Blockade of CD40 pathway enhances the induction of immune tolerance by immature dendritic cells genetically modified to express cytotoxic T lymphocyte antigen 4 immunoglobulin.
BACKGROUND
Immature dendritic cells (DCs) have the tolerogenic potential to induce alloantigen-specific immune tolerance. Cytotoxic T lymphocyte antigen 4 immunoglobulin (CTLA4Ig) gene-modified immature DCs have been shown to maintain their tolerogenicity and prolong allograft survival to some extent. We investigated whether blockade of CD40 pathway by anti-CD40 ligand (L) monoclonal antibody (mAb) could enhance the immune tolerance induction by immature DCs genetically modified to express CTLA4Ig (DC-CTLA4Ig).


METHODS
The tolerogenic properties of DC-CTLA4Ig were analyzed. In the vascularized heterotopic heart transplantation murine model, 2 x 10(6) DC-CTLA4Ig were infused intravenously into recipients, with or without a concomitant administration of anti-CD40L mAb 7 days before transplantation. Host responses to donor alloantigen were quantified by mixed leukocyte reaction and CTL assays. Donor major histocompatibility complex class II (Iab) expression in recipient lymph nodes was detected posttransplantation by semiquantitative reverse transcriptase-polymerase chain reaction.


RESULTS
The allostimulatory activity of DC-CTLA4Ig was reduced. DC-CTLA4Ig also induced alloantigen-specific T-cell hyporesponsiveness and polarized T helper 2 cytokine production. Pretreatment of the recipients with DC-CTLA4Ig modestly prolonged allograft survival, without long-term allograft acceptance. Combined administration of DC-CTLA4Ig and anti-CD40L mAb significantly prolonged cardiac allograft survival, with long-term (>100 days) survival of 50% of the allografts in the pretreated recipients. More potent donor-specific inhibition of immune response against alloantigens and increased microchimerism were observed in these recipients.


CONCLUSIONS
Blockade of CD40 pathway with anti-CD40L mAb potentiates the tolerogenic potential of DC-CTLA4Ig and enhances the induction of antigen-specific immune tolerance more effectively.
Sun
Wenji
W
Institute of Immunology, Zhejiang University, Hangzhou, China.
Wang
Quanxing
Q
Zhang
Lihuang
L
Liu
Yushan
Y
Zhang
Min
M
Wang
Chunmei
C
Wang
Jianli
J
Cao
Xuetao
X
D000069594:Abatacept; D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology; D002454:Cell Differentiation; D003602:Cytotoxicity, Immunologic; D017931:DNA Primers; D003713:Dendritic Cells / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D018796:Immunoconjugates / Q000235:genetics*; D007165:Immunosuppression Therapy; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection; D014184:Transplantation, Homologous
D019013:CD40 Antigens; D017931:DNA Primers; D000949:Histocompatibility Antigens Class II; D018796:Immunoconjugates; D023201:CD40 Ligand; D000069594:Abatacept