B- and T-lymphocyte attenuator targeting protects against the acute phase of graft versus host reaction by inhibiting donor anti-host cytotoxicity.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: These findings place BTLA receptor as a potential immunoregulatory target for the modulation of cytotoxic T-lymphocyte-mediated alloresponses.