Anti-LFA-1 antibody postpones T-cell receptor triggering while preserving generation of regulatory T cells in T-cell receptor anti-HY transgenic mice.
BACKGROUND
Anti-LFA-1 (CD11a) antibody increases allograft survival and/or induces tolerance in murine models, but its mechanisms of action remain to be elucidated.


METHODS
Rag-2-/- H-2b recipient mice, bearing a transgenic T-cell receptor specific for the male antigen HY presented by MHC class II molecule, were transplanted with a C57BL/6 (H-2b) male heart with or without administration of anti-LFA-1 antibody from days -1 to 9.


RESULTS
Treatment prevented the transient episode of acute graft rejection observed in nontreated mice and maintained a naive phenotype and proliferative characteristics comparable to that of naive transgenic lymphocytes on day 7 during treatment, with decreased IFN-gamma mRNA and increased IL-4 mRNA. On day 14, phenotype and proliferative response of lymphocytes in treated mice was comparable to those of untreated animals. Furthermore, treatment did not interfere with the generation of CD4+Vbeta6+CD25+ (Foxp3) cells that were observed in long-term nontreated tolerant mice.


CONCLUSIONS
This in vivo model demonstrates that anti-LFA-1 treatment induced a transient blockade of antigen recognition, which inhibited and postponed induction of signal 1 via the TCR and decreased the intensity of the Th1 response. Importantly, LFA-1 blockade did not disturb spontaneous generation of regulatory mechanism. This treatment would be compatible in clinical settings with other therapeutics inducing regulatory mechanisms.
Go
Seitetsu
S
1INSERM, U793, Paris, France.
Fleischmann
Audrey
A
Lantz
Olivier
O
Cretolle
Célia
C
Brousse
Nicole
N
Cerf-Bensussan
Nadine
N
Sarnacki
Sabine
S
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D040881:CD11a Antigen / Q000276:immunology; D015704:CD4 Antigens / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006182:H-Y Antigen / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D040881:CD11a Antigen; D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D006182:H-Y Antigen; D016169:Lymphocyte Function-Associated Antigen-1; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; C114320:anti-LFA-1 monoclonal antibody; D015847:Interleukin-4; D007371:Interferon-gamma