B- and T-Lymphocyte Attenuator Targeting Protects Against the Acute Phase of Graft Versus Host Reaction by Inhibiting Donor Anti-Host Cytotoxicity

Abstract

B- and T-lymphocyte attenuator (BTLA) functions as a coinhibitory/costimulatory molecule that belongs to the immunoglobulin superfamily and exhibits a pattern of expression restricted to the hematopoietic compartment. Engagement of BTLA by its ligand, herpes virus entry mediator (HVEM), delivers negative signals to T cells, whereas engagement of HVEM receptor on T cells by surface BTLA expressed on other immune cells costimulates T activation. Previous work has reported that parental donor BTLA knock-out or HVEM knock-out T cells adoptively transferred into nonirradiated F1 recipient mice survived poorly, and the rejection of host hematopoietic cells was attenuated compared with F1 recipients receiving wild-type T cells. Parent into nonirradiated immunocompetent F1 murine model of acute graft versus host reaction, which is induced with the adoptive transfer of splenocytes from donor B6 mice (H-2(b)) into F1 recipients (BALB/c×B6, H-2(d/b)), was used as an experimental approach to test the therapeutic effect of targeting BTLA during the course of an allogeneic immune response. We herein provide evidence that administration of an anti-BTLA monoclonal antibody leads to significant reduction of donor anti-host allogeneic immune response against bone marrow and thymus during the acute phase of graft versus host reaction in a parent into nonirradiated F1 murine model of alloreactivity. Anti-BTLA protection against donor anti-host hematopoietic cell rejection correlated with impaired anti-host cytotoxic T-lymphocyte activity than reduction in T-cell number infiltrating host tissues. These findings place BTLA receptor as a potential immunoregulatory target for the modulation of cytotoxic T-lymphocyte-mediated alloresponses.