LFA-1 blockade induces effector and regulatory T-cell enrichment in lymph nodes and synergizes with CTLA-4Ig to inhibit effector function
Autor: | Mandy L. Ford, Tamara L. Floyd, Allan D. Kirk, Christian P. Larsen, Maylene E. Wagener, Natalie M. Reisman |
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Rok vydání: | 2011 |
Předmět: |
Male
Immunoconjugates Regulatory T cell Lymphocyte Immunology Drug Evaluation Preclinical Down-Regulation chemical and pharmacologic phenomena Mice Transgenic Biology Biochemistry T-Lymphocytes Regulatory Antibodies Abatacept Mice medicine Animals Lymphocyte function-associated antigen 1 Lymphocyte Count Cell Proliferation Immunobiology Mice Inbred BALB C Effector FOXP3 hemic and immune systems Drug Synergism Cell Biology Hematology T-Lymphocytes Helper-Inducer Lymphocyte Function-Associated Antigen-1 Blockade Transplantation Mice Inbred C57BL medicine.anatomical_structure Female Lymph Lymph Nodes |
Zdroj: | Blood. 118(22) |
ISSN: | 1528-0020 |
Popis: | 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. |
Databáze: | OpenAIRE |
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