THE USE OF NEW IMMUNOMODULATORS AT SECONDARY IMMUNODEFICIENCY

Vestnik ◽  
2021 ◽  
pp. 220-225
Author(s):  
Г.Д. Даулет ◽  
Л.К. Бактыбаева ◽  
А.С. Соколенко ◽  
Н.Н. Беляев ◽  
А.Ж. Молдакарызова ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Hematopoietic Growth Factors ◽  
Secondary Immunodeficiency ◽  
Effector Functions ◽  
The Past ◽  
Blood Formation ◽  
Cyclophosphamide Administration

В данной статье рассматривается использование нового иммуномодулятора у животных, страдающих вторичным иммунодефицитом за период последнего года. В исследованиях России и Китая в качестве новых иммуномодуляторов применялись Ganodermalucidum (Gl-PS) полисахариды и стимфорт на фоне введения циклофосфана. Иммуномодуляция играет важную роль в кроветворении. На мышах исследовали возможный механизм активации миелопоэза при миелосупрессии, вызванной циклофосфамидом. Показано, что иммуномодулятор обладает способностью корригировать количественный и субпопуляционный состав МЛ селезенки, структуру центральных и периферических органов лимфопоэза, эффекторные функции клеток иммунитета, нарушенные при введении цитостатика. В настоящем исследовании invivo и invitro обнаружили, что иммуномодуляторы избирательно связываются со стромальными клетками костного мозга, стимулирует секрецию гемопоэтических факторов роста и усиливают клоногенную активность гемопоэтических и стромальных клеток, способствуя гемопоэзу у мышей с миелосупрессией. This article reviews the use of a new immunomodulator in animals for secondary immunodeficiency in the past year. In a study in Russia and China, Ganoderma lucidum (Gl-PS) polysaccharides and stimforte were used as new immunomodulators against the background of cyclophosphamide administration. Immunomodulation plays an important role in blood formation. A possible mechanism of myelopoiesis activation in cyclophosphamide-induced myelosuppression was investigated in mice. It was shown that the immunomodulator has the ability to correct the quantitative and subpopulation composition of spleen ML, the structure of the central and peripheral organs of lymphopoiesis, the effector functions of immunity cells, impaired by the introduction of a cytostatic. In the present study, in vivo and in vitro, it was found that immunomodulators selectively bind to bone marrow stromal cells, stimulate the secretion of hematopoietic growth factors and enhance the clonogenic activity of hematopoietic and stromal cells, promoting hematopoiesis in mice with myelosuppression.

p38MAPK Inhibitor LSN2322600 Modulates the Bone Marrow Microenvironment and Inhibits Osteoclastogenesis in Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5042-5042
Author(s):  
Kenji Ishitsuka ◽  
Teru Hideshima ◽  
Paola Neri ◽  
Sonia Vallet ◽  
Norihiko Shiraishi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Mononuclear Cells ◽  
Severe Combined Immunodeficiency ◽  
Marrow Stromal Cells ◽  
Skeletal Complications

Abstract The interaction between multiple myeloma (MM) cells and the bone marrow (BM) microenvironment plays a crucial role not only in proliferation and survival of MM cells, but also in osteoclastogenesis. In this study, we examined diverse potential of novel p38MAPK inhibitor LSN2322600 (LSN) for MM therapy in vitro and in vivo. The cytotoxic activity of LSN against MM cell lines was modest; however, LSN significantly enhances the cytotoxicity of Bortezomib by down-regulating Bortezomib-induced heat shock protein (HSP) 27 phosphorylation. We next examined the effects of LSN on cytokine secretion in MM cells, bone marrow stromal cells and osteoclast precursor cells. LSN inhibited IL-6 secretion from long-term cultured-bone marrow stromal cells (LT-BMSCs) and bone marrow mononuclear cells (BMMNCs) from MM patients in remission. LSN also inhibited MIP-1 α secretion by fresh tumor cells, BMMNCs and CD14 positive cells. Since these cytokines mediate osteoclastogenesis, we further examined whether LSN could inhibit osteoclastogenesis. Importantly, LSN inhibited in vitro osteoclastogenesis induced by macrophage-colony stimulating factor (M-CSF) and soluble receptor activator of nuclear factor- κ B ligand (sRANKL), as well as osteoclastogenesis in the severe combined immunodeficiency (SCID)-Hu mouse model of human MM. These results suggest that LSN represents a promising novel targeted strategy to reduce skeletal complications as well as to sensitize or overcome resistance to Bortezomib.

scholarly journals Secreted Factors from Bone Marrow Stromal Cells Upregulate IL-10 and Reverse Acute Kidney Injury

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Jack M. Milwid ◽  
Takaharu Ichimura ◽  
Matthew Li ◽  
Yunxin Jiao ◽  
Jungwoo Lee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Kidney Injury ◽  
Standard Of Care ◽  
Marrow Stromal Cells ◽  
Secreted Factors

Acute kidney injury is a devastating syndrome that afflicts over 2,000,000 people in the US per year, with an associated mortality of greater than 70% in severe cases. Unfortunately, standard-of-care treatments are not sufficient for modifying the course of disease. Many groups have explored the use of bone marrow stromal cells (BMSCs) for the treatment of AKI because BMSCs have been shown to possess unique anti-inflammatory, cytoprotective, and regenerative propertiesin vitroandin vivo. It is yet unresolved whether the primary mechanisms controlling BMSC therapy in AKI depend on direct cell infusion, or whether BMSC-secreted factors alone are sufficient for mitigating the injury. Here we show that BMSC-secreted factors are capable of providing a survival benefit to rats subjected to cisplatin-induced AKI. We observed that when BMSC-conditioned medium (BMSC-CM) is administered intravenously, it prevents tubular apoptosis and necrosis and ameliorates AKI. In addition, we observed that BMSC-CM causes IL-10 upregulation in treated animals, which is important to animal survival and protection of the kidney. In all, these results demonstrate that BMSC-secreted factors are capable of providing support without cell transplantation, and the IL-10 increase seen in BMSC-CM-treated animals correlates with attenuation of severe AKI.

scholarly journals Bone Marrow Stromal Cells: Characterization and Clinical Application

1999 ◽  
Vol 10 (2) ◽  
pp. 165-181 ◽  
Author(s):  
P.H. Krebsbach ◽  
S.A. Kuznetsov ◽  
P. Bianco ◽  
P. Gehron Robey
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Hematopoietic Cells ◽  
Marrow Stromal Cells ◽  
Proliferative Potential ◽  
Bone Marrow Stroma ◽  
Marrow Stroma

The bone marrow stroma consists of a heterogeneous population of cells that provide the structural and physiological support for hematopoietic cells. Additionally, the bone marrow stroma contains cells with a stem-cell-like character that allows them to differentiate into bone, cartilage, adipocytes, and hematopoietic supporting tissues. Several experimental approaches have been used to characterize the development and functional nature of these cells in vivo and their differentiating potential in vitro. In vivo, presumptive osteogenic precursors have been identified by morphologic and immunohistochemical methods. In culture, the stromal cells can be separated from hematopoietic cells by their differential adhesion to tissue culture plastic and their prolonged proliferative potential. In cultures generated from single-cell suspensions of marrow, bone marrow stromal cells grow in colonies, each derived from a single precursor cell termed the colony-forming unit-fibroblast. Culture methods have been developed to expand marrow stromal cells derived from human, mouse, and other species. Under appropriate conditions, these cells are capable of forming new bone after in vivo transplantation. Various methods of cultivation and transplantation conditions have been studied and found to have substantial influence on the transplantation outcome The finding that bone marrow stromal cells can be manipulated in vitro and subsequently form bone in vivo provides a powerful new model system for studying the basic biology of bone and for generating models for therapeutic strategies aimed at regenerating skeletal elements.

Targeting MEK1/2 Signaling Cascade by AS703026, a Novel Selective MEK1/2 Inhibitor, Induces Pleiotropic Anti-Myeloma Activity in Vitro and In Vivo.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3848-3848 ◽  
Author(s):  
Yu-Tzu Tai ◽  
Kihyun Kim ◽  
Xian-Feng Li ◽  
Mariateresa Fulciniti ◽  
Weihua Song ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Growth ◽  
Tumor Growth ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Marrow Stromal Cells ◽  
Time Dependent ◽  
Dependent Manner

Abstract Abstract 3848 Poster Board III-784 The mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway plays a crucial role in the pathogenesis of human multiple myeloma (MM) by promoting interactions of MM cells with bone marrow stromal cells (BMSCs) that secrete cytokines and growth factors for MM cell growth, survival, and resistance to chemotherapeutic drugs. Accumulating studies have supported targeting this signaling pathway in MM. Here we investigate cytotoxicity of AS703026, a novel selective MEK1/2 inhibitor with highly oral bioavailability, in MM cell lines and patient MM cells and define its mechanisms of action. AS703026, more potently (∼9-10 fold) than AZD6244, inhibits growth and survival of MM cells and cytokine-induced osteoclast differentiation. It specifically blocks baseline and adhesion-induced pERK1/2, but not pSTAT3. Selective MEK1/2 inhibition by AS703026 led to a cessation of cell proliferation accompanied by G0-G1 cell cycle arrest, as shown by increased subG0 cells, and concurrently abolished S phase cells. AS703026 also reduced expression of c-maf oncogene in a time-dependent manner, suggesting a MEK1/2-dependent regulation of c-maf that may contribute MM cell growth inhibition. AS703026 further induced apoptosis in MM cells, as manifested by caspase 3 and PARP cleavages in a time-dependent manner. It blocked osteoclastogenesis in vitro, as measured by number of TRAP-positive multinuclear cells following culturing PBMCs with RANKL and M-CSF. Importantly, AS703026 sensitized drug-resistant MM cells to a broad spectrum of conventional (dexamethasone, melphalan), as well as novel or emerging (lenalidomide, perifosine, bortezomib, rapamycin) anti-MM therapies. Synergistic or additive cytotoxicity (combination index < 1) induced by these combinations was further validated by annexin-V/PI staining and flow cytometric analysis. Combining these agents led to a significantly increased apoptosis and cell death than AS703026 alone, confirming enhanced cytotoxicity against MM cells. In vivo studies demonstrate that treatment of MM cell line H929-bearing mice with AS703026 (n=4 at 30 mg/kg; n=6 at 15 mg/kg), but not vehicle alone (n=6), blocked MM tumor growth in a dose-dependent manner (p<0.008 at 30 mg/kg; p<0.02 at 15 mg/kg). Immunoblotting and immunohistochemistrical staining showed that AS703026-reduced tumor growth was associated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels in vivo. Moreover, AS703026 (<200 nM) triggered significant cytotoxicity against the majority of patients with relapsed and refractory MM (>84%, n=18), regardless mutation status of 3 RAS and BRAF genes. Bone marrow stromal cells-induced viability of MM patient cells is similarly blocked within the same dose range. Our results therefore strongly support clinical protocols evaluating AS703026, alone or with other anti-MM agents, to improve patient outcome in MM. Disclosures: Chauhan: Progenra, Inc: Consultancy. Richardson:Keryx Biopharmaceuticals: Honoraria. Clark:EMD Serono: Employment. Ogden:EMD Serono: Employment. Andreas:EMD Serono: Employment. Rastelli:EMD Serono: Employment. Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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