Zwitterionic Phospholipidation of Cationic Polymers Facilitates Systemic mRNA Delivery to Spleen and Lymph Nodes

Author(s):  
Shuai Liu ◽  
Xu Wang ◽  
Xueliang Yu ◽  
Qiang Cheng ◽  
Lindsay T. Johnson ◽  
...  
2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Di Hua ◽  
Jie Yang ◽  
Qinghai Meng ◽  
Yuanyuan Ling ◽  
Qin Wei ◽  
...  

Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease. Soufeng sanjie formula (SF), which is composed of scolopendra (dried body of Scolopendra subspinipes mutilans L. Koch), scorpion (dried body of Buthus martensii Karsch), astragali radix (dried root of Astragalus membranaceus (Fisch.) Bge), and black soybean seed coats (seed coats of Glycine max (L.) Merr), is a traditional Chinese prescription for treating RA. However, the mechanism of SF in treating RA remains unclear. This study was aim to investigate the anti-arthritic effects of SF in a collagen-induced arthritis (CIA) mouse model and explore the mechanism by which SF alleviates arthritis in CIA mice. Methods For in vivo studies, female DBA/1J mice were used to establish the CIA model, and either SF (183 or 550 mg/kg/day) or methotrexate (MTX, 920 mg/kg, twice/week) was orally administered to the mice from the day of arthritis onset. After administration for 30 days, degree of ankle joint destruction and serum levels of IgG and inflammatory cytokines were determined. The balance of Th17/Treg cells in the spleen and lymph nodes was analyzed using flow cytometry. Moreover, the expression levels of retinoic acid receptor-related orphan nuclear receptor (ROR) γt and phosphorylated STAT3 (pSTAT3, Tyr705) in the spleen were detected by immunohistochemistry. Furthermore, the effect of SF on Th17 cells differentiation in vitro was investigated in CD4+ T cells under Th17 polarization conditions. Results SF decreased the arthritis score, ameliorated paw swelling, and reduced cartilage loss in the joint of CIA mice. In addition, SF decreased the levels of bovine collagen-specific IgG in sera of CIA mice. SF decreased the levels of inflammatory cytokines (TNF-α, IL-6, and IL-17A) and increased the level of IL-10 both in the sera and the joint of CIA mice. Moreover, SF treatment rebalanced the Th17/Treg ratio in the spleen and lymph nodes of CIA mice. SF also reduced the expression levels of ROR γt and pSTAT3 (Tyr705) in the spleen of CIA mice. In vitro, SF treatment reduced Th17 cell generation and IL-17A production and inhibited the expression of RORγt, IRF4, IL-17A, and pSTAT3 (Tyr705) under Th17 polarization conditions. Conclusions Our results suggest that SF exhibits anti-arthritic effects and restores Th17/Treg homeostasis in CIA mice by inhibiting Th17 cell differentiation.


2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii89-ii89
Author(s):  
Subhajit Ghosh ◽  
Ran Yan ◽  
Sukrutha Thotala ◽  
Arijita Jash ◽  
Anita Mahadevan ◽  
...  

Abstract BACKGROUND Patients with glioblastoma (GBM) are treated with radiation (RT) and temozolomide (TMZ). These treatments can cause prolonged severe lymphopenia, which is associated with shorter survival. NT-I7 (efineptakin alfa) is a long-acting recombinant human IL-7 that supports the proliferation and survival CD4+ and CD8+ cells in both human and mice. We tested whether NT-I7 would protect T cells from treatment-induced lymphopenia and improve survival. METHODS C57BL/6 mice bearing intracranial tumors (GL261 or CT2A) were treated with RT (1.8 Gy/day x 5 days), TMZ (33 mg/kg/day x 5 days) and/or NT-17 (10 mg/kg on the final day of RT completion). We followed for survival and profiled CD3, CD8, CD4, FOXP3 in peripheral blood over time. In parallel, we assessed cervical lymph nodes, bone marrow, thymus, spleen, and the tumor 6 days after NT-I7 treatment. RESULTS Median survival in mice treated with NT-I7 combined with RT was significantly better than RT alone (GL261: 40d vs 34d, p< 0.0021; CT2A: 90d vs 40d, p< 0.0499) or NT-I7 alone (GL261: 40d vs 24d, p< 0.008; CT2A: 90d vs 32d, p< 0.0154). NT-17 with RT was just as effective as NT-I7 combined with RT and TMZ in both GL261 (40d vs 47d) and CT2A (90d vs 90d). NT-I7 treatment significantly increased the amount of CD8+ cells in the peripheral blood and tumor. NT- I7 rescued CD8+ T cells from RT induced lymphopenia in peripheral blood, spleen, and lymph nodes. NT-I7 alone or NT-I7 in combination with RT increased the CD8+ T cells in peripheral blood and tumor while reducing the FOXP3+ T-reg cells in the tumor microenvironment. CONCLUSIONS NT-I7 protects T-cells from RT induced lymphopenia, improves cytotoxic CD8+ T lymphocytes systemically and in the tumor, and improves survival. Presently, a phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957).


1989 ◽  
Vol 39 (3) ◽  
pp. 212-215
Author(s):  
Hitoshi Kubosawa ◽  
Akio Konno ◽  
Teisuke Komatsu ◽  
Hideo Ishige ◽  
Yoichiro Kondo

2001 ◽  
Vol 276 (40) ◽  
pp. 37594-37601 ◽  
Author(s):  
Botond Bánfi ◽  
Gergely Molnár ◽  
Andres Maturana ◽  
Klaus Steger ◽  
Balázs Hegedûs ◽  
...  

A one-step separation procedure is described for both depleting and obtaining in pure form Fc receptor (FcRL), C'3 receptor (CRL) and surface immunoglobulin bearing (IgL) lymphocytes from rat lymphoid populations. The method is a modification of the Bӧyum (1968) technique for separating lymphocytes from whole blood by sedimentation on Ficoll/Isopaque, and is based on the fact that when a lymphocyte forms a rosette with sensitized erythrocytes it will sediment with the red cells rather than float with the non-rosetting lymphocytes. The technique is > 99.5% efficient at depleting thoracic duct lymphocytes (TDL) of FcRL, CRL and IgL and these subpopulations can be recovered 93-98% pure. The total recovery of lymphocytes applied is usually > 90% and the separated lymphocytes are > 95% viable. This technique allowed the cellular distribution of Fc receptors, C'3 receptors and surface Ig to be determined. It was found that ( a ) Almost all CRL carry surface Ig, although a very small sub-population of CRL (0.2-0.8%) which lacks surface Ig could regularly be detected. ( b ) A substantial proportion of IgL (12-25%) lacks C'3 receptors. ( c ) IgL and CRL which lack Fc receptors are more frequent in spleen and lymph nodes than in TDL. The proportion of this subpopulation increases in TDL after prolonged thoracic duct drainage. ( d ) Some FcRL exist which lack both C'3 receptors and surface Ig. These cells are more evident in TDL after prolonged thoracic duct drainage and in lymph nodes (20-30% of FcRL) than in early TDL or spleen (5-10% of FcRL). ( e ) The thymus contains very few FcRL, CRL or IgL. ( f ) A large population of lymphocytes exists in B rats (32-42% of TDL) which is killed by an anti-B serum but which lacks surface Ig. These cells are much less frequent in normal TDL ( < 5%) and probably also lack Fc and C'3 receptors. ( g ) Large lymphocytes probably shed their Fc and C'3 receptors, but retain their surface Ig, during S-phase. ( h ) Studies on a secondary anti-DNP response showed that a substantial proportion of direct and indirect plaque forming cells (PFC) in the spleen express Fc receptors, whereas only indirect PFC carry C'3 receptors. Virtually all PFC ( > 98%) possess surface Ig.


2001 ◽  
Vol 7 (1-2) ◽  
pp. 238-246 ◽  
Author(s):  
H. A. Al Shamahy ◽  
S. G. Wright

We studied the clinical characteristics of brucellosis among all patients with brucellosis referred to the Central Health Laboratory from the main hospitals in Sana’a during a 2-year period [1992-93] [235 adults and children]. A history was taken from each patient and clinical examination, general laboratory tests and brucellosis laboratory tests carried out. The overall clinical picture of brucellosis in this study is very similar to that reported by other workers in this geographical area. Awareness of the presenting features and the realization that brucellosis should be part of the differential diagnosis of febrile patients with enlarged liver, spleen and lymph nodes will lead to an increasing index of suspicion for this disease.


1986 ◽  
pp. 588-600 ◽  
Author(s):  
Kurt D. Ackerman ◽  
Suzanne Y. Felten ◽  
Denise L. Bellinger ◽  
Shmuel Livnat ◽  
David L. Felten

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