scholarly journals Dimethyl fumarate inhibits antibody-induced platelet destruction in immune thrombocytopenia mouse

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Huan Tong ◽  
Yangyang Ding ◽  
Xiang Gui ◽  
Zengtian Sun ◽  
Guozhang Wang ◽  
...  
Keyword(s):  
Platelet Count ◽  
Immune Thrombocytopenia ◽  
Mononuclear Cells ◽  
Dimethyl Fumarate ◽  
Treg Cells ◽  
Antiplatelet Antibody ◽  
Platelet Destruction ◽  
Immune Mediated ◽  
Ifn Γ

Abstract Background Immune thrombocytopenia (ITP) is an autoimmune disease characterized as a low platelet count resulting from immune-mediated platelet destruction. Dimethyl fumarate (DMF) is widely applied for the treatment of several autoimmune diseases with immunosuppressive effect. However, whether it ameliorates ITP is unclear. This study aims to evaluate whether DMF has a preventive effect on ITP in mice. Methods DMF (30, 60 or 90 mg/kg body weight) was intraperitoneally injected into mice followed by injection of rat anti-mouse integrin GPIIb/CD41antibody to induce ITP. Peripheral blood was isolated to measure platelet count and spleen mononuclear cells were extracted to measure Th1 and Treg cells along with detecting the levels of IFN-γ, and TGFβ-1 in plasma and CD68 expression in spleen by immuohistochemical staining. Additionally, macrophage cell line RAW264.7 was cultured and treated with DMF followed by analysis of cell apoptosis and cycle, and the expression of FcγRI, FcγRIIb and FcγRIV mRNA. Results DMF significantly inhibited antiplatelet antibody-induced platelet destruction, decreased Th1 cells and the expression of T-bet and IFN-γ, upregulated Treg cells and the expression of Foxp3 and TGF-β1 as well as reduced CD68 expression in the spleen of ITP mouse. DMF-treated RAW264.7 cells showed S-phase arrest, increased apoptosis and downregulated expression of FcγRI and FcγRIV. Meanwhile, in vitro treatment of DMF also decreased the expression of cyclin D1 and E2, reduced Bcl-2 level and increased Bax expression and caspase-3 activation. Conclusions In conclusion, DMF prevents antibody-mediated platelet destruction in ITP mice possibly through promoting apoptosis, indicating that it might be used as a new approach for the treatment of ITP.

CD49d provides access to “untouched” human Foxp3+ Treg free of contaminating effector cells

Blood ◽  
2009 ◽  
Vol 113 (4) ◽  
pp. 827-836 ◽  
Author(s):  
Markus Kleinewietfeld ◽  
Mireille Starke ◽  
Diletta Di Mitri ◽  
Giovanna Borsellino ◽  
Luca Battistini ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Treg Cells ◽  
Interferon Γ ◽  
Clinical Applications ◽  
Interleukin 17 ◽  
Peripheral Blood Mononuclear ◽  
Effector Cells ◽  
Ifn Γ

Abstract The adoptive transfer of regulatory Foxp3+ T (Treg) cells has been shown in various animal models to prevent inflammatory immune and autoimmune diseases. Translation into therapeutic applications, however, is hindered by the lack of suitable techniques and markers. CD25, commonly used to isolate Treg cells from mice, has only limited value in humans as it is also present on proinflammatory CD4+ effector cells. Here we show that clean populations of human Foxp3+ Treg cells can be obtained with antibodies directed against CD49d. The marker is present on proinflammatory peripheral blood mononuclear cells but is absent on immune-suppressive Treg cells. Depletion with α-CD49d removes contaminating interferon-γ (IFN-γ)– and interleukin-17 (IL-17)–secreting cells from Treg preparations of CD4+CD25high cells. More importantly, in combination with α-CD127 it allows the isolation of “untouched” Foxp3+ Treg (ie, cells that have not been targeted by an antibody during purification). The removal of CD49d+/CD127+ cells leaves a population of Foxp3+ Treg virtually free of contaminating CD25+ effector cells. The cells can be expanded in vitro and are effective suppressors both in vitro and in vivo. Thus, CD49d provides access to highly pure populations of untouched Foxp3+ Treg cells conferring maximal safety for future clinical applications.

scholarly journals Co-Inhibition of the Immunoproteasome Subunits LMP2 and LMP7 Ameliorates Immune Thrombocytopenia

2021 ◽  
Vol 11 ◽  
Author(s):  
Sheng-hong Du ◽  
Yu-jiao Xiang ◽  
Lu Liu ◽  
Mu Nie ◽  
Yu Hou ◽  
...  
Keyword(s):  
Platelet Count ◽  
Immune Thrombocytopenia ◽  
Mononuclear Cells ◽  
Th1 Cells ◽  
20S Proteasome ◽  
Healthy Controls ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

The immunoproteasome, a special isoform of the 20S proteasome, is expressed when the cells receive an inflammatory signal. Immunoproteasome inhibition proved efficacy in the treatment of autoimmune diseases. However, the role of the immunoproteasome in the pathogenesis of immune thrombocytopenia (ITP) remains unknown. We found that the expression of the immunoproteasome catalytic subunit, large multifunctional protease 2 (LMP2), was significantly upregulated in peripheral blood mononuclear cells of active ITP patients compared to those of healthy controls. No significant differences in LMP7 expression were observed between patients and controls. ML604440, an specific LMP2 inhibitor, had no significant impact on the platelet count of ITP mice, while ONX-0914 (an inhibitor of both LMP2 and LMP7) increased the number of platelets. In vitro assays revealed that ONX-0914 decreased the expression of FcγRI in ITP mice and decreased that of FcγRIII in ITP patients, inhibited the activation of CD4+ T cells, and affected the differentiation of Th1 cells in patients with ITP. These results suggest that the inhibition of immunoproteasome is a potential therapeutic approach for ITP patients.

scholarly journals Effects of intravenous immunoglobulin on platelet count and antiplatelet antibody disposition in a rat model of immune thrombocytopenia

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2087-2093 ◽  
Author(s):  
Ryan J. Hansen ◽  
Joseph P. Balthasar
Keyword(s):  
Platelet Count ◽  
Intravenous Immunoglobulin ◽  
Rat Model ◽  
Immune Thrombocytopenia ◽  
Time Course ◽  
Ivig Therapy ◽  
Ivig Treatment ◽  
Antiplatelet Antibody ◽  
Dose Dependent

Experiments were conducted to investigate the effects of intravenous immunoglobulin (IVIG) in a rat model of immune thrombocytopenia (ITP). Rats were pretreated with 0 to 2 g/kg IVIG and then challenged with an antiplatelet antibody (7E3, 8 mg/kg). IVIG effects on 7E3-induced thrombocytopenia and on 7E3 pharmacokinetics were determined. IVIG pretreatment led to significant changes in the degree and time-course of 7E3-induced thrombocytopenia (P = .031). Nadir percent platelet counts were 121% to 279% greater in animals treated with IVIG (0.4-2 g/kg) than in animals receiving 7E3 alone. IVIG treatment also led to dose-dependent increases in 7E3 clearance (P < .001), with more than 2-fold increases in 7E3 clearance seen following the highest dose of IVIG. In vitro experiments showed that IVIG effects on platelet count are not likely due to anti-idiotypic inhibition of 7E3-platelet binding and that IVIG did not directly bind to 7E3. Consequently, IVIG-7E3 binding cannot explain the increase of 7E3 clearance following IVIG treatment. We propose that the observed increase in 7E3 clearance with IVIG therapy is due to saturation of the FcRn salvage receptor for IgG. The importance of the effect of IVIG on 7E3 clearance to the prevention of thrombocytopenia in these animals is unclear at present; nonetheless, these data provide experimental support for a new mechanism of IVIG action in ITP (ie, IVIG-mediated increases in antiplatelet antibody elimination). This model of ITP will be useful for further investigations of IVIG mechanism of action and for development of new therapies for ITP.

scholarly journals Persistent thrombocytopenia in Dengue Fever is rare but not uncommon - can be treated with steroid successfully

2021 ◽  
Vol 32 (1) ◽  
pp. 62-64
Author(s):  
Md Daharul Islam ◽  
Khaleda Akter ◽  
Ranajit Sen Chowdhury ◽  
Mohammad Abdus Sattar Sarkar ◽  
Aminur Rahman
Keyword(s):  
Platelet Count ◽  
Dengue Fever ◽  
Immune Thrombocytopenia ◽  
Haemorrhagic Fever ◽  
Platelet Destruction ◽  
Immune Mediated ◽  
Immune Injury ◽  
Underlying Mechanisms ◽  
Common Manifestation ◽  
Persistent Thrombocytopenia

Fever, skin rash, thrombocytopenia and bleeding are common manifestation of dengue fever (DF). Thrombocytopenia usually gets better and platelet count normalizes by day 10 of fever. Chronic thrombocytopenia is not a feature of dengue fever. Proposed mechanisms behind thrombocytopenia are many. Direct platelet destruction by dengue virus, immune-mediated platelet destruction and evenmegakaryocytic immune injury are proposed as underlying mechanisms. We are reporting a case of a 43 year old female who presented in dengue season in 2019 with fever and bleeding and wasdiagnosed as a case of dengue haemorrhagic fever. She had persistent thrombocytopenia which neededto be treated on the lines of immune thrombocytopenia and responded to steroids. Other causes of thrombocytopenia were ruled out. Bangladesh J Medicine January 2021; 32(1) : 62-64

scholarly journals Effects of intravenous immunoglobulin on platelet count and antiplatelet antibody disposition in a rat model of immune thrombocytopenia

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2087-2093 ◽  
Author(s):  
Ryan J. Hansen ◽  
Joseph P. Balthasar
Keyword(s):  
Platelet Count ◽  
Intravenous Immunoglobulin ◽  
Rat Model ◽  
Immune Thrombocytopenia ◽  
Time Course ◽  
Ivig Therapy ◽  
Ivig Treatment ◽  
Antiplatelet Antibody ◽  
Dose Dependent

Abstract Experiments were conducted to investigate the effects of intravenous immunoglobulin (IVIG) in a rat model of immune thrombocytopenia (ITP). Rats were pretreated with 0 to 2 g/kg IVIG and then challenged with an antiplatelet antibody (7E3, 8 mg/kg). IVIG effects on 7E3-induced thrombocytopenia and on 7E3 pharmacokinetics were determined. IVIG pretreatment led to significant changes in the degree and time-course of 7E3-induced thrombocytopenia (P = .031). Nadir percent platelet counts were 121% to 279% greater in animals treated with IVIG (0.4-2 g/kg) than in animals receiving 7E3 alone. IVIG treatment also led to dose-dependent increases in 7E3 clearance (P < .001), with more than 2-fold increases in 7E3 clearance seen following the highest dose of IVIG. In vitro experiments showed that IVIG effects on platelet count are not likely due to anti-idiotypic inhibition of 7E3-platelet binding and that IVIG did not directly bind to 7E3. Consequently, IVIG-7E3 binding cannot explain the increase of 7E3 clearance following IVIG treatment. We propose that the observed increase in 7E3 clearance with IVIG therapy is due to saturation of the FcRn salvage receptor for IgG. The importance of the effect of IVIG on 7E3 clearance to the prevention of thrombocytopenia in these animals is unclear at present; nonetheless, these data provide experimental support for a new mechanism of IVIG action in ITP (ie, IVIG-mediated increases in antiplatelet antibody elimination). This model of ITP will be useful for further investigations of IVIG mechanism of action and for development of new therapies for ITP.

scholarly journals Protection of BALB/c Mice against Brucella abortus 544 Challenge by Vaccination with Bacterioferritin or P39 Recombinant Proteins with CpG Oligodeoxynucleotides as Adjuvant

2001 ◽  
Vol 69 (8) ◽  
pp. 4816-4822 ◽  
Author(s):  
Ayman Al-Mariri ◽  
Anne Tibor ◽  
Pascal Mertens ◽  
Xavier De Bolle ◽  
Patrick Michel ◽  
...  
Keyword(s):  
Recombinant Proteins ◽  
Brucella Abortus ◽  
Mononuclear Cells ◽  
Brucella Melitensis ◽  
Cpg Odn ◽  
Peripheral Blood Mononuclear ◽  
Recombinant Antigens ◽  
Cpg Oligodeoxynucleotides ◽  
Ifn Γ

ABSTRACT The P39 and the bacterioferrin (BFR) antigens of Brucella melitensis 16M were previously identified as T dominant antigens able to induce both delayed-type hypersensivity in sensitized guinea pigs and in vitro gamma interferon (IFN-γ) production by peripheral blood mononuclear cells from infected cattle. Here, we analyzed the potential for these antigens to function as a subunitary vaccine against Brucella abortus infection in BALB/c mice, and we characterized the humoral and cellular immune responses induced. Mice were injected with each of the recombinant proteins alone or adjuvanted with either CpG oligodeoxynucleotides (CpG ODN) or non-CpG ODN. Mice immunized with the recombinant antigens with CpG ODN were the only group demonstrating both significant IFN-γ production and T-cell proliferation in response to either Brucella extract or to the respective antigen. The same conclusion holds true for the antibody response, which was only demonstrated in mice immunized with recombinant antigens mixed with CpG ODN. The antibody titers (both immunoglobulin G1 [IgG1] and IgG2a) induced by P39 immunization were higher than the titers induced by BFR (only IgG2a). Using a B. abortus 544 challenge, the level of protection was analyzed and compared to the protection conferred by one immunization with the vaccine strain B19. Immunization with P39 and CpG ODN gave a level of protection comparable to the one conferred by B19 at 4 weeks postchallenge, and the mice were still significantly protected at 8 weeks postchallenge, although to a lesser extent than the B19-vaccinated group. Intriguingly, no protection was detected after BFR vaccination. All other groups did not demonstrate any protection.

scholarly journals Evaluation of Immunostimulatory Activities of Synthetic Mannose-Containing Structures Mimicking the β-(1→2)-Linked Cell Wall Mannans of Candida albicans

2012 ◽  
Vol 19 (11) ◽  
pp. 1889-1893 ◽  
Author(s):  
Kaarina Ranta ◽  
Kaisa Nieminen ◽  
Filip S. Ekholm ◽  
Moniká Poláková ◽  
Mattias U. Roslund ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Peripheral Blood Mononuclear ◽  
Content Type ◽  
Mouse Macrophages ◽  
Ifn Γ ◽  
Low Levels ◽  
Necrosis Factor

ABSTRACTImmunostimulatory properties of synthetic structures mimicking the β-(1→2)-linked mannans ofCandida albicanswere evaluatedin vitro. Contrary to earlier observations, tumor necrosis factor (TNF) production was not detected after stimulation with mannotetraose in mouse macrophages. Divalent disaccharide 1,4-bis(α-d-mannopyranosyloxy)butane induced TNF and some molecules induced low levels of gamma interferon (IFN-γ) in human peripheral blood mononuclear cells (PBMC).

scholarly journals Local Immune Responses to Chlamydia pneumoniae in the Lungs of BALB/c Mice during Primary Infection and Reinfection

1998 ◽  
Vol 66 (11) ◽  
pp. 5113-5118 ◽  
Author(s):  
Jenni M. Penttilä ◽  
Marjukka Anttila ◽  
Mirja Puolakkainen ◽  
Aino Laurila ◽  
Kari Varkila ◽  
...  
Keyword(s):  
Primary Infection ◽  
Bacterial Infections ◽  
Chlamydia Pneumoniae ◽  
Mononuclear Cells ◽  
Relative Increase ◽  
Culturable Bacteria ◽  
Ifn Γ ◽  
Tissue Reactions

ABSTRACT Cell-mediated immune (CMI) responses play a major role in protection as well as pathogenesis of many intracellular bacterial infections. In this study, we evaluated the infection kinetics and assessed histologically the lymphoid reactions and local, in vitro-restimulated CMI responses in lungs of BALB/c mice, during both primary infection and reinfection with Chlamydia pneumoniae. The primary challenge resulted in a self-restricted infection with elimination of culturable bacteria by day 27 after challenge. A mild lymphoid reaction characterized the pathology in the lungs. In vitro CMI responses consisted of a weak proliferative response and no secretion of gamma interferon (IFN-γ). The number of lung-derived mononuclear cells increased substantially during the primary infection; the largest relative increase was observed in B cells (B220+). After reinfection, the number of lung-derived mononuclear cells increased further, and the response consisted mainly of T cells. The reinfection was characterized in vivo by significant protection from infection (fewer cultivable bacteria in the lungs for a shorter period of time) but increased local lymphoid reaction at the infection site. In vitro, as opposed to the response in naive mice, acquired immunity was characterized by a strongly Th1-biased (IFN-γ) CMI response. These results suggest that repeated infections with C. pneumoniae may induce Th1-type responses with similar associated tissue reactions, as shown in C. trachomatis infection models.

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