased phagocytosis as assayed by flow cytometric analysis of macrophage ingestion of CFDA-labeled platelets. Antibody mediated platelet phagocytosis by THP-1 cells was enhanced 26% by LPS after a 2 hour incubation (median increase in 5 experiments; range = 14-125%.) Conclusions: Exposure to high dose IgG increased the expression of FcgammaRIIB but had no effect on FcgammaRIIA. Therefore, the net functional effect was to tip the balance toward inhibition of antibody-mediated phagocytosis, as was observed in our in vitro assay of human platelet phagocytosis. Furthermore, treatment with IgG was able to partially overcome the negative effects of LPS on expression of the inhibiting receptor, FcgammaRIIB. These data clearly support the hypothesis that the balance of the activating (FcgammaRIIA) and inhibiting (FcgammaRIIB) receptors is important in mediating the therapeutic effects of IVIG as a treatment for human immune thrombocytopenia. Disclosures: Pels: National Hemophilia Foundation-Baxter: NHF-Baxter Clinical Fellowship Awardee, Research Funding. Beardsley:ITP Foundation: Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees.

scholarly journals HIV-associated neurocognitive disorders: recent advances in pathogenesis, biomarkers, and treatment

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 312 ◽  
Author(s):  
Antonia Carroll ◽  
Bruce Brew
Keyword(s):  
Neurocognitive Disorders ◽  
Screening Tools ◽  
Viral Reservoirs ◽  
Cns Inflammation ◽  
Ccr5 Chemokine Receptor ◽  
Optimal Population ◽  
The Central Nervous System ◽  
Neuropsychologic Testing ◽  
Inflammatory Milieu ◽  
Hiv Associated Neurocognitive Disorders

HIV-associated neurocognitive disorders (HAND) remain prevalent despite plasma viral suppression by antiretroviral agents. In fact, the prevalence of milder subtypes of cognitive impairment is increasing. Neuropsychologic testing remains the “gold standard” of diagnosis; however, this is time consuming and costly in a resource-poor environment. Recently developed screening tools, such as CogState and the revised HIV dementia scale, have very good sensitivity and specificity in the more severe stages of HAND. However, questions remain regarding the utility of, optimal population for, and insensitivity of tests in mild HAND.Recognition of ongoing viral persistence and the inflammatory milieu in the central nervous system (CNS) has advanced our understanding of the pathogenesis of HAND and facilitated the development of biomarkers of CNS disease. The importance of the monocyte-macrophage lineage cell and the astrocyte as viral reservoirs, HIV viral proteins, self-perpetuating CNS inflammation, and CCR5 chemokine receptor neurotropism has been identified. Whilst biomarkers demonstrate monocyte activation, inflammation, and neuronal injury, they remain limited in their clinical utility. The improved understanding of pathogenic mechanisms has led to novel approaches to the treatment of HAND; however, despite these advances, the optimal management is still undefined.

scholarly journals HIV associated neurocognitive disorders

2013 ◽  
Vol 5 (1S) ◽  
pp. 8 ◽  
Author(s):  
Li Zhou ◽  
Nitin K. Saksena
Keyword(s):  
Cognitive Deficits ◽  
Highly Active Antiretroviral Therapy ◽  
Neurocognitive Disorders ◽  
Future Research ◽  
Clear Understanding ◽  
Motor Impairments ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Hiv Associated Neurocognitive Disorders

Human immunodeficiency virus type 1 is associated with the development of neurocognitive disorders in many infected individuals, including a broad spectrum of motor impairments and cognitive deficits. Despite extensive research, the pathogenesis of HIV-associated neurocognitive disorders (HAND) is still not clear. This review provides a comprehensive view of HAND, including HIV neuroinvasion, HAND diagnosis and different level of disturbances, influence of highly-active antiretroviral therapy to HIV-associated dementia (HAD), possible pathogenesis of HAD, etc. Together, this review will give a thorough and clear understanding of HAND, especially HAD, which will be vital for future research, diagnosis and treatment.

Acute immunologic effects of interleukin-2 therapy in cancer patients: decreased delayed type hypersensitivity response and decreased proliferative response to soluble antigens.

1988 ◽  
Vol 6 (9) ◽  
pp. 1440-1449 ◽  
Author(s):  
E A Wiebke ◽  
S A Rosenberg ◽  
M T Lotze
Keyword(s):  
Cancer Patients ◽  
Skin Test ◽  
T Lymphocyte ◽  
Interleukin 2 ◽  
Lymphoid Cells ◽  
Delayed Type Hypersensitivity ◽  
High Dose ◽  
In Vitro Proliferation ◽  
Activation Markers

We prospectively evaluated responses to recall antigen in ten cancer patients undergoing immunotherapy and correlated these responses with in vitro proliferation data. Before therapy, eight of ten patients responded normally to at least two of seven antigens of a multitest system (greater than or equal to 2 mm induration at 48 hours), with a mean induration score of 17.9 +/- 4.4 mm and 2.7 +/- 0.5 positive responses per patient. This decreased to 5.9 +/- 2.7 mm (P = .01) and 1.2 +/- 0.5 responses (P = .03) after a week of interleukin-2 (IL-2) therapy, and further to 0.7 +/- 0.7 mm and 0.1 +/- 0.1 positive responses during a second week of therapy consisting of IL-2 plus activated autologous lymphocytes (P less than .01). The in vitro proliferation indices for lymphocytes obtained before skin test application were significantly less after IL-2 compared with pretreatment for concanavalin A ([con-A] Miles Laboratory, Elkhart, IN) stimulation (3.3 +/- 0.7 to 1.3 +/- 0.1; P = .03) and in mixed lymphocyte culture (MLC) (41.5 +/- 8.5 to 16.8 +/- 3.8; P = .02), and during the second week of therapy for in vitro IL-2 stimulation (83.3 +/- 16.8 to 42.9 +/- 12.0; P less than .01). When skin responses were directly compared with in vitro proliferation data, a significant correlation was observed for tetanus (r = .75; P less than .01), streptococcal antigen (r = .83; P less than .01), tuberculin (r = .83; P less than .01), and candida (r = .78; P less than .01). Thus, significant decreases in skin test responses and in vitro proliferation were demonstrated after therapy compared with pretreatment. Flow cytometry revealed marked increases in T-lymphocyte numbers after IL-2 alone (973 +/- 252 to 3,436 +/- 754 cells/mL; P less than .01) and IL-2 receptor-bearing cells (105 +/- 28 to 983 +/- 215; P less than .01), but not in numbers of B-lymphocytes or monocytes. Induced anergy to skin test antigens was seen during a period of relative and absolute T-lymphocyte expansion. We conclude that immunotherapy with high-dose IL-2 with or without activated lymphocytes results in a decreased response to recall antigens during a period in which lymphoid cells with nominal activation markers (Tac, DR) increase.

Significance of Platelet β-Adrenoceptors for Platelet Responses In Vivo and In Vitro

1992 ◽  
Vol 68 (06) ◽  
pp. 687-693 ◽  
Author(s):  
P T Larsson ◽  
N H Wallén ◽  
A Martinsson ◽  
N Egberg ◽  
P Hjemdahl
Keyword(s):  
Ex Vivo ◽  
High Dose ◽  
Platelet Aggregability ◽  
Adrenoceptor Agonist ◽  
Dose Infusion ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

SummaryThe significance of platelet β-adrenoceptors for platelet responses to adrenergic stimuli in vivo and in vitro was studied in healthy volunteers. Low dose infusion of the β-adrenoceptor agonist isoprenaline decreased platelet aggregability in vivo as measured by ex vivo filtragometry. Infusion of adrenaline, a mixed α- and β-adrenoceptor agonist, increased platelet aggregability in vivo markedly, as measured by ex vivo filtragometry and plasma β-thromboglobulin levels. Adrenaline levels were 3–4 nM in venous plasma during infusion. Both adrenaline and high dose isoprenaline elevated plasma von Willebrand factor antigen levels β-Blockade by propranolol did not alter our measures of platelet aggregability at rest or during adrenaline infusions, but inhibited adrenaline-induced increases in vWf:ag. In a model using filtragometry to assess platelet aggregability in whole blood in vitro, propranolol enhanced the proaggregatory actions of 5 nM, but not of 10 nM adrenaline. The present data suggest that β-adrenoceptor stimulation can inhibit platelet function in vivo but that effects of adrenaline at high physiological concentrations are dominated by an α-adrenoceptor mediated proaggregatory action.

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