title: Intragraft mechanisms associated with the immunosuppressive versus the tolerogenic effect of CD3 antibodies in a mouse model of islet allografts.
abstract: We previously demonstrated the ability of CD3-specific antibodies (Abs) to induce tolerance of fully mismatched pancreatic islets when administered at the time of effector T-cell priming (day +7). When administered on day -1, CD3 Abs only displayed an immunosuppressive effect with no permanent acceptance. Here we show that rejection correlates with progressive migration of CD4(+) and CD8(+) T cells into the graft. In contrast, the day +7 CD3 Ab tolerogenic effect is associated with absence of de novo accumulation of CD8(+) T cells within the allograft while CD4(+) T-cell migration is not altered. Furthermore, the increased proportion in T-regulatory cells, observed both in the draining lymph nodes and in the transplanted islets, was more pronounced after the delayed (day +7) than the early (day -1) CD3 Ab course. Last, tolerance-promoting (day +7), but not immunosuppressive (day -1) CD3 Ab treatment was associated with an elevated in situ Foxp3/α-1,2-mannosidase gene expression ratio, identified as a biomarker predicting tolerance in renal transplant patients. In conclusion, intragraft-enhanced regulation over effector function after the delayed but not the early CD3 antibody therapy discriminates between the tolerance-promoting and immunosuppressive effect of CD3 Ab treatment and further highlights the importance of the therapeutic window.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unit 1013, Hôpital Necker, Paris, France.
authors.forename: M C
authors.initials: MC
authors.lastname: Baas
authors.forename: A
authors.initials: A
authors.lastname: Besançon
authors.forename: B
authors.initials: B
authors.lastname: Sawitzki
authors.forename: C
authors.initials: C
authors.lastname: Mangez
authors.forename: F
authors.initials: F
authors.lastname: Valette
authors.forename: L
authors.initials: L
authors.lastname: Chatenoud
authors.forename: S
authors.initials: S
authors.lastname: You
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D060888:Real-Time Polymerase Chain Reaction; D014184:Transplantation, Homologous
chemical_list: D001323:Autoantibodies; D017252:CD3 Complex