Gene transfer of Ig-fusion proteins into B cells prevents and treats autoimmune diseases

被引:100
作者
Melo, MEF
Qian, JH
El-Amine, M
Agarwal, RK
Soukhareva, N
Kang, YB
Scott, DW
机构
[1] Amer Red Cross, Holland Lab, Dept Immunol, Rockville, MD 20855 USA
[2] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA
关键词
D O I
10.4049/jimmunol.168.9.4788
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Based on the tolerogenic properties of IgG carriers and B cell Ag presentation, we developed a retrovirally mediated gene expression approach for treatment of autoimmune conditions. In this study, we show that the IgG-Ag retroviral constructs, expressing myelin basic protein (MBP) or glutamic acid decarboxylase in B cells, can be used for the treatment of murine models for multiple sclerosis and diabetes. Transduction of syngeneic B cells with MBP-IgG leads to the amelioration of ongoing experimental allergic encephalomyelitis induced by the transfer of primed cells from PLxSJL F-1 mice with ongoing disease and could be effective even after symptoms appeared. This effect is specific and does not involve bystander suppression because treatment with MBP-IgG does not affect disease induced after immunization with proteolipid protein immunodominant peptide plus MBP. Interestingly, if donor B cells are derived from g/d mice (Fas ligand-negative), then tolerance is not induced with a model Ag although there was no evidence for Fas ligand-mediated deletion of target T cells. In spontaneous diabetes in nonobese diabetic mice, we were able to stop the ongoing autoimmune process by treatment at 7-10 wk with glutamic acid decarboxylase-IgG retrovirally transduced B cells, or attenuate it with B cells transduced with an insulin B chain (B9-23) epitope IgG fusion protein. Furthermore, IgG fusion protein gene therapy can also protect primed recipients from Ag-induced anaphylactic shock, and thus does not cause immune deviation. These results demonstrate proof of principle for future efforts to develop this approach in a clinical setting.
引用
收藏
页码:4788 / 4795
页数:8
相关论文
共 30 条
[1]   Retroviral gene therapy with an immunoglobulin-antigen fusion construct protects from experimental autoimmune uveitis [J].
Agarwal, RK ;
Kang, YB ;
Zambidis, E ;
Scott, DW ;
Chan, CC ;
Caspi, RR .
JOURNAL OF CLINICAL INVESTIGATION, 2000, 106 (02) :245-252
[2]   Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: Results of a phase II clinical trial with an altered peptide ligand [J].
Bielekova, B ;
Goodwin, B ;
Richert, N ;
Cortese, I ;
Kondo, T ;
Afshar, G ;
Gran, B ;
Eaton, J ;
Antel, J ;
Frank, JA ;
McFarland, HF ;
Martin, R .
NATURE MEDICINE, 2000, 6 (10) :1167-1175
[3]   Induction of autoimmune diabetes by oral administration of autoantigen [J].
Blanas, E ;
Carbone, FR ;
Allison, J ;
Miller, JFAP ;
Heath, WR .
SCIENCE, 1996, 274 (5293) :1707-1709
[4]   HAPTENS BOUND TO SELF IGG INDUCE IMMUNOLOGICAL-TOLERANCE, WHILE WHEN COUPLED TO SYNGENEIC SPLEEN-CELLS THEY INDUCE IMMUNE SUPPRESSION [J].
BOREL, Y .
IMMUNOLOGICAL REVIEWS, 1980, 50 :71-104
[5]  
BOREL Y, 1980, SCIENCE, V182, P76
[6]   Mechanisms of tolerance induction by a gene-transferred peptide-IgG fusion protein expressed in B lineage cells [J].
El-Amine, M ;
Melo, M ;
Kang, YB ;
Hao, N ;
Qian, JH ;
Scott, DW .
JOURNAL OF IMMUNOLOGY, 2000, 165 (10) :5631-5636
[7]   Treatment of experimental encephalomyelitis with a novel chimeric fusion protein of myelin basic protein and proteolipid protein [J].
Elliott, EA ;
McFarland, HI ;
Nye, SH ;
Cofiell, R ;
Wilson, TM ;
Wilkins, JA ;
Squinto, SP ;
Matis, LA ;
Mueller, JP .
JOURNAL OF CLINICAL INVESTIGATION, 1996, 98 (07) :1602-1612
[8]   Oral tolerance: Mechanisms and therapeutic applications [J].
Faria, AMC ;
Weiner, HL .
ADVANCES IN IMMUNOLOGY, VOL 73, 1999, 73 :153-264
[9]  
GARSIDE P, 1995, J IMMUNOL, V154, P5649
[10]   AMELIORATION OF AUTOIMMUNE ENCEPHALOMYELITIS BY MYELIN BASIC-PROTEIN SYNTHETIC PEPTIDE INDUCED ANERGY [J].
GAUR, A ;
WIERS, B ;
LIU, A ;
ROTHBARD, J ;
FATHMAN, CG .
SCIENCE, 1992, 258 (5087) :1491-1494