scholarly journals Preclinical Studies into Specific Toxicity of a Candidate Drug Based on Complement C3 neodeterminant Recombinant Humanized Antibody for Treating Traumatic Brain Injuries

Biomeditsina ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. 68-80
Author(s):  
K. A. Nekrasova ◽  
A. V. Trofimov ◽  
A. V. Zhahov ◽  
S. V. Rodin ◽  
N. P. Gorbunov ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dosage Form ◽  
Brain Injuries ◽  
Cell Activity ◽  
Complement C3 ◽  
Preclinical Studies ◽  
Female Reproduction ◽  
Humanized Antibody ◽  
Candidate Drug ◽  
Reproduction Toxicity

This study aims to assess the specific toxicity (allergenicity, immunotoxicity and reproduction toxicity) of a dosage form of complement C3 neodeterminant recombinant humanized antibody. The reactions of general anaphylaxis, active cutaneous anaphylaxis and delayed-type reaction demonstrated no drug-related signs of experimental animal sensitization and immediate or delayed hypersensitivity in the treated animals. It was found that, in doses exceeding significantly the expected human therapeutic dose, the drug has no effect on humoral and cell-mediated immune responses. In addition, the drug does not suppress the phagocytic cell activity thereby indicating the absence of immunotoxic effect. Moreover, the drug has no adverse effects on male and female reproduction, progeny embryonal development, as well as prenatal and postnatal progeny development. The obtained data can be used in future clinical studies of the drug safety.

PRECLINICAL STUDIES TO ASSESS ACUTE AND CHRONIC TOXICITIES OF A CANDIDATE DRUG BASED ON COMPLEMENT C3 NEODETERMINANT RECOMBINANT HUMANIZED ANTIBODY FOR TREATMENT OF TRAUMATIC BRAIN INJURIES

2021 ◽  
Vol 1 (19) ◽  
pp. 48-49
Author(s):  
A.V. Trofimov ◽  
A.V. Zhakhov ◽  
S.V. Rodin ◽  
N.P. Gorbunov ◽  
A.V. Petrov ◽  
...  
Keyword(s):  
Brain Injuries ◽  
Traumatic Brain Injuries ◽  
Low Risk ◽  
Complement C3 ◽  
Preclinical Studies ◽  
Class Iii ◽  
Humanized Antibody ◽  
Candidate Drug

A drug based on complement C3 neodeterminant recombinant humanized antibody for the treatment of traumatic brain injuries belongs to the class III of low-risk drugs.

scholarly journals The Role of NKT Cells in Glioblastoma

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1641
Author(s):  
Emily E. S. Brettschneider ◽  
Masaki Terabe
Keyword(s):  
Immune Responses ◽  
Cell Activity ◽  
Nkt Cells ◽  
Type I ◽  
Type Ii ◽  
Central Nervous System Diseases ◽  
Nkt Cell ◽  
Lipid Antigens ◽  
Immunoregulatory Mechanisms

Glioblastoma is an aggressive and deadly cancer, but to date, immunotherapies have failed to make significant strides in improving prognoses for glioblastoma patients. One of the current challenges to developing immunological interventions for glioblastoma is our incomplete understanding of the numerous immunoregulatory mechanisms at play in the glioblastoma tumor microenvironment. We propose that Natural Killer T (NKT) cells, which are unconventional T lymphocytes that recognize lipid antigens presented by CD1d molecules, may play a key immunoregulatory role in glioblastoma. For example, evidence suggests that the activation of type I NKT cells can facilitate anti-glioblastoma immune responses. On the other hand, type II NKT cells are known to play an immunosuppressive role in other cancers, as well as to cross-regulate type I NKT cell activity, although their specific role in glioblastoma remains largely unclear. This review provides a summary of our current understanding of NKT cells in the immunoregulation of glioblastoma as well as highlights the involvement of NKT cells in other cancers and central nervous system diseases.

scholarly journals A Critical Role for Fas Ligand in the Active Suppression of Systemic Immune Responses by Ultraviolet Radiation

1999 ◽  
Vol 189 (8) ◽  
pp. 1285-1294 ◽  
Author(s):  
Laurie L. Hill ◽  
Vijay K. Shreedhar ◽  
Margaret L. Kripke ◽  
Laurie B. Owen-Schaub
Keyword(s):  
Dna Damage ◽  
Immune Responses ◽  
Immune Suppression ◽  
Fas Ligand ◽  
Critical Role ◽  
Cell Activity ◽  
Contact Hypersensitivity ◽  
Delayed Type Hypersensitivity ◽  
Intact Cells

Induction of antigen-specific suppression elicited by environmental insults, such as ultraviolet (UV)-B radiation in sunlight, can inhibit an effective immune response in vivo and may contribute to the outgrowth of UV-induced skin cancer. Although UV-induced DNA damage is known to be an initiating event in the immune suppression of most antigen responses, the underlying mechanism(s) of such suppression remain undefined. In this report, we document that Fas ligand (FasL) is critical for UV-induced systemic immune suppression. Normal mice acutely exposed to UV exhibit a profound suppression of both contact hypersensitivity and delayed type hypersensitivity (DTH) reactions and the development of transferable antigen-specific suppressor cells. FasL-deficient mice exposed to UV lack both transferable suppressor cell activity and primary suppression to all antigens tested, with the exception of the DTH response to allogeneic spleen cells. Interestingly, suppression of this response is also known to occur independently of UV-induced DNA damage. Delivery of alloantigen as protein, rather than intact cells, restored the requirement for FasL in UV-induced immune suppression of this response. These results substantiate that FasL/Fas interactions are essential for systemic UV-induced suppression of immune responses that involve host antigen presentation and suggest an interrelationship between UV-induced DNA damage and FasL in this phenomenon. Collectively, our results suggest a model whereby UV-induced DNA damage disarms the immune system in a manner similar to that observed in immunologically privileged sites.

scholarly journals Matrix metalloproteinases cleave membrane-bound PD-L1 on CD90+ (myo-)fibroblasts in Crohn’s disease and regulate Th1/Th17 cell responses

2019 ◽  
Vol 32 (1) ◽  
pp. 57-68 ◽  
Author(s):  
Jose E Aguirre ◽  
Ellen J Beswick ◽  
Carl Grim ◽  
Gabriela Uribe ◽  
Marissa Tafoya ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Matrix Metalloproteinases ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Surface Membrane ◽  
Cell Activity ◽  
Th1 Cell ◽  
Mmp Inhibitors ◽  
Membrane Bound

Abstract Increased T helper (Th)1/Th17 immune responses are a hallmark of Crohn’s disease (CD) immunopathogenesis. CD90+ (myo-)fibroblasts (MFs) are abundant cells in the normal (N) intestinal mucosa contributing to mucosal tolerance via suppression of Th1 cell activity through cell surface membrane-bound PD-L1 (mPD-L1). CD-MFs have a decreased level of mPD-L1. Consequently, mPD-L1-mediated suppression of Th1 cells by CD-MFs is decreased, yet the mechanism responsible for the reduction in mPDL-1 is unknown. Increased expression of matrix metalloproteinases (MMPs) has been reported in CD. Herein we observed that when compared to N- and ulcerative colitis (UC)-MFs, CD-MFs increase in LPS-inducible levels of MMP-7 and -9 with a significant increase in both basal and inducible MMP-10. A similar pattern of MMP expression was observed in the CD-inflamed mucosa. Treatment of N-MFs with a combination of recombinant human MMP-7, -9 and -10 significantly decreased mPD-L1. In contrast, inhibition of MMP activity with MMP inhibitors or anti-MMP-10 neutralizing antibodies restores mPD-L1 on CD-MFs. CD-MFs demonstrated reduced capacity to suppress Th1 and Th17 responses from activated CD4+ T cells. By contrast, supplementation of the CD-MF:T-cell co-cultures with MMP inhibitors or anti-MMP neutralizing antibodies restored the CD-MF-mediated suppression. Our data suggest that (i) increased MMP-10 expression by CD-MFs and concomitant cleavage of PD-L1 from the surface of CD-MFs are likely to be one of the factors contributing to the decrease of mPD-L1-mediated suppression of Th1/Th17 cells in CD; and (ii) MMPs are likely to have a significant role in the intestinal mucosal immune responses.

Long-term exposure to gaseous formaldehyde promotes allergen-specific IgE-mediated immune responses in a murine model

2008 ◽  
Vol 27 (1) ◽  
pp. 37-43 ◽  
Author(s):  
YH Gu ◽  
Y Fujimiya ◽  
N Kunugita
Keyword(s):  
Immune Responses ◽  
Murine Model ◽  
Inflammatory Responses ◽  
Killer Cell ◽  
Cell Activity ◽  
Specific Ige ◽  
World Health ◽  
Indoor Environments ◽  
Allergic Symptoms ◽  
Ige Mediated

It has long been questioned that whether exposure to formaldehyde in indoor environments may be a risk factor for developing allergen-specific IgE-mediated inflammatory responses, because there is limited clinical or experimental evidence that formaldehyde is involved in the cascade for IgE production. There is no known lower limit, below which there is no threat of serious allergic symptoms. The present study illustrates that the threshold limit of formaldehyde, 0.08 ppm (as defined by the World Health Organization), did not cause ovalbumin-specific IgE inflammatory immune responses, but higher than threshold concentrations of formaldehyde gas result in both enhanced allergen-specific IgE responses and NK (Natural Killer)-cell activity in peripheral blood cells in a murine model. Thus, formaldehyde gas may be involved in promoting allergic inflammatory effects in subjects primed with specific allergens by NK-cell activation. These results indicate that even threshold concentrations of formaldehyde gas may play a regulatory role for ‘systemic’ cell-mediated immune responses. The extensive use of adhesives for building materials has resulted in higher levels of indoor air pollutants. It is conceivable that increased time indoors may enhance pre-existing allergic symptoms by concomitant exposure to volatile organic compounds and formaldehyde. The affordable limit for formaldehyde might be much lower than currently established levels in indoor environments.

Significance of systemic and local immune responses to the pathological therapeutic effect of neoadjuvant chemotherapy in breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12084-e12084
Author(s):  
Ryungsa Kim ◽  
Ami Kawai ◽  
Megumi Wakisaka ◽  
Yuri Funaoka ◽  
Sayaka Sawada ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Neoadjuvant Chemotherapy ◽  
Immune Responses ◽  
Nk Cells ◽  
Therapeutic Effect ◽  
Cell Activity ◽  
Multivariate Logistic Regression Analysis ◽  
Therapeutic Effects ◽  
Axillary Lymph

e12084 Background: Activation of the immune response including T lymphocytes, natural killer (NK) cells, and tumor microenvironment factors (TMEFs) is important in inducing a therapeutic response after neoadjuvant chemotherapy (NAC) in breast cancer. We examined the significance of systemic and local immune responses to the pathological therapeutic effect of NAC in breast cancer. Methods: From 2012 to 2018, 38 patients with stage II–III breast cancer received NAC with anthracyclines and taxanes followed by surgery. Therapeutic effects were evaluated according to the histopathology criteria for the assessment of therapeutic effects in breast cancer indicated by the Japanese Breast Cancer Society. Peripheral NK (pNK) cell activity was measured by chromium release assay. Levels of TMEFs were assessed by next-generation sequencing for CD4, CD8, NK, FOXP3, CTLA-4, PD-1, PD-L1, IL-2, IL-6, IL-12, IFN-γ, IL-10, TGF-β, and VEGF in FFPE sections collected from preoperative VAB samples and surgical specimens. Results: The stages, tumor subtypes, and therapeutic outcomes were as follows: II (N = 21), III (N = 17); luminal (N = 22), HER-2 positive (N = 12), TN (N = 4); G1a (N = 8), G1b (N = 13), G2a (N = 7), G2b (N = 4), G3 (i.e. complete) (N = 6). A G2 or better therapeutic effect were significantly associated with high post-NAC levels of NK, and potentially associated with higher CD4, CD8, and lower CTLA-4 after NAC. Multivariate logistic regression analysis showed that a G2 or better therapeutic effect was significantly associated with higher NK after NAC (OR = 1.07; 95% CI, 1.00–1.14; P = .0255). Disappearance of axillary lymph node metastasis was significantly associated with increased NK and pNK cell activity, as well as decreased VEGF level, and potentially associated with lower CTLA-4 after NAC. Conclusions: Increased NK cells after NAC are critical in producing a better therapeutic effect in collaboration with increased CD4 and CD8, and decreased CTLA-4 and VEGF. Systemic activation of pNK cells may improve the elimination of metastatic tumor cells in axillary lymph nodes by coordinating with release of immunosuppression derived from VEGF and activation of immune cells in the tumor microenvironment in breast cancer patients after NAC. An immune checkpoint inhibitor targeting CTLA-4 may improve NAC efficacy for breast cancer.

Solannm lyratum extract affected immune response in normal and leukemia murine animal in vivo

2010 ◽  
Vol 29 (5) ◽  
pp. 359-367 ◽  
Author(s):  
Jai-Sing Yang ◽  
Chia-Chun Wu ◽  
Chao-Lin Kuo ◽  
Chin-Chung Yeh ◽  
Fu-Shin Chueh ◽  
...  
Keyword(s):  
Immune Responses ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Folk Medicine ◽  
Cell Activity ◽  
Colon Adenocarcinoma ◽  
Target Cells ◽  
Peripheral Blood Mononuclear ◽  
Macrophage Phagocytosis

Solanum lyratum Thunberg (Solanaceae) has been used as a folk medicine for treating liver, lung and esophagus in the Chinese population. Our previous studies have shown that the crude extract of S. lyratum Thunberg (SLE) induced apoptosis in colo 205 human colon adenocarcinoma cells; however, there is no report to show SLE affect immune responses in vivo. In this study, the in vivo effects of SLE on leukemia WEHI-3 cells and immune responses such as phagocytosis and natural killer (NK) cell activity in normal and leukemia mice were investigated. The SLE treatment decreases surface markers of CD3 and Mac-3 in normal and leukemia mice but promoted the cell markers of CD19 and CD11b in normal mice and CD11b in leukemia mice indicating that the precursors of T cells was inhibited and B cells and macrophage were promoted. The SLE treatment promoted the activity of macrophage phagocytosis in the peripheral blood mononuclear cells (PBMC) and peritoneal cells from normal and leukemia mice. The results also showed that NK cells from the normal and leukemia mice after treatment with SLE can kill the YAC-1 target cells. Therefore, the SLE treatment increased macrophage and NK cell activities. These consistent results indicate SLE could be a potent immune responses agent.

scholarly journals CELL-MEDIATED IMMUNE RESPONSES IN VITRO

1974 ◽  
Vol 140 (2) ◽  
pp. 356-369 ◽  
Author(s):  
Duane L. Peavy ◽  
Carl W. Pierce
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cell Activity ◽  
Suppressor Cell ◽  
Regulatory Control ◽  
Cytotoxic Lymphocytes ◽  
Spleen Cells ◽  
Con A

The effects of soluble concanavalin A (Con A) or Con A-activated spleen cells on the generation of cytotoxic lymphocytes (CL) in mixed leukocyte cultures (MLC) were examined. Mitogenic concentrations of soluble Con A or small numbers of Con A-activated spleen cells substantially inhibited CL responses. The suppression was partial rather than absolute and was critically dependent upon the concentration and time of addition of soluble Con A or Con A-activated spleen cells to the MLC. Suppressive effects of Con-A activated spleen cells were mediated by T cells since suppressor cell activity was abrogated by treatment of spleen cells with anti-θ serum and complement before or after Con A activation. X irradiation of spleen cells before Con A treatment also abrogated generation of suppressor cell activity. After activation by Con A, however, the function of suppressor cells was radioresistant. Although the precise mechanism(s) of suppression is, as yet, unknown, the precursors of CL must be exposed to Con A-activated cells during the early phases of the immune response for suppression to occur. Kinetic studies revealed that suppression of CL responses was not due to a failure to initiate an immune response, but represented a response which developed initially, but subsequently aborted. The relevance of these observations to the concepts of T-cell-T-cell interaction and regulatory control of immune responses by T cells is discussed.

Immunological Evaluation of Children Treated with Antiepileptic Drugs

1996 ◽  
Vol 9 (1) ◽  
pp. 23-27
Author(s):  
A. Verrotti ◽  
S. Domizio ◽  
F. Chiarelli ◽  
G. Sabatino ◽  
G. Morgese
Keyword(s):  
Natural Killer Cell ◽  
Natural Killer ◽  
Natural Killer Cell Activity ◽  
Killer Cell ◽  
Cell Activity ◽  
Serum Levels ◽  
Complement C3 ◽  
Healthy Children ◽  
Normal Number ◽  
Killer Cell Activity

In order to evaluate cellular and humoral immunity in children who were given carbamazepine (CBZ), sodium valproate (VPA) or phenobarbital (PHB) as monotherapy, we studied 137 children and adolescents suffering from various types of epilepsy and 50 healthy control children. The patients were subdivided according to the type of drug received: in particular, Group 1: 50 (26 female, 24 male) children received only CBZ; their age ranged from 2.3 years to 16.0 years (mean ± SD, 8.1 ± 7.9 years); Group 2: 50 (26 female, 24 male) children received only VPA with age from 2.8 to 15.1 (8.9 ± 7.1) years; Group 3: 37 (20 female, 17 male) children who were given only PHB with age from 2.0 to 13.9 (8.4 ± 7.8) years. 50 sex and age- matched healthy children served as controls. All the patients of groups 1, 2 and 3 were studied before the beginning of antiepileptic drug therapy and after 6, 12 and 18 months of therapy. All plasma levels of AEDs were within the therapeutic range. All children of the three groups had a normal number of lymphocytes per millimeter of blood; also the values of CD3, CD4, CD8, CD20 and CD56 and the serum levels of complement (C3 and C4) were similar to those of healthy controls. The natural killer cell activity of children receiving CBZ showed a significant reduction: this reduction was present after 6 months of therapy (baseline: 45.2%; after 6 months: 32.6%; after 12 months 31.3 %; (all determinations vs baseline:p<0.01) and continued to be present until the end of the study (36.9%; p<0.05). Our data suggest that, in children receiving CBZ, VPA and PHB on monotherapy significant abnormalities of serum immunoglobulin concentrations, serum complement values and lymphocyte subsets are not present. CBZ is shown to have a reducing effect on the natural killer cell activity, but the real role of this abnormality in the immune system of these patients needs more investigation.

scholarly journals Differential Effects ofNaja naja atraVenom on Immune Activity

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Jian-Qun Kou ◽  
Rong Han ◽  
Yin-Li Xu ◽  
Xiao-Lan Ding ◽  
Shu-Zhi Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Lymphocyte Proliferation ◽  
Natural Killer Cell Activity ◽  
Killer Cell ◽  
Cell Activity ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Delayed Type Hypersensitivity ◽  
T Lymphocyte Proliferation

Previous studies reported thatNaja naja atravenom (NNAV) inhibited inflammation and adjuvant arthritis. Here we investigated the role of NNAV in regulation of immune responses in mice. Oral administration of NNAV to normal mice showed significant increase in natural killer cell activity, B lymphocyte proliferation stimulated by lipopolysaccharides, and antibody production in response to sheep red blood cells. Meanwhile, NNAV markedly decreased T lymphocyte proliferation stimulated by concanavalin A, arrested the cell cycle at G0/G1phase, and suppressed CD4 and CD8 T cell divisions. Furthermore, NNAV inhibited the dinitrofluorobenzene-induced delayed-type hypersensitivity reaction. This modulation of immune responses may be partly attributed to the selective increase in Th1 and Th2 cytokines (IFN-γ, IL-4) secretion and inhibition of Th17 cytokine (IL-17) production. In dexamethasone-induced immunosuppressed mice, NNAV restored the concentration of serum IgG and IgM, while decreasing the percentage of CD4 and CD8 T-cell subsets. These results indicate that NNAV enhances the innate and humoral immune responses while inhibiting CD4 Th17 and CD8 T cell actions, suggesting that NNAV could be a potential therapeutic agent for autoimmune diseases.

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