CTLA4Ig gene transfer alleviates abortion in mice by expanding CD4+CD25+ regulatory T cells and inducing indoleamine 2,3-dioxygenase.
Successful pregnancy requires a state of immunological tolerance since normally the maternal immune system does not reject the semi-allogeneic conceptus. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a ligand for B7, delivers negative signals to antigen presenting cells (APCs) to compete with CD28 for binding to B7 molecules and down-regulate proinflammatory responses, thus inhibiting T cell activation. Using CBA/J x DBA/2 matings as an abortion-prone model, we observed that adenovirus-mediated CTLA4Ig (Ad-CTLA4Ig) gene transfer improves pregnancy outcome. Ad-CTLA4Ig therapy skewed the ability of serum cytokine production toward a Th2 bias. Flow cytometry revealed that Ad-CTLA4Ig administration expanded peripheral CD4(+)CD25(+) regulatory T cell populations in CBA/J x DBA/2 matings. Furthermore, Ad-CTLA4Ig administration induced indoleamine 2,3-dioxygenase (IDO) and Foxp3 mRNA expression at the materno-fetal interface. Our results demonstrate that adenovirus-mediated CTLA4Ig gene transfer improves pregnancy outcome in a murine model of abortion by expanding the CD4(+)CD25(+) regulatory T cell population and inducing IDO mRNA expression.
Li
Weihong
W
Department of Obstetrics and Gynecology, Center of Reproductive Medicine, The Second West China Hospital, Sichuan University, Sichuan Province 610041, China.
Li
Bin
B
Fan
Wei
W
Geng
Lihong
L
Li
Xiaohong
X
Li
Lei
L
Huang
Zhongying
Z
Li
Shangwei
S
D000069594:Abatacept; D000022:Abortion, Spontaneous / Q000097:blood / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D000256:Adenoviridae; D000818:Animals; D015704:CD4 Antigens; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D015316:Genetic Therapy; D006801:Humans; D018796:Immunoconjugates / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D018613:Microscopy, Confocal; D011247:Pregnancy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology; D014161:Transduction, Genetic
D015704:CD4 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018796:Immunoconjugates; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053645:Interleukin-2 Receptor alpha Subunit; D000069594:Abatacept