title: LFA-1 blockade induces effector and regulatory T-cell enrichment in lymph nodes and synergizes with CTLA-4Ig to inhibit effector function.
abstract: Despite encouraging results using lymphocyte function antigen-1 (LFA-1) blockade to inhibit BM and solid organ transplantation rejection in nonhuman primates and humans, the precise mechanisms underlying its therapeutic potential are still poorly understood. Using a fully allogeneic murine transplantation model, we assessed the relative distribution of total lymphocyte subsets in untreated versus anti-LFA-1-treated animals. Our results demonstrated a striking loss of naive T cells from peripheral lymph nodes, a concomitant gain in blood after LFA-1 blockade, and a shift in phenotype of the cells remaining in the node to a CD62LloCD44hi profile. We determined that this change was due to a specific enrichment of activated, graft-specific effectors in the peripheral lymph nodes of anti-LFA-1-treated mice compared with untreated controls, and not to a direct effect of anti-LFA-1 on CD62L expression. LFA-1 blockade also resulted in a dramatic increase in the frequency of CD4+ FoxP3+ regulatory T cells in graft-draining nodes. Our results suggest that the differential impact of LFA-1 blockade on the distribution of naive versus effector and regulatory T cells may underlie its ability to inhibit alloreactive T-cell responses after transplantation.
authors.affiliation: Emory Transplant Center, Atlanta, GA 30322, USA.
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Reisman
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Floyd
authors.forename: Maylene E
authors.initials: ME
authors.lastname: Wagener
authors.forename: Allan D
authors.initials: AD
authors.lastname: Kirk
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ford
mesh_terms: D000069594:Abatacept; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D018796:Immunoconjugates / Q000008:administration & dosage / Q000494:pharmacology*; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects*; D018655:Lymphocyte Count; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000502:physiology
chemical_list: D000906:Antibodies; D018796:Immunoconjugates; D016169:Lymphocyte Function-Associated Antigen-1; D000069594:Abatacept