Effects of Anti CD3 Monoclonal Antibody on Immunity and Gene Expression Profiles of Cynomolgus Monkeys
GENG Xing-chao1, ZHOU Yang1, LIN Zhi1, MIAO Yu-fa1, ZHANG Lin1,WANG Ju-feng1, LI Bo2,*, WANG Jun-zhi2,*
1. Beijing Key Laboratory, National Center for Safety Evaluation of Drugs, Beijing 100176, China; 2. National Institute for Food and Drug Control, Beijing 100050, China
Abstract��OBJECTIVE To investigate the effects of anti CD3 monoclonal antibody (Ant-CD3 McAb) on immune function in cynomolgus monkeys, using the traditional immunotoxicity assessment methods and T cell dependent antibody response (TDAR) test, microarray, etc, and further explore the mechanism of Ant-CD3 McAb. METHODS Eighteen Cynomolgus monkeys were individually dosed with saline, 0.5 and 2.5 mg��kg-1Ant-CD3 McAb for 7 d. The clinical observation, body weight, hematological test, antibody detection, TDAR test, lymphocyte subsets, bone marrow, histopathological examination and whole blood gene expression profile analysis were evaluated. RESULTS Ant-CD3 McAb significantly inhibited the immune response to keyhole limpet hemocyanin (KLH) in cynomolgus monkey, and caused the decrease of peripheral white blood cell counts and CD3+ cells, the decrease of lymphocytes in thymus cortex. Microarray test showed that the gene function of differently expressed genes mainly involved in cell proliferation, immune response, cytokine secretion, apoptosis etc. CONCLUSION Ant-CD3 McAb could induce obvious immunosuppression effects in cynomolgus monkeys. Detection of gene expression profile of whole peripheral blood is feasible in immunotoxicity evaluation. The apoptosis induction and proliferation inhibition of T lymphocytes might be the main cause of the decreased T lymphocytes. IL-8 might play an important role in the mechanism of Ant-CD3 McAb.
ZIMMERMAN M A, KELLY M A, CAMPSEN J, et al. The influence of OKT3 therapy on hepatocellular carcinoma recurrence following liver transplantation . Clin Transplant, 2010, 24(4): 103-108.
[2]
HEROLD K C, HAGOPIAN W, AUGER J A, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus . N Engl J Med, 2002, 346(22): 1692-1698.
[3]
AMBERY P, DONNER T W, BISWAS N, et al. Efficacy and safety of low-dose otelixizumab anti-CD3 monoclonal antibody in preserving C-peptide secretion in adolescent type 1 diabetes: DEFEND-2, a randomized, placebo-controlled, double-blind, multi-centre study . Diabet Med, 2014, 31(4): 399-402.
[4]
METIDIERI H T, MANCIO R D, MAYORAL �F E, et al. Effects of anti-CD3 monoclonal antibody in salivary glands of spontaneously diabetic mice . Microsc Res Tech, 2012, 75(7): 928-934.
[5]
PERRUCHE S, ZHANG P, LIU Y, et al. CD3-Specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells. Nat Med, 2008, 14(5): 528-535.
[6]
BOMMIREDDY R, DOETSCHMAN T. TGF-beta, T-cell tolerance and anti-CD3 therapy . Trends Mol Med, 2004, 10(1): 3-9.
[7]
TUSHER V G, TIBSHIRANI R, CHU G. Significance analysis of microarrays applied to the ionizing radiation response . Proc Natl Acad Sci USA, 2001, 98(9): 5116-5121.
[8]
HENRY M L, PELLETIER R P, ELKHAMMAS E A, et al. A randomized prospective trial of OKT3 induction in the current immunosuppression era . Clin Transplant, 2001, 15(6): 410-414.
[9]
LE GALL F, REUSCH U, MOLDENHAUER G, et al. Immunosuppressive properties of anti-CD3 single-chain Fv and diabody . J Immunol Methods, 2004, 285(1): 111-127.
[10]
HOGQUIST K A, JAMESON S C, HEATH W R, et al. T Cell receptor antagonist peptides induce positive selection . Cell, 1994, 76(1): 17-27.
[11]
LIU F, HE D, GUO Z. Detection of mouse thymocytes apoptosis induced with CD3 McAb by flow cytometer . Prog Microbiol Immunol (����ѧ����ѧ��չ), 1999, 27(4): 55-58.
[12]
GENG X C, HONG M, SONG Y, et al. Effect of triptolide on immunotoxicity related gene expression in rats with microarray . Chin J Pharmacol Toxicol (�й�ҩ��ѧ�붾��ѧ��־), 2012, 26(6): 870-875.
[13]
ZHENG J N,XIE S L,CHENG J C, et al. Effect of Anti-CD3 monoclonal antibody and some cytokines on the apoptosis of human peripheral blood mononuclear cells . Shanghai J Immunol (�Ϻ�����ѧ��־), 1998, 18(6): 348-351.
[14]
FERRAN C, SHEEHAN K, DY M, et al. Cytokine-related syndrome following injection of anti-CD3 monoclonal antibody: Further evidence for transient in vivo T cell activation . Eur J Immunol, 1990, 20(3): 509-515.
SUN Z L, CUI J G, LU X Y, et al. Effects of Solanum lyratum Thunb alkaloids on immunity and mRNA expression of some cytokine in mice . Chin Pharm J (�й�ҩѧ��־), 2005, 40(22): 1706-1709.
2016, Vol. 51 
